Fibrinous inflammation, exudate and scarring in monotonous movements and ageing

I have palpated many hard organs during my work and studies. I have seen many young and old people who have hard organs, like very hard shoulder - very common. I have interviewed some of them, some points

  • only one type of weight lifting
  • no running
  • no stretching
  • no stretching before training
  • no stretching after training
  • not age dependent only - very old can be healthy
  • dynamical movement dependent

There are two mechanisms of fibrinous inflammation

  • trigger the release of fibrinogen
  • trigger release of fibrinogen-to-fibrin reaction

which both result in the production fibrin in the interstitium:

The area may also be mixed with serous so two variations of fibrinous inflammation

  • serofibrinous
  • fibrinous.

I am interested in the mechanism that leads to this hard tissue throughout the organ. This raised to me an idea about Fibrinous inflammation in the shoulder. Robbins say that if the exudate cannot be sucked out, it leads to scarring. I think this is what is making the organ feel hard.

What is the pathogenesis in such monotonous movements without stretching?

I would now say that the hardening is just local acute venous congestion if in the short term. Without stretching after practice, it just takes more days to recover. So lymphatic drainage is the one which helps the muscle get its needs and nutrients.

If this happens during years, it is difficult to say what is the causal factor. It depends on many factors. One key factor is how well the lymphatic circulation can recover the body back. So genomics of the patient comes in the picture. Many other factors too like anatomical structure of chest. Then, depending on these factors and other pathological processes may happen many processes like

  • accumulation of fibrinoid
  • accumulation of calcium deposits
  • shorter diffuse distances
  • smaller total area of cells

which are some adaptation processes to the ageing (also of prolonged monotonous weight lifting). They can lead to

  • acute lymphangitis (reddening of the skin)
  • Chronic lymphangitis
  • Chronic Granulomatous Lymphadenitis (fibrosis happening between muscles and connection points - not in all cases granulomatous - rare only)
  • lymphadenopathy (very, very late - after many years)

during ageing (adaptation).

Better question would probably be: what are processes happening during ageing? And then cover pathologies of ageing separately and also the physiological processes on the weight lifting separately.


Symptoms and Pathology . In about 75 per cent of patients the onset of rheumatoid arthritis is gradual, with only mild symptoms at the beginning. Early symptoms include malaise, fever, weight loss, and morning stiffness of the joints. One or more joints may become swollen, painful, and inflamed. Some patients may experience only mild episodes of acute symptoms with lengthy remissions. The more typical patient, however, experiences increasingly severe and frequent attacks with subsequent joint damage and deformity. The pattern of remissions and exacerbations continues throughout the course of the disease.

If untreated, and sometimes in spite of treatment, the joint pathology goes through four stages: (1) proliferative inflammation of the synovium with increased exudate, which eventually leads to thickening of the synovium (2) formation of a layer of granulation tissue (pannus) that erodes and destroys the cartilage and eventually spreads to contiguous areas, causing destruction of the bone capsule and parts of the muscles that control the joint (3) fibrous ankylosis resulting from invasion of the pannus by tough fibrous tissue and (4) bony ankylosis as the fibrous tissue becomes calcified.

In addition to the joint changes there is atrophy of muscles, bones, and skin adjacent to the affected joint. The most characteristic lesions of rheumatoid arthritis are subcutaneous nodules, which may be present for weeks or months and are most commonly found over bony prominences, especially near the elbow.

Because rheumatoid arthritis is a systemic disease, there is involvement of connective tissues other than those in the musculoskeletal system. Degenerative lesions may be found in the collagen in the lungs, heart, blood vessels, and pleura.

Patients with rheumatoid arthritis appear undernourished and chronically ill. Most are anemic because of the effect of the disease on blood-forming organs. The erythrocyte sedimentation rate is elevated and the WBC may be slightly elevated.

Rest and Exercise. It is recommended that the patient with rheumatoid arthritis plan for 10 to 12 hours of sleep out of each 24. The patient should be careful to maintain good posture while lying in bed and avoid pillows or other devices that support the joints in a flexed position. A firm mattress is recommended, with only one pillow under the head. During periods of severe attacks, the patient may require continuous bed rest.

The purpose of rest is to allow the body's natural defenses against inflammation to work at optimal level. It is necessary, however, even in the acute phase to balance rest with prescribed exercises which take into account the severity of the case, the joints affected, and the patient's individual needs and tolerance.

Physical Therapy. The goals of physical therapy for the patient with rheumatoid arthritis are to prevent and correct deformities, control pain, strengthen weakened muscles, and improve function.

Therapeutic exercise is of major importance in the physical therapy program established for the patient. It is necessary to enlist the patient's cooperation, and this can be done most effectively by explaining the purposes of the exercises and teaching ways to exercise that will not increase pain. In many instances proper exercise can actually diminish pain. The patient's tolerance for exercise must be carefully monitored. While it is expected that some discomfort may be present during exercise, there should not be persistent pain that continues for hours after the exercises have been done. If such pain and fatigue do occur, the exercise program should be reviewed and revised so that a good balance of rest and exercise is obtained. It should be remembered that overactivity can contribute to the inflammatory process.

Applications of heat or cold may be used in the management of rheumatoid arthritis. Heat applications improve circulation, promote relaxation, and relieve pain. When used in conjunction with exercise, heat can allow more freedom of joint movement. Various forms of heat therapy may be used, including dry heat, moist heat, diathermy , and ultrasound . For dry heat a therapeutic infrared heat lamp may be most convenient during home care. Hot water bottles or electric heating pads also may be used. For treatment of the hands, paraffin baths are effective. Wet heat can be applied by hot tub baths with the water temperature not exceeding 39°C (102°F) or by means of a towel dipped in hot water, wrung out, and applied to the joint. Whirlpool baths are effective, especially when prolonged treatment is indicated. Relief from pain and stiffness can be provided for some patients by applications of cold packs to the affected joints. This can be done by placing ice packs directly over the joint. When either heat or cold is used, care must be taken to protect the patient's skin. It should be remembered that rheumatoid arthritis affects the skin as well as other tissues.

Whenever it is necessary to handle the joints and limbs of a patient with rheumatoid arthritis, it is extremely important to move slowly and gently, avoiding sudden, jarring movements which stimulate muscle contraction and produce pain. The affected joints should be supported so that there is no excessive motion.

Medication. There is no drug that will cure arthritis. The health care provider does have a variety of medications that may be prescribed, depending on the needs and tolerance of the patient. It is important that the patient be advised of the expected results and possible undesirable side effects that may accompany ingestion of certain drugs. He or she should also be advised that therapeutic trials of several different drugs may be necessary. With this information at hand, he or she can work cooperatively with the physician in determining which drug or drugs can be most beneficial for treatment of the condition.

Aspirin was among the first drugs used to treat rheumatoid arthritis and remains a low-cost treatment option. It is a potent antiinflammatory agent when given at dosages that achieve a serum level of 20&ndash30 mg/100 ml. For those prone to stomach upset or other gastrointestinal side effects from aspirin, enteric-coated tablets or antacid mixtures of aspirin are available.

Other nonaspirin, nonsteroidal antiinflammatory drugs (NSAIDs) include the indole derivatives indomethacin , sulindac , and tolmetin and the phenylalkanoic acid derivatives fenoprofen , ibuprofen , and naproxen . Nowadays NSAIDs are the most used group of medications for treatment of arthritis. They may provide more relief than aspirin for certain patients, but they also may have side effects related to the gastrointestinal and nervous systems. COX-2 (cyclooxygenase-2) inhibitors are the latest class of NSAIDs. They have fewer gastrointestinal side effects than other NSAIDs.

Cytotoxic agents may also be used these drugs act as immunosuppressants and block the inflammatory process of the disease. methotrexate is the most common of these. The dosage for the management of rheumatoid arthritis is much lower than the dosages for malignancies thus the associated side effects are fewer. gold compounds or penicillamine may be prescribed for selected patients who cannot tolerate or are not responding well to more conservative methods of treatment.

The corticosteroids may be used in treating rheumatoid arthritis, but they are not a substitute for other forms of treatment. In some cases these drugs produce side effects that are more difficult to treat than arthritis. They also may worsen certain features of the disease rather than relieve them. Drugs included in this group are cortisone , hydrocortisone , prednisone , prednisolone , and dexamethasone .

Another group of medications that reduce inflammation are the biological response modifiers . Members of this group used to treat arthritis include etanercept and infliximab .

Surgical Intervention and Orthopedic Devices. In the past, surgical intervention was reserved for patients who had already suffered severe joint deformity. There is presently a trend toward the use of surgery in the early stages of the disease so that deformities and serious mechanical abnormalities can be prevented or at least modified.

One surgical procedure employed is synovectomy (excision of the synovial membrane of a joint). The goal of this treatment is to interrupt the destructive inflammatory processes that eventually lead to ankylosis and invasion of surrounding cartilage and bone tissues.

Surgical repair of a hip joint (arthroplasty) may be performed when there is extensive damage and ambulation is not possible. The purpose of this procedure is to restore, improve, or maintain joint function. In cases in which it is not possible to restore the damaged hip joint there is a surgical procedure in which the diseased joint is completely replaced with a total hip prosthesis. The procedure is called a total hip replacement . A similar procedure involving total replacement of the knee can be done when there is extensive damage to the knee joint.

Braces, casts, or splints are sometimes used to immobilize the affected part so that it can rest during an active stage of the disease. Devices that immobilize the affected joint also may allow for motion of adjacent muscle, thereby improving muscle strength and permitting more independence on the part of the patient. Braces also may be used to prevent deformities by maintaining good position of the joints.

Patient Education. Unfortunately, arthritis is so widespread and such a crippling disease that its victims may be easy prey for charlatans and promoters of &ldquomiraculous cures.&rdquo The nature of the disease, with its unexplained remissions and relief of symptoms, makes it easy for unscrupulous individuals to convince the arthritic patient that some bizarre treatment they have used has indeed &ldquocured&rdquo the arthritis. It is important that members of the health team recognize the need for patient education and work diligently with the patient and family so that they can cooperatively participate in a program of care that is most effective for the individual patient.

Home care is an essential part of the management of arthritis. To help in education of the public The Arthritis Foundation provides a number of pamphlets and other educational materials, supports a broad program of research and education, and helps finance improvement of local facilities for treatment of arthritis. The address of the foundation is The Arthritis Foundation, 1330 W. Peachtree St., Atlanta, GA 30309, telephone 404-872-7100.

1. Introduction and scope of the problem

Bone loss and subsequent repair are important issues in orthopaedics and related specialties. A clear understanding of the principles underlying bone loss and repair is essential for the treatment of traumatic injuries (fractures and non-unions), patients with bone infection, osteonecrosis, arthritis, osteoporosis, spinal fusion, wear particle associated osteolysis, metabolic bone disease, tumors and other diseases affecting bone. The subject of bone loss and repair has great clinical and economic importance. Approximately 100,000 fractures develop a non-union each year in the USA [1]. The average cost for treatment of an established non-union is approximately US$11,333 [2]. Fragility fractures secondary to senile osteoporosis are a major source of pain and disability, and affect 50% of women and 25% of men over age 50 [3]. Medical care for these fractures will cost over US$25 billion by 2025. The number of surgical cases that use auto- or allograft bone to repair bone defects or obtain a robust fusion totals approximately 1.5 million cases in the USA, with an additional 2.2 million cases worldwide per year [4]. In 2011 alone, there were about 465,070 spinal fusion procedures performed in the USA, the majority of which use bone grafts or byproducts [5]. These are but a few examples of the social and financial burden that bone loss and repair places on our society, and the urgent need for a deeper understanding of the etiology, biological mechanisms, and methods for prevention of fracture non-unions and healing of bone.

Although bone loss and repair were once simply thought to involve only osteoblasts and osteoclasts, currently there has been great emphasis on more complex interactions among cells of the mesenchymal stem cell-osteoblast lineage, and the monocyte-macrophage-osteoclast lineage. Indeed it is now generally appreciated that crosstalk amongst inflammatory cells and cells related to bone healing is essential to the formation repair and remodeling of bone [6]. This fact is not surprising, given that acute inflammation has been recognized as the first stage of fracture healing [7].

The processes of bone healing are biologically intertwined with those of acute inflammation and the innate immune system. When humans or lower organisms experience a perturbing stimulus that may potentially jeopardize their existence or function, the innate immune system is activated in order to re-establish the normal homeostatic state [8�]. Local and circulating cells of the monocyte/macrophage lineage function as tissue sentinels that become activated and respond immediately to serious adverse stimuli via a pre-programmed non-antigen specific series of events. Monocyte/macrophages sense and regulate subsequent biological events to mitigate the adverse stimulus and re-establish pre-morbid local anatomy and physiology. If this does not occur, permanent tissue alterations may result due to ongoing active inflammation, fibrosis, or chronic inflammation, in which active inflammation, fibrosis and attempts at repair all occur simultaneously [12].

Bone is a complex organ with numerous functions including hematopoiesis, regulation and storage of key minerals, the protection of vital life-sustaining organs, facilitation of locomotion etc. When bone is subjected to injurious, pro-inflammatory stimuli (trauma, infection and so forth), the same biological processes regulated by the innate immune system ensue, as with other tissues and organ systems, to effect local repair and bone healing. These events necessitate ongoing communication between cells of the monocyte-macrophage-osteoclast lineage, which directly confronts the offending stimulus (such as with infection), but then initiates repair through the process of macrophage transformation (polarization) into a pro-healing phenotype, and through the liberation of cytokines, chemokines and other factors that promote angiogenesis and the homing of cells of the mesenchymal stem cell-osteoblast lineage [6, 8, 10, 13�]. In addition, mesenchymal-derived cells modulate inflammatory cells to promote resolution of pro-inflammatory activities, and reconstitution of normal tissue.

This review will summarize the fundamental principles of bone healing and repair after exposure to adverse physical and biological trauma, elucidate the mechanisms by which this occurs, emphasize the important interactions and cross-talk among cells of the monocyte-macrophage-osteoclast and mesenchymal stem cell-osteoblast lineages, and provide discussion on new opportunities for enhancing bone repair by modulating the processes of inflammation.


Exudate and blood collection collection

Twelve patients (2 female, 10 male) with a visible hypoechoic area following an acute muscle strain in either the hamstrings (n = 3) or the calf muscles (n = 9) gave their informed consent to participate in this study. The study was approved by the ethical committee of the Capital Region of Copenhagen (H-005-2014) and registered at (NCT02152098). By ultrasound guidance, the injury EX was aspirated aseptically. Immediately following the collection of the fluid into a syringe, the EX was added to blood collection tubes (Vacuette Greiner Bio-One, Kremsmünster, Austria) containing 3.5% sodium citrate to avoid coagulation. To compare the injury EX with the systemic response, a blood sample (PL) was taken from the antecubital vein using blood collection tubes with 3.5% sodium citrate. Both the EX and the PL samples were kept on ice for ∼40 min followed by centrifugation at 4°C for 10 min at 800 g to separate the supernatant from the pellet. The supernatant was divided into vials and stored at −80°C until analysis.

For isolation of cells in the blood (BL) and injury EX that are not erythrocytes, the cell pellet was resuspended and transferred into a Ficoll tube (Vacutainer, 362781 BD Biosciences, San Jose, CA, USA) and thereafter centrifuged at 1800 g for 60 min to separate the erythrocytes from all other bloodborne cells. This cell layer was transferred into an Eppendorf tube, diluted in PBS, and the fluid was removed by centrifugation. The remaining cell pellet was resuspended in 1 ml of TriReagent (Molecular Research Center, Cincinnati, OH, USA) and stored at −80°C until analysis.

Isolation of human fibroblasts and myoblasts

Primary fibroblasts and myoblasts were isolated from Musculus semitendinosus and M. gracilis the tissue was obtained during anterior cruciate ligament reconstruction from 4 male donors (aged 18–32 yr approved by the Ethical Committee of the Capital Region of Copenhagen H-2010-070). Tissue classified as surgical waste was cut into smaller pieces and transferred into a tube containing skeletal muscle basal medium with 0.2% collagenase B and 0.2% dispase II for digestion at 37°C for 1 h with regular resuspension. The resulting suspension was filtered and seeded into cell culture flasks for 7 d.

Thereafter, cells were divided into a fraction containing CD56 + cells (muscle progenitor cells and myoblasts) and a CD56 − cell (fibroblasts) applying superparamagnetic microbeads conjugated to a CD56 primary antibody (130-050-401 Miltenyi Biotec, Bergisch Gladbach, Germany), separating magnetic-labeled cells from unlabeled cells by the MiniMacs separator (Milteneyi Biotec) (20). Myoblasts were cultured in either skeletal muscle growth medium plus supplement mix (C-23060 PromoCell, Heidelberg, Germany) containing 15% fetal bovine serum (FBS), and fibroblasts were cultured in DMEM /F12 medium (Thermo Fisher Scientific, Waltham, MA, USA) with 10% FBS. Myoblasts and fibroblasts were stained with myogenic or fibrogenic markers, counted, and the number of positive cells was expressed as a percentage of the total count (Supplemental Table S2). To increase cell number, cells were cultured and used for experiments up to the fourth passage.

Cell proliferation determination on 2-dimensional cell culture

The proliferative capacity of human primary fibroblasts and myoblasts was measured after incubation with either the injury EX or PL samples by bromodeoxyuridine (BrdU) incorporation in a colorimetric immunoassay (11647229001 Roche, Basel, Switzerland). The respective cells were detached with trypsin and EDTA, counted, and seeded into 96-well plates with a concentration of 5 × 10 3 cells per well. Fibroblasts were cultured for 24 h in growth medium for attachment, followed by serum-free medium for 24 h. Next, serum-free medium was removed and medium (DMEM high glucose Ca2 + -free) containing either 50% injury EX or 50% matched PL (v/v) from the same injured subject was added to the cells for 24 h. Thereafter, BrdU was added for 18 h to the cells and analyzed afterwards. Myoblasts were supplemented with growth medium for attachment for 24 h, the growth medium was removed, and cells were incubated with medium containing either 50% injury EX or 50% matched PL (v/v) for 24 h. The BrdU incubation time was set to 6 h and the assay ran thereafter. Serum-free medium and growth medium with 10% FBS was used as control. The manual by the supplier was followed and absorbance was read at 450 and 690 nm with the Multiskan FC Microplate Photometer (Thermo Fisher Scientific). Results are presented as means from the 4 different donor cell lines (cell isolation and separation described above).

3D cell culture

Fibroblasts and myoblasts from the 4 different human donors (cell isolation and separation described above) were seeded into a fibrin gel (total volume, 815 µl) consisting of 100,000 cells per well (CellStar 6-Well Cell Culture Multiwell Plates GR-657160 Greiner Bio-One). Fibroblasts and myoblasts were cultured separately as in a direct coculture (i.e., combining fibroblasts and myoblasts in the same fibrin gel). Because of limited volume of the aspirated EX, only 7 patients were available for this experiment (Table 1). The fibrin gel was developed based on 4 mg/ml human fibrinogen (F3879 MilliporeSigma, Burlington, MA, USA) and 0.5 U/ml human thrombin (T6884 MilliporeSigma) with 20 µg/ml aprotinin and 50% (v/v) of the respective supplement (i.e., either human EX or human PL) in DMEM (high glucose, Ca2 + -free) supplemented with 0.2 mM l -ascorbic acid 2-phosphate and 0.05 mM l -proline. After gel formation, 1 ml medium containing either 50% EX or 50% PL (v/v) supplemented with 0.2 mM l -ascorbic acid 2-phosphate and 0.05 mM l -proline was placed over the gel. Cells were incubated at 37°C and 5% CO2 for 6 d before they were harvested without medium change. Samples were snap frozen in liquid nitrogen and stored until analysis.

Patient Gender Age (yr) Grade of severity Injured muscle Aspiration (days postinjury) EX (ml)
1 Male 43 3B Medial gastrocnemius 3 5
2 a , b Male 32 4 Biceps femoris caput longum 5 10
3 Male 25 4 Semitendinosous 48 3
4 a , b Male 37 3B Medial gastrocnemius 7 20
5 a Male 51 4 Medial gastrocnemius 3 5
6 a Male 40 3B Medial gastrocnemius 5 5
7 b Male 40 3A Medial gastrocnemius 60 10
8 b Male 40 3A Medial gastrocnemius 33 50
9 Male 54 3B Biceps femoris caput longum 14 3
10 b Female 50 3A Medial gastrocnemius 16 10
11 b Male 44 3B Medial gastrocnemius 11 10
12 b Female 31 3A Medial gastrocnemius 12 8
  • Injury severity was graded according to classification system by Mueller-Wohlfahrt et al. (57).
  • a Samples taken for analysis of EX- and blood-derived cells.
  • b Samples taken for 3D cell culture.

Cytokine and growth-factor profile of the EX and PL

The EX and PL cytokine and chemokine profile was established by multiplex assay applying a V-Plex Proinflammatory Panel 1 (K15049D Meso Scale Discovery, Rockville, MD, USA) customized with antibodies against IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, and TNF-α, a Cytokine Panel 1 (K15050D-1 Meso Scale Discovery) customized with antibodies against IL-1α, IL-15, IL-17, and VEGF-A, and a customized Chemokine Panel 1 (K15047D Meso Scale Discovery) customized with antibodies against MCP-1 and IP-10, as well as the Human TGF-β 1 Kit (K151IUC-1 Meso Scale Discovery), following the instructions in the supplier's manual. Standards and samples were run as duplicates and PL and EX dilutions were first determined by serial dilution ranges on randomly selected samples. Dilutions for the proinflammatory panel were 2 and 4 times (EX) and 2 times (PL), 4 and 8 times (EX) and 4 times (PL) for the cytokine panel, and 16 and 32 times (EX) and 4 times (PL) for the chemokine panel. For the TGF-β1 assay, dilutions were 4 and 8 times (EX) and 4 times (PL).

Gene expression of EX- and blood-derived cells and cells in 3D cultures

The amount of mRNA for selected targets in EX- and BL-derived cells was measured with real-time RT-PCR (Table 1). Snap-frozen pieces of the 3D gels were homogenized with 5 steel beads in 1 ml of TriReagent thereafter, l-bromo-3-chloropropane (Molecular Research Center) was added to separate the samples into an aqueous phase and an organic phase. To EX- and BL-derived cells frozen in TriReagent, l-bromo-3-chloropropane was pipetted into the tube without homogenization. Glycogen was added to the samples to improve RNA precipitation. Following isolation of the aqueous phase, RNA was precipitated using isopropanol, washed in ethanol, and dissolved in RNAse-free water. RNA concentrations were determined using RiboGreen RNA Assay Kit (Thermo Fisher Scientific). Synthesis of cDNA was performed using the Omniscript RT Kit (Qiagen, Germantown, MD, USA) on 50 ng of RNA. For each target mRNA, 5 µl of 20 × diluted cDNA was amplified in 20 µl QuantiTect SYBR Green Master Mix (Qiagen) with specific primers (100 nM each Supplemental Table S1) on a real-time PCR machine (MX3005P Stratagene, San Diego, CA, USA). The thermal profile was 95°C, 10 min → (95°C, 15 s → 58°C, 30 s → 63°C, 90 s) * 50 → 95°C, 60 s → 55°C, 30 s → 95°C, 60 s. Signal intensity was acquired at the 63°C step and the threshold cycle values were related to a standard curve made with the cloned PCR product. Specificity was confirmed by melting-curve analysis after amplification (the 55–95°C step). The large ribosomal protein P0 mRNA, which was stably expressed relative to both glyceraldehyde 3-phosphate dehydrogenase mRNA and total RNA, was chosen as internal control. The mRNA data are shown relative to either the mean of blood-derived cells or PL in the 3D wound assay. In some samples, no mRNA was detectable, meaning that these samples were below the detection limit (=1 molecule) and were thus set to 1 molecule to enable statistical analysis. For the 3D culture, nondetected samples were single events, except for collagen type XXII-α1 chain (3 PL and 1 EX nondetectable samples), Myogenic factor 6 (Myf6) (3 PL, 4 EX) in the fibroblast 3D culture, and insulin-like growth factor 1 (IGF-1 3 PL, 1 EX) in the cocultured fibroblasts plus myoblasts. For the blood-derived cells, nondetectable samples were frequent in collagen type I-α1 chain (4 BL, 0 EX), collagen type III-α1 chain (4 BL, 0 EX), fibronectin (3 BL, 0 EX), collagen type XXII-α1 chain (4 BL, 4 EX), tenascin C (4 BL, 0 EX), angiopoietin-like 4 (ANGPTL4 4 BL, 0 EX), and IGF-1 (4 BL, 4 EX). As a consequence, the calculated difference between the EX-and BL-derived cells is likely underestimated because of the use of 1 molecule in the calculations.

RNA sequencing of EX- and blood-derived cells

Total RNA samples from the EX- and blood-derived cells (n = 4) were submitted to BGI Europe (Copenhagen, Denmark) for RNA sequencing. The RNA integrity was tested with a Bioanalyzer (RIN 8.5–10.0 Agilent, Santa Clara, CA, USA) and the mRNA was enriched by oligo deoxythymidine selection followed by RNA fragmentation and RT by N6 random priming. The synthesized cDNA was subjected to end repair and 3′ adenylated. Adaptors were ligated to the ends of these 3′-adenylated cDNA fragments, and the ligation products were purified and subjected to PCR amplification. The PCR products were denatured by heat and the single-strand DNA was cyclized by splint oligo and DNA ligase. From this, DNA nanoballs were generated and sequenced on the BGISeq-500 (BGI Europe, Copenhagen Denmark) platform (24–31 million 50 base reads per sample).

The reads were filtered against low-quality reads (>98.8% clean reads) and mapped to the human reference genome using HIS AT (21). Ninety-two to ninety-three percent of the reads could be mapped to the genome. To get expression levels, the clean reads were mapped to the human reference transcripts using Bowtie2 (22) and expression levels were calculated with RSEM (23). Sixty-four to seventy-three percent of the reads could be mapped to the reference transcripts, and the general distribution of expression levels for each sample were very similar (data not shown). Differential expression [fold change (FC) >2 and false discovery rate (FDR) P < 0.05] between the 2 sample types was measured using DEseq2 (24). Pathway enrichment was assessed for the Reactome pathway (25) and for Biologic Processes in Gene Ontology (GO) (26) using ReactomePA (27) and clusterProfiler (28), respectively. The full data are available in the Gene Expression Omnibus database (GSE130836 National Center for Biotechnology Information Bethesda, MD, USA


The level of statistical significance for all tests was set at P < 0.05 trends were reported when P < 0.1. The effect of EX or PL on cell proliferation was analyzed by 2-way repeated-measure ANOVA with the type of supplement (EX or PL) and cell line as factors. Comparison between EX and PL levels of cytokines and growth factors were made with the paired Student's t test on log-transformed protein levels. The mRNA data were log transformed and analyzed using SigmaPlot for Windows v.11.0 (Systat Software, San Jose, CA, USA). Comparisons between EX- and PL-treated cultures within the 3 cell types (fibroblasts, myoblasts, and the cocultured fibroblasts plus myoblasts) were performed with paired Student's t tests.

Patho II Exam 2

A. They are the receptors for interleukin-2, which is produced by macrophages when they attack the donor cells.

B. They are recognized by helper T cells, which then activate cytotoxic T cells to kill the donor cells.

C. They induce the production of blocking antibodies that protect the graft.

C. CD4-positive T lymphocytes.

C. phagocytosis of IgE-coated bacteria.

A. B cells that can kill without complement.

C. increased by immunization.

A. a humoral immune response has occurred.

B. a cell-mediated immune response has occurred.

C. both the T and B cell systems are functional.

A. from the same host infected with any virus.

B. infected by virus A and identical at class I MHC loci of the cytotoxic T cells.

C. infected by virus A and identical at class II MHC loci of the cytotoxic T cells.

D. infected with a different virus and identical at class I MHC loci of the cytotoxic cells.

A. enzymatic digestion of the cell membrane.

B. activation of adenylate cyclase.

C. insertion of complement proteins into the cell membrane.

C. helper T cells and macrophages.

A. It is unlikely that the patient has encountered this organism previously.

B. The patient is predisposed to IgE-mediated hypersensitivity reactions.

C. The information given is irrelevant to previous antigen exposure.

A. Perforins from cytotoxic T cells lyse the red cells.

B. Neutrophils release proteases that lyse the red cells.

C. Interleukin-2 binds to its receptor on the red cells, which results in lysis of the red cells.

C. T cell-B cell interaction.

B. lyse virus-infected target cells.

C. activate cytotoxic T cells.

A. matching the complement components of donor and recipient

B. administering alpha interferon

C. removing mature T cells from the graft

Possible Answers:
part of immunological memory

derivatives of natural killer (NK) cells

part of the innate immune system

Possible Answers:
A deficiency of B-cells, with a relative abundance of T-cells

Deficiency of both T-cells and B-cells

A deficiency of T-cells, with a relative abundance of B-cells

Excess production of both T-cells and B-cells

Possible Answers:
Mast cells

Possible Answers:
T-cells could not be generated

T3 and T4 levels would decrease

Hypothyroidism would occur

B-cells would not be able to mature

In the muscle fibers, the effects of the disease can be exacerbated by auto-immune interference. Weakness of the sarcolemma leads to damage and tears in the membrane. The body's immune system recognizes the damage and attempts to repair it. However, since the damage exists as a chronic condition, leukocytes begin to present the damaged protein fragments as antigens, stimulating a targeted attack on the damaged parts of the muscle fiber. The attack causes inflammation, fibrosis, and necrosis, further weakening the muscle.

Studies have shown that despite the severe pathology of the muscle fibers, the innervation of the muscle is unaffected.

Which of the following does not play a key role in the adaptive immune response?

Possible Answers:
dendritic cells

Possible Answers:
Macrophages use isolation as their main defense, and wall off pathogens

Macrophages produce antibodies to target pathogens

Macrophages use reactive oxygen species after ingesting pathogens

Macrophages only recruit other cells that are then able to kill pathogens

I. They present their antigens on major histocompatibility complex molecules.

II. They migrate to lymph nodes to present their antigens to B-cells and T-cells.

III. Antigen-presenting cells form a link between the innate and adaptive immune systems.


a localized protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissue. adj., adj inflam´matory. &emsp

The inflammatory response can be provoked by physical, chemical, and biologic agents, including mechanical trauma, exposure to excessive amounts of sunlight, x-rays and radioactive materials, corrosive chemicals, extremes of heat and cold, or by infectious agents such as bacteria, viruses, and other pathogenic microorganisms. Although these infectious agents can produce inflammation, infection and inflammation are not synonymous.

The classic signs of inflammation are heat, redness, swelling, pain, and loss of function. These are manifestations of the physiologic changes that occur during the inflammatory process. The three major components of this process are (1) changes in the caliber of blood vessels and the rate of blood flow through them (hemodynamic changes) (2) increased capillary permeability and (3) leukocytic exudation.

Hemodynamic changes begin soon after injury and progress at varying rates, according to the extent of injury. They start with dilation of the arterioles and the opening of new capillaries and venular beds in the area. This causes an accelerated flow of blood, accounting for the signs of heat and redness. Next follows increased permeability of the microcirculation, which permits leakage of protein-rich fluid out of small blood vessels and into the extravascular fluid compartment, accounting for the inflammatory edema.

Leukocytic exudation occurs in the following sequence. First, the leukocytes move to the endothelial lining of the small blood vessels (margination) and line the endothelium in a tightly packed formation (pavementing). Eventually, these leukocytes move through the endothelial spaces and escape into the extravascular space (emigration). Once they are outside the blood vessels they are free to move and, by chemotaxis , are drawn to the site of injury. Accumulations of neutrophils and macrophages at the area of inflammation act to neutralize foreign particles by phagocytosis .

Chemical mediators of the inflammatory process include a variety of substances originating in the plasma and the cells of uninjured tissue, and possibly from the damaged tissue. The major kinds of mediators are (1) vasoactive amines, such as histamine and serotonin (2) plasma endopeptidases that comprise three interrelated systems, the kinin system that produces bradykinin , the complement system that produces proteins that interact with antigen--antibody complexes and mediate immunologic injury and inflammation, and the clotting system that increases vascular permeability and chemotactic activity for the leukocytes (3) prostaglandins , which can reproduce several aspects of the inflammatory process (4) neutrophil products (5) lymphocyte factors and (6) other mediators, such as slow-reacting substance of anaphylaxis and endogenous pyrogen .

Hormonal Response. Some hormones, such as cortisol , have an antiinflammatory action that limits inflammation to a local reaction while others are proinflammatory. Thus, the endocrine system has a regulatory effect on the process of inflammation so that it can be balanced and beneficial in the body's attempts to recover from injury.

Fibrinous inflammation, exudate and scarring in monotonous movements and ageing - Biology

Novel elastin-based scaffolds have demonstrated efficacy.

Elastin-based skin substitutes improve clinical outcomes in burn wounds when transplanted beneath split-thickness skin grafts.

Functionalized elastin recombinamers enhance in vitro endothelial and fibroblast cell proliferation as well as in vivo angiogenesis.

Recombinant human tropoelastin promotes early angiogenesis and harmonizes with the therapeutic benefits of existing dermal dressings.

Tropoelastin improves wound healing and promotes de novo elastin synthesis.

Tropoelastin-based constructs can be polymerized using a range of methods, including photocrosslinking, chemical crosslinking and heat to enhance healing.

Wound healing has historically relied on endogenous processes, but engineered materials are increasingly being used to assist tissue repair. Elastin is an essential functional component of the dermal extracellular matrix and is an important part of skin wound repair that encompasses an elastic dermis. Advances in modern technology have better elucidated the specific signaling factors and cells that contribute to the physiological process and have led to new developments in wound care technology. We review elastin-based materials that are used to encourage wound repair. Elastin-related biomaterials, particularly those based on tropoelastin, are particularly promising because tropoelastin is assembled to make elastin. We present insights into the roles of elastin-related biomaterials and their associated in vitro and in vivo benefits on wound healing.


Aller, M. A., J. L. Arias, et al. (2006). "The inflammatory response: an efficient way of life." Med Sci Monit 12(10): RA225-234.

Azuma, Y., M. Ito, et al. (2001). "Low-intensity pulsed ultrasound accelerates rat femoral fracture healing by acting on the various cellular reactions in the fracture callus." J Bone Miner Res 16(4): 671-680.

Beck, A., K. Salem, et al. (2005). "Nonsteroidal anti-inflammatory drugs (NSAIDs) in the perioperative phase in traumatology and orthopedics effects on bone healing." Oper Orthop Traumatol 17(6): 569-578.

Bjordal, J. M., R. A. Lopes-Martins, et al. (2006). "A randomised, placebo controlled trial of low level laser therapy for activated Achilles tendinitis with microdialysis measurement of peritendinous prostaglandin E2 concentrations." Br J Sports Med 40(1): 76-80 discussion 76-80.

Bossini, P. S., R. Fangel, et al. (2009). "Low-level laser therapy (670 nm) on viability of random skin flap in rats." Lasers Med Sci 24(2): 209-213.

Boursinos, L. A., T. Karachalios, et al. (2009). "Do steroids, conventional non-steroidal anti-inflammatory drugs and selective Cox-2 inhibitors adversely affect fracture healing?" J Musculoskelet Neuronal Interact 9(1): 44-52.

Bring, D. K., A. Kreicbergs, et al. (2007). "Physical activity modulates nerve plasticity and stimulates repair after Achilles tendon rupture." J Orthop Res 25(2): 164-172.

Broughton, G., 2nd, J. E. Janis, et al. (2006). "The basic science of wound healing." Plast Reconstr Surg 117(7 Suppl): 12S-34S.

Butterfield, T. A., T. M. Best, et al. (2006). "The dual roles of neutrophils and macrophages in inflammation: a critical balance between tissue damage and repair." J Athl Train 41(4): 457-465.

Calatroni, A., A. Avenoso, et al. (2008). "Transient increase with strenuous exercise of plasma levels of glycosaminoglycans in humans and horses." Connect Tissue Res 49(6): 416-425.

Chao, Y. H., Y. H. Tsuang, et al. (2008). "Effects of shock waves on tenocyte proliferation and extracellular matrix metabolism." Ultrasound Med Biol 34(5): 841-852.

Cheung, W. H., W. C. Chin, et al. (2011). "Low intensity pulsed ultrasound enhances fracture healing in both ovariectomy-induced osteoporotic and age-matched normal bones." J Orthop Res.

Culav, E. M., C. H. Clark, et al. (1999). "Connective tissues : Matrix composition and its relevance to physical therapy." Physical Therapy 79(3): 308-319.

Cyr, L. M. and R. G. Ross (1998). "How controlled stress affects healing tissues." Journal of Hand Therapy 11(2): 125-130.

Dierich, M. P., O. Forster, et al. (1987). "Inflammation and phagocytosis." J Clin Chem Clin Biochem 25: 785-793.

Dimmen, S., L. Nordsletten, et al. (2009). "The effect of parecoxib and indometacin on tendon-to-bone healing in a bone tunnel: an experimental study in rats." J Bone Joint Surg Br 91(2): 259-263.

Egozi, E. I., A. M. Ferreira, et al. (2003). "Mast cells modulate the inflammatory but not the proliferative response in healing wounds." Wound Repair Regen 11(1): 46-54.

Fitzsimmons, R. J., S. L. Gordon, et al. (2008). "A pulsing electric field (PEF) increases human chondrocyte proliferation through a transduction pathway involving nitric oxide signaling." J Orthop Res 26(6): 854-859.

Forrest, L. (1983). "Current concepts in soft connective tissue wound healing." Br J Surgery 70: 133-140.

Frick, M. A. and N. S. Murthy (2010). "Imaging of the elbow: muscle and tendon injuries." Semin Musculoskelet Radiol 14(4): 430-437.

Fujiwara, Y., M. Uesugi, et al. (2005). "Down-regulation of basic fibroblast growth factor production from cartilage by excessive mechanical stress." J Orthop Sci 10(6): 608-613

Gabbiani, G. (2003). "The myofibroblast in wound healing and fibrocontractive diseases." J Pathol 200(4): 500-503.

Gomez, M. A., S. L. Woo, et al. (1991). "The effects of increased tension on healing medical collateral ligaments." Am J Sports Med 19(4): 347-354.

Granger, D. N. and E. Senchenkova (2010). Inflammation and the Microcirculation. San Francisco, Morgan and Claypool.

Handschin, C. and B. M. Spiegelman (2008). "The role of exercise and PGC1[alpha] in inflammation and chronic disease." Nature 454(7203): 463-469.

Hardy, M. A. (1989). "The biology of scar formation." Physical Therapy 69(12): 1014-1024.

Hildebrand, K. A., S. L. Woo, et al. (1998). "The effects of platelet-derived growth factor-BB on healing of the rabbit medial collateral ligament. An in vivo study." Am J Sports Med 26(4): 549-554

Hill, M., A. Wernig, et al. (2003). "Muscle satellite (stem) cell actiation during local tissue injury and repair." J Anat 203: 89-99.

Hurley, J. V. (1985). Inflammation. Muir's Textbook of Pathology. J.R.Anderson.

Hurst, S. M., T. S. Wilkinson, et al. (2001). "IL-6 and Its Soluble Receptor Orchestrate a Temporal Switch in the Pattern of Leukocyte Recruitment Seen during Acute Inflammation." Immunity 14(6): 705-714.

Ingber, D. E. (2003). "Mechanobiology and diseases of mechanotransduction." Annals of Medicine 35: 564-577.

Ingber, D. E. (2008). "Tensegrity and mechanotransduction." J Bodyw Mov Ther 12(3): 198-200

Jimenez, P. A. and S. E. Jimenez (2004). "Tissue and cellular approaches to wound repair." The American Journal of Surgery 187: 56s-64s.

Khan, K. M. and A. Scott (2009). "Mechanotherapy: how physical therapists' prescription of exercise promotes tissue repair." Br J Sports Med 43(4): 247-252

Khanna, A., R. T. Nelmes, et al. (2009). "The effects of LIPUS on soft-tissue healing: a review of literature." Br Med Bull 89: 169-182.

Kido, S., R. Kuriwaka-Kido, et al. (2009). "Mechanical stress induces Interleukin-11 expression to stimulate osteoblast differentiation." Bone 45(6): 1125-1132.

Killian, M. L., L. Cavinatto, et al. (2012). "The role of mechanobiology in tendon healing." J Shoulder Elbow Surg 21(2): 228-237.

Kuo, Y. R., C. T. Wang, et al. (2009). "Extracorporeal shock-wave therapy enhanced wound healing via increasing topical blood perfusion and tissue regeneration in a rat model of STZ-induced diabetes." Wound Repair Regen 17(4): 522-530.

Leung, M. C., G. Y. Ng, et al. (2006). "Therapeutic ultrasound enhances medial collateral ligament repair in rats." Ultrasound Med Biol 32(3): 449-452.

Li, J., J. Chen, et al. (2007). "Pathophysiology of acute wound healing." Clin Dermatol 25(1): 9-18.

Li, J. K., W. H. Chang, et al. (2003). "Cytokine release from osteoblasts in response to ultrasound stimulation." Biomaterials 24(13): 2379-2385.

Li, Z., G. Yang, et al. (2004). "Inflammatory response of human tendon fibroblasts to cyclic mechanical stretching." Am J Sports Med 32(2): 435-440

Lin, T. W., L. Cardenas, et al. (2004). "Biomechanics of tendon injury and repair." Journal of Biomechanics 37(6): 865-877.

Lorena, D., K. Uchio, et al. (2002). "Nornal scarring : importance of myofibroblasts." Wound Repair Regen 10(2): 86-92.

Lu, H., L. Qin, et al. (2008). "Low-intensity pulsed ultrasound accelerated bone-tendon junction healing through regulation of vascular endothelial growth factor expression and cartilage formation." Ultrasound Med Biol 34(8): 1248-1260.

Luster, A. D. (1998). "Chemokines &mdash Chemotactic Cytokines That Mediate Inflammation." New England Journal of Medicine 338(7): 436-445.

Mackey, A. L., K. M. Heinemeier, et al. (2008). "Dynamic adaptation of tendon and muscle connective tissue to mechanical loading." Connect Tissue Res 49(3): 165-168.

McAnulty, R. J. (2007). "Fibroblasts and myofibroblasts: their source, function and role in disease." Int J Biochem Cell Biol 39(4): 666-671.

McBrier, N. M., J. M. Lekan, et al. (2007). "Therapeutic ultrasound decreases mechano-growth factor messenger ribonucleic acid expression after muscle contusion injury." Arch Phys Med Rehabil 88(7): 936-940.

Medzhitov, R. (2008). "Origin and physiological roles of inflammation." Nature 454(7203): 428-435.

Mesquita-Ferrari, R. A., M. D. Martins, et al. (2011). "Effects of low-level laser therapy on expression of TNF-alpha and TGF-beta in skeletal muscle during the repair process." Lasers Med Sci 26(3): 335-340

Metz, M., M. A. Grimbaldeston, et al. (2007). "Mast cells in the promotion and limitation of chronic inflammation." Immunol Rev 217: 304-328.

Metz, M. and M. Maurer (2007). "Mast cells--key effector cells in immune responses." Trends Immunol 28(5): 234-241.

Molloy, T., Y. Wang, et al. (2003). "The roles of growth factors in tendon and ligament healing." Sports-Med. 33(5): 381-394.

Niinikoski, J. (1979). Current concepts in wound nutrition. Symposium on Wound Healing, Helsinki, Finland, A Lindgren & Soner.

Nussbaum, E. L. and M. Locke (2007). "Heat shock protein expression in rat skeletal muscle after repeated applications of pulsed and continuous ultrasound." Arch Phys Med Rehabil 88(6): 785-790

Ostrowski, K., P. Schjerling, et al. (2000). "Physical activity and plasma interleukin-6 in humans--effect of intensity of exercise." Eur J Appl Physiol 83(6): 512-515.

Peacock, E. E. (1984). Wound Repair, W B Saunders.

Pitzer, J. A. (2006). Progress in Inflammation Research, Nova Science Pub Inc.

Poltawski, L. and T. Watson (2009). "Bioelectricity and microcurrent therapy for tissue healing - a narrative review." Physical Therapy Reviews 14(2): 104-114

Radi, Z. A. and N. K. Khan (2005). "Effects of cyclooxygenase inhibition on bone, tendon, and ligament healing." Inflamm Res 54(9): 358-366.

Rankin, J. A. (2004). "Biological mediators of acute inflammation." AACN Clinical Issues: Advanced Practice in Acute and Critical Care 15(1): 3-17.

Rego, E. B., T. Inubushi, et al. (2010). "Ultrasound stimulation induces PGE(2) synthesis promoting cementoblastic differentiation through EP2/EP4 receptor pathway." Ultrasound Med Biol 36(6): 907-915.

Reher, P., M. Harris, et al. (2002). "Ultrasound stimulates nitric oxide and prostaglandin E2 production by human osteoblasts." Bone 31(1): 236-241.

Rompe, J. D., J. P. Furia, et al. (2008). "Mid-portion Achilles tendinopathy--current options for treatment." Disabil Rehabil 30(20-22): 1666-1676.

Rutkowski, M. J., M. E. Sughrue, et al. (2010). "The complement cascade as a mediator of tissue growth and regeneration." Inflamm Res 59(11): 897-905.

Safavi, S. M., B. Kazemi, et al. (2008). "Effects of low-level He-Ne laser irradiation on the gene expression of IL-1beta, TNF-alpha, IFN-gamma, TGF-beta, bFGF, and PDGF in rat's gingiva." Lasers Med Sci 23(3): 331-335

Sakurai, T., S. Terashima, et al. (2008). "Enhanced secretion of prostaglandin E2 from osteoblasts by exposure to a strong static magnetic field." Bioelectromagnetics 29(4): 277-283.

Sawasaki, I., V. R. Geraldo-Martins, et al. (2009). "Effect of low-intensity laser therapy on mast cell degranulation in human oral mucosa." Lasers Med Sci 24(1): 113-116.

Saygun, I., S. Karacay, et al. (2008). "Effects of laser irradiation on the release of basic fibroblast growth factor (bFGF), insulin like growth factor-1 (IGF-1), and receptor of IGF-1 (IGFBP3) from gingival fibroblasts." Lasers Med Sci 23(2): 211-215.

Serhan, C. N., P. A. Ward, et al. (2010). Fundamentals of inflammation. Cambridge New York, Cambridge University Press.

Singer, A. J. and R. A. Clark (1999). "Cutaneous wound healing." N Engl J Med 341(10): 738-746.

Smith, C., M. J. Kruger, et al. (2008). "The inflammatory response to skeletal muscle injury: illuminating complexities." Sports Med 38(11): 947-969.

Sugita, Y., S. Mizuno, et al. (2008). "Nitric oxide generation directly responds to ultrasound exposure." Ultrasound Med Biol 34(3): 487-493.

Takao, M., T. Okinaga, et al. (2011). "Role of heme oxygenase-1 in inflammatory response induced by mechanical stretch in synovial cells." Inflamm Res 60(9): 861-867

Taljanovic, M. S., J. K. Nisbet, et al. (2011). "Humeral avulsion of the inferior glenohumeral ligament in college female volleyball players caused by repetitive microtrauma." Am J Sports Med 39(5): 1067-1076.

Vanable, J. (1989). Integumentary potentials and wound healing. Electric Fields in Vertebrate Repair. R. Borgens. New York, Alan Liss Inc: 171-224.

Vernon Roberts, B. (1988). "Inflammation 1987 An overview." Agents Actions Suppl 24: 1-18.

Wagner, S., S. Coerper, et al. (2003). "Comparison of inflammatory and systemic sources of growth factors in acute and chronic human wounds." Wound Repair and Regeneration 11(4): 253-260

Walter, J. B. and M. S. Israel (1987). General Pathology, Churchill Livingstone.

Watson, T. (2003). "Soft Tissue Healing." In Touch 104: 2-9.

Watson, T. (2006). "Tissue repair: The current state of the art." Sportex-Medicine. 28: 8-12.

Watson, T. (2008). Electrical Properties of Tissues. Electrotherapy : Evidence Based Practice. T. Watson. Edinburgh, Churchill Livingstone / Elsevier: 37-52.

Watson, T., Ed. (2008). Electrotherapy : Evidence Based Practice. Edinburgh, Churchill Livingstone - Elsevier.

Watson, T. (2011). An Extended Model of Physical Therapy Modes of Action. 16th International WCPT Congress. Amsterdam, Physiotherapy (2011)(). 97: A-210-0032-02387.

Wipff, P. J. and B. Hinz (2009). "Myofibroblasts work best under stress." J Bodyw Mov Ther 13(2): 121-127.

Zederfeldt, B. (1979). Factors influencing wound healing. Symposium on Wound Healing, Helsinki, Finland, A Lindgren & Soner.

Zhang, S. P., J. S. Zhang, et al. (2004). "Non-opioid-dependent anti-inflammatory effects of low frequency electroacupuncture." Brain Res Bull 62(4): 327-334

Zhao, M., H. Bai, et al. (2004). "Electrical stimulation directly induces pre-angiogenic responses in vascular endothelial cells by signaling through VEGF receptors." J Cell Sci 117(Pt 3): 397-405


The third phase of healing consists of remodeling, which begins two to three weeks after the onset of the lesion and can last for one year or more. The core aim of the remodeling stage is to achieve the maximum tensile strength through reorganization, degradation, and resynthesis of the extracellular matrix. In this final stage of the lesion's healing, an attempt to recover the normal tissue structure occurs, and the granulation tissue is gradually remodeled, forming scar tissue that is less cellular and vascular 3 and that exhibits a progressive increase in its concentration of collagen fibers ( Figure 7 ). This stage is marked by the maturing of the elements with deep changes in the extracellular matrix and the resolution of the initial inflammation. As soon as the surface of the lesion is covered by a monolayer of keratinocytes, its epidermal migration ceases and a new stratified epidermis with a subjacent basal lamina is reestablished from the borders of the wound to its inner portion. 5 At this stage, there is a deposition of the matrix and subsequent change in its composition. 14 With the closure of the wound, type III collagen undergoes degradation, and synthesis of type I collagen increases. Throughout the remodeling, there is a reduction in the hyaluronic and fibronectic acid, which are degraded by cells and plasmatic metalloproteinase, and the growing type I collagen expression mentioned above is concomitantly processed. 17

Electromicrography showing collagenous beams in different directions in the extracellular matrix, indicating the beginning of the process of fibroplasia, beginning on the seventh day after the onset of a skin wound, in an experimental model (Scanning Electron Microscopy – 12,000X)

Many authors, such as Sampaio & Riviti, have confirmed that, in this final stage, the collagen fibers become thicker and are placed in parallel, resulting in an enhanced tensile strength for the tissue. 33 The resolution stage is essential for the restoration of functionality and the "normal" appearance of the lesioned tissue. 1 This results from the low production of chemokines by anti-inflammatory cytokines, such as IL-10 or TGF-㬡. The regulation of the collagen synthesis is controlled by a wide range of growth factors, such as TGF-㬡 and FGF, which cause a strong effect upon the genic expression of this protein.

During the maturation and remodeling processes, the majority of blood vessels, fibroblasts, and inflammatory cells disappear from the wound area due to emigration processes, apoptosis, or other unknown mechanisms of cell death. This fact leads to the formation of a scar with a reduced number of cells. At a later stage, the fibroblasts of the granulation tissue change their phenotype and begin to temporarily express the smooth muscle actin, which have received the specific name of myofibroblasts. 6,27

Myofibroblasts, according to Calin et al. 27 , acquire some contraction properties from smooth muscle cells, moving closer to the borders of the wound and becoming responsible for its contraction. In this manner, the referent cells present well-developed bands of contractible microfilaments composed of actin. These remain joined through communication junctures, and their cytoplasmatic filaments of actin are connected by integrin receptors to the fibronectin fibrils and to collagen I and III of the extracellular matrix. 1,14 It is important to note that the myofibroblasts are the main producers of the extracellular matrix in processes of fibrosis. 31

According to Midwood et al. 34 and Badylak 35 , the extracellular matrix is not a static element and is capable of playing a relevant role in this stage of tissue repair through the interaction between its structural components and the different cell types present in the tissue. Such structural components, represented by proteins such as collagen, fibronectin, fibrin, among others, provide signs and unleash specific cell activities in the wound area. The fibronectin, for example, generates a framework that makes the adhesion and cell migration feasible. Another adhesive glycoprotein, vitronectin, can contribute to the contraction of the tissue mediated by the collagen produced by the fibroblasts. Due to the existence of these processes, the local control of the cell/matrix interactions have been the target of promising therapeutic approaches.

In all of the processes cited above, it is important to emphasize that exogenous and endogenous factors can modulate such events and influence the healing process. More specifically, systemic disorders, such as diabetes, immunosuppression, venous stasis, as well as those resulting from external agents, such as the use of corticotherapy and smoking, can hinder the early closure of the wound. In addition to these complicating factors is the appearance of hypertrophic scars and keloids. 36

Fibrinous inflammation, exudate and scarring in monotonous movements and ageing - Biology


Inflammation (from Latin inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

​ ​ The classical signs of inflammation are heat, pain, redness, swelling, and loss of function. Inflammation is a generic response, and therefore it is considered as a mechanism of innate immunity, as compared to adaptive immunity, which is specific for each pathogen. Too little inflammation could lead to progressive tissue destruction by the harmful stimulus (e.g. bacteria) and compromise the survival of the organism. In contrast, chronic inflammation may lead to a host of diseases, such as hay fever, periodontitis, atherosclerosis, rheumatoid arthritis, and even cancer (e.g., gallbladder carcinoma). Inflammation is therefore normally closely regulated by the body.

염증형성(염증)( i nflammation , 라틴어 inflammatio 에서 유래)이란 병원체, 손상된 세포나 자극물과 같은 유해 자극물질에 대하여 신체 조직이 일으키는 복합적 생체반응의 일부로서 면역세포, 혈관 및 분자 매개체가 관여하는 보호반응을 말한다. 염증의 기능은 세포를 손상시키는 원인을 제거하고 괴사세포와 손상 및 염증형성 과정으로 인해 최초로 피해를 입은 조직을 제거함으로써 조직의 복원을 개시하는 것이다.

염증이 형성되는 고전적 증후는 발열, 발적(發赤), 종창, 기능상실이다. 염증은 유전적 반응이므로 선천성 면역 메커니즘이라고 생각되고 있으며 후천 면역에 비해 각 병원체에 특이적이다. 염증반응은 매우 미미할 경우에도 유해한 자극체(예컨대 세균)에 의해 조직이 서서히 파괴될 수 있으며 생물의 생존이 억제될 수 있다. 대조적으로 염증이 만성화되면 건초열, 치주염, 죽상동맥경화증, 류머티스성 관절염, 심지어는 암(예컨대 담낭암)과 같은 많은 질환이 유발될 수 있다. 따라서 염증은 일반적으로 신체에 의해 정밀하게 조절되고 있다.

​ ​ Inflammation can be classified as either acute or chronic. Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues. A series of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process.

​ ​ Inflammation is not a synonym for infection. Infection describes the interaction between the action of microbial invasion and the reaction of the body's inflammatory response — the two components are considered together when discussing an infection, and the word is used to imply a microbial invasive cause for the observed inflammatory reaction. Inflammation on the other hand describes purely the body's immunovascular response, whatever the cause may be. But because of how often the two are correlated, words ending in the suffix -itis (which refers to inflammation) are sometimes informally described as referring to infection. For example, the word urethritis strictly means only "urethral inflammation", but clinical health care providers usually discuss urethritis as a urethral infection because urethral microbial invasion is the most common cause of urethritis.

​ ​ It is useful to differentiate inflammation and infection as there are many pathological situations where inflammation is not driven by microbial invasion – for example, atherosclerosis, type III hypersensitivity, trauma, ischaemia. There are also pathological situations where microbial invasion does not result in classic inflammatory response — for example, parasitosis, eosinophilia.

​염증은 급성염증 및 만성염증으로 나눌 수 있다. 급성 염증은 유해한 자극에 대한 최초의 신체 반응으로서 혈액으로부터 손상된 조직으로 혈장 및 백혈구(특히 과립구)의 이동이 증가함으로써 발생한다. 손상된 조직 내에서는 국소 혈관계, 면역계 및 다양한 세포를 포함하여 일련의 생화학적 사건들이 염증반응을 촉진하고 성숙시킨다. 장기적 염증은 만성 염증이라고 하는데, 이 경우 염증부위에 있는 단핵세포( mononuclear cell )와 같은 세포의 유형이 점진적으로 교체되며 염증과정으로 인해 조직이 파괴됨과 동시에 치유되는 것이 특징이다.

염증은 감염증상이 아니다.​ 감염이란 세균의 침입과 체내 염증반응 간의 상호작용을 말한다 - 이 두 가지는 감염을 논의할 경우 함께 고려되고 있으며 감염이라는 용어는 관찰된 염증 반응의 원인으로서 세균의 침입을 뜻한다. 반면 염증은 원인이 무엇이든지 간에 신체의 면역혈관 반응만을 의미한다. 그러나 이 두 가지가 상호 관련되는 빈도에 따라 때로는 비공식적으로 감염을 의미하는 말로 접미사 -itis (염증을 뜻한다)로 끝나는 말을 사용하기도 한다. 예컨대 urethritis (요도염)은 엄밀히는 "요도의 염증"만을 의미하지만 임상 보건업 종사자는 대개 요도염을 요도감염으로 논의하는데 그 이유는 요도염이 요도의 세균감염으로 인해 발생하는 경우가 가장 흔하기 때문이다.

염증과 감염을 구별하는 것은 유용한데 그 이유는 예컨대 죽상동맥경화증, 제 3 형 과민반응, 외상(外傷), 국소허혈과 같이 세균 침입 외의 원인으로 염증이 발생하는 병리적 상황이 많기 때문이다.​ 또한 예컨대 기생충병, 호산구증가증( eosinophilia )과 같이 세균이 침입해도 고전적인 염증반응이 유발되지 않는 병리적 상황도 존재한다.

1 Causes (원인)

2.1 Cardinal signs (발적증후)

2.2 Process of acute inflammation (급성염증 형성 과정)

3 Vascular component (혈관 성분)

3.1 Vasodilation and increased permeability (혈관확장 및 투과성 증가)

3.2 Plasma cascade systems (혈장 다단계 시스템)

3.3 Plasma-derived mediators (혈장 유도 매개체)

4 Cellular component (세포 성분)

4.1 Leukocyte extravasation (백혈구의 세포외 유출)

4.2 Phagocytosis (식세포작용)

4.3 Cell-derived mediators (세포 유도 매개체)

5 Morphologic patterns (형태적 패턴)

6 Inflammatory disorders (염증성 질환)

6.1 Atherosclerosis (죽상동맥경화증)

6.2 Allergy (알러지)

6.3 Myopathies (근위축증)

6.4 Leukocyte defects (백혈구 결함)

6.5 Pharmacological (약리적 염증)

6.6 Cancer (암)

6.7 HIV and AIDS (HIV 및 AIDS)

6.8 Resolution of inflammation (소염)

6.9 Connection to depression (우울증과의 관련성)

7 Systemic effects (전신 효과)

7.1 Acute-phase proteins (급성기 단백질)

7.2 Leukocyte numbers (백혈구의 수)

7.3 Systemic inflammation and obesity (전신 염증 및 비만)

7.4 Systemic inflammation and overeating (전신염증 및 과식)

8 Outcomes (결과)

9 Examples (사례)

10 Diet and inflammation (식단과 염증)

11 Exercise and inflammation (신체운동과 염증)

11.1 Exercise-induced acute inflammation (신체운동 유도성 급성 염증)

11.2 Post-inflammatory muscle growth and repair (염증형성 후 근육생장 및 수선)

11.3 Chronic inflammation and muscle loss (만성 염증과 근육상실)

11.4 Exercise as a treatment for inflammation (염증치료법으로서의 신체운동)

11.5 Signal-to-noise theory (신호대 잡음 이론)

​1-1. Physical:

● Physical injury, blunt or penetrating

● Foreign bodies, including splinters, dirt and debris

1-2. Biological:

● Immune reactions due to hypersensitivity

1-3. Chemical:

1-4. Psychological:

d. 나무나 금속 등의 조각, 먼지, 파편 등 이물질

Appendicitis, Bursitis, Colitis, ​ Cystitis, ​ Dermatitis, ​ Encephalitis, ​ Gingivitis, ​ Meningitis, ​ Myelitis

​ Nephritis, Neuritis, Periodontitis, Phlebitis, Prostatitis, RSD/CRPS, Rhinitis, Sinusitis, Tendonitis,

Testiculitis, Tonsillitis, Urethritis, Vasculitis

충수염, 활액낭염, 대장염, ​방광염, 피부염, 뇌염, 치은염, 뇌수막염, 척수염, 신장염, 신경염, 치주염, 정맥염, 전립선염, 반사교감신경이상증/복합부위통증증후군, 비염, 부비동염(副鼻洞炎), 건염, 고환염, 편도선염, 요도염, 혈관염

2-1. Cardinal signs

Acute inflammation is a short-term process, usually appearing within a few minutes or hours and begins to cease upon the removal of the injurious stimulus. It involves a coordinated and systemic mobilization response locally of various immune, endocrine and neurological mediators of acute inflammation. In a normal healthy response, it becomes activated, clears the pathogen and begins a repair process and then ceases. It is characterized by five cardinal signs:

An acronym that may be used to remember the key symptoms is "PRISH", for pain, redness, immobility (loss of function), swelling and heat.

급성 염증은 단기적인 과정으로, 보통 수 분 또는 수 시간 내에 나타나며 손상을 유발하는 자극이 제거되면 중단되기 시작한다. 이 경우 급성염증의 다양한 면역 매개체, 내분비 및 신경 매개체의 협동적 전신 동원반응이 국소적으로 수반된다. 정상적이고 건강한 반응의 경우 염증은 활성화되고 병원균을 제거하며 복원과정을 시작한 후 중단된다. 이 염증은 5 가지 발적 증후가 특징이다.

" PRISH "는 핵심 증상을 기억하기 위해 사용하기도 하는 ​두문자어로서 통증( pain ), 발적( redness ), 기능상실( immobility ), 종창( swelling ) 및 발열( heat )을 말한다.

The traditional names for signs of inflammation come from Latin:

● Functio laesa (loss of function)

이 전통적인 염증 증후의 명칭은 라틴어에서 온 것이다.

​ The first four (classical signs) were described by Celsus (ca. 30 BC – 38 AD), while loss of function was probably added later by Galen. However, the addition of this fifth sign has also been ascribed to Thomas Sydenham and Virchow.

​ Redness and heat are due to increased blood flow at body core temperature to the inflamed site swelling is caused by accumulation of fluid pain is due to the release of chemicals such as bradykinin and histamine that stimulate nerve endings. Loss of function has multiple causes.

​ Acute inflammation of the lung (usually caused in response to pneumonia) does not cause pain unless the inflammation involves the parietal pleura, which does have pain-sensitive nerve endings.

​앞의 4 가지(고전적 증후)는 켈수스( Celsus, 약 30 BC

38 AD )에 의해 기술되었으며 기능상실은 갈렌( Galen )에 의해 추가된 것으로 보인다. 그러나 이 5 번째 증후는 토머스 시든햄( Thomas Sydenham ) 및 비르초우( Virchow )가 추가한 것이기도 하다.

발적(發赤) 및 발열은 신체 심부온도에서 혈액흐름이 증가하여 염증 부위로 흐르기 때문에 발생한다 종창은 체액이 축적됨으로써 유발된다 통증은 신경말단을 자극하는 브래디키닌( bradykinin ) 및 히스타민( histamine )과 같은 화학물질이 방출된 때문이다.​ 기능상실의 원인은 매우 많다.

폐의 급성 염증(일반적으로 폐렴에 대한 반응으로 발생한다)은 그 염증이 흉막(胸膜, parietal pleura )과 관련이 없으면 통증을 유발하지 않는다 흉막에는 통증에 민감한 신경말단이 있다.

​ ​ 2-2. Process of acute inflammation

The process of acute inflammation is initiated by resident immune cells already present in the involved tissue, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells and mast cells. These cells possess surface receptors known as pattern recognition receptors (PRRs), which recognize (i.e., bind) two subclasses of molecules: pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs are compounds that are associated with various pathogens, but which are distinguishable from host molecules. DAMPs are compounds that are associated with host-related injury and cell damage.

급성 염증의 과정은 관련 조직 에 이미 존재하는 상주 면역세포, 주로 상주하고 있는 대식세포(大食細胞, macrophages ), 수지상(樹枝狀) 세포( dendritic cells ), 조직구(組織球, histiocytes ), 쿠퍼세포( Kupffer cells ) 및 비만세포에 의해 시작된다. 이러한 세포는 패 턴인식수용체( pattern recognition receptors, PRRs )라고 하는 표면 수용체를 가지고 있는데 이 수용체는 두 개의 아종 분자 - 병원체 관련 분자형( pathogen-associated molecular patterns, PAMPs ) 및 손상 관련 분자형( damage-associated molecular patterns, DAMPs ) - 를 인식한다(즉, 이에 결합한다). PAMP 는 다양한 병원체와 관련이 있지만 숙주 분자와는 구별되는 화합물이다. DAMP 는 숙주관련 손상 및 세포손상 관련 화합물이다.

At the onset of an infection, burn, or other injuries, these cells undergo activation (one of the PRRs recognize a PAMP or DAMP) and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes the redness (rubor) and increased heat (calor). Increased permeability of the blood vessels results in an exudation (leakage) of plasma proteins and fluid into the tissue (edema), which manifests itself as swelling (tumor). Some of the released mediators such as bradykinin increase the sensitivity to pain (hyperalgesia, dolor). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly neutrophils and macrophages, outside of the blood vessels (extravasation) into the tissue. The neutrophils migrate along a chemotactic gradient created by the local cells to reach the site of injury. The loss of function (functio laesa) is probably the result of a neurological reflex in response to pain.

감염, 화상 또는 다른 손상 이 시작될 때 이러한 세포들은 활성화되며( PRR 중 하나가 PAMP 나 DAMP 를 인식한다) 염증의 임상적 증후를 일으키는 염증 매개체를 방출한다. 혈관이 확장되고 그 결과 혈류량이 증가하면 발적 및 체온상승이 유발된다. 혈관의 투과성이 증가하면 혈장 단백질 및 체액이 삼출 (누출)되어 조직 속으로 들어가는데(부종) 이것이 종창으로 나타난다. 브래디키닌( bradykinin )과 같은 방출된 매개체 중 일부는 통증민감성을 증가시킨다(통각과민증). 매개체의 분자는 또한 혈관을 변화시킴으로써 중성구 및 대식세포와 같은 백혈구가 혈관 밖에서 조직 내로 이동할 수 있게 해 준다(혈관외 유출) . 이 중 성구( 中性球 )는 손 상부위에 도착한 국소 세포에 의해 형성된 주화구배( 走化句配, chemotactic gradient )를 따라 이동한다. 기능 상실은 통증에 대한 반응시 일어나는 신경 반사의 결과로 보인다.

In addition to cell-derived mediators, several acellular biochemical cascade systems consisting of preformed plasma proteins act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria and the coagulation and fibrinolysis systems activated by necrosis, e.g. a burn or a trauma.

​ Acute inflammation may be regarded as the first line of defense against injury. Acute inflammatory response requires constant stimulation to be sustained. Inflammatory mediators are short-lived and are quickly degraded in the tissue. Hence, acute inflammation begins to cease once the stimulus has been removed.

세포에서 유도된 매개체 외에 전형성 혈장 단백질로 구성되어 있는 몇 가지 비세포성 생화학적 연쇄반응계도​ 동시에 작용하여 염증반응을 시작하고 전파한다. 이에는 세균에 의해 활성화되는 보체 시스템과 괴사, 예컨대 화상이나 외상에 의해 활성화되는 응고 및 섬유소용해 시스템이 있다.

급성 염증은 손상에 대한 제 1 선 방어체계로 간주할 수 있다. 급성 염증 반응을 위해서는 일정한 자극이 지속되어야 한다. 염증 매개체는 수명이 짧으며 조직 속에서 빠르게 분해된다. 그러므로 자극이 제거되면 급성 염증반응은 멈추기 시작한다.​

3. Vascular component

3-1. Vasodilation and increased permeability

As defined, acute inflammation is an immunovascular response to an inflammatory stimulus. This means acute inflammation can be broadly divided into a vascular phase that occurs first, followed by a cellular phase involving immune cells (more specifically myeloid granulocytes in the acute setting). The vascular component of acute inflammation involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins (antibodies), into inflamed tissue.

3-1. 혈관확장 및 투과성 증대

정의한 바와 같이 급성 염증반응은 염증 자극에 대한 면역혈관 반응( immunovascular response )이다. 이는 급성 염증이 크게 보아 일차적으로 발생하는 혈관 단계( vascular phase )와 그 이후 뒤따르는 면역세포가 관여하는(더 특수하게는 급성 환경의 미엘린 과립구) 세포단계( cellular phase )로 구분됨을 의미한다. 혈관의 급성 염증시에는 섬유소( fibrin ) 및 면역글로불린(항체)과 같은 중요한 단백질을 포함하고 있는 혈장액( plasma fluid )이 염증발생 조직 내로 이동한다.

​ Upon contact with PAMPs, tissue macrophages and mastocytes release vasoactive amines such as histamine and serotonin, as well as eicosanoids such as prostaglandin E2 and leukotriene B4 to remodel the local vasculature. Macrophages and endothelial cells release nitric oxide. These mediators vasodilate and permeabilize the blood vessels, which results in the net distribution of blood plasma from the vessel into the tissue space. The increased collection of fluid into the tissue causes it to swell (edema). This exuded tissue fluid contain various antimicrobial mediators from the plasma such as complement, lysozyme, antibodies, which can immediately deal damage to microbes, and opsonise the microbes in preparation for the cellular phase. If the inflammatory stimulus is a lacerating wound, exuded platelets, coagulants, plasmin and kinins can clot the wounded area and provide haemostasis in the first instance. These clotting mediators also provide a structural staging framework at the inflammatory tissue site in the form of a fibrin lattice – as would construction scaffolding at a construction site – for the purpose of aiding phagocytic debridement and wound repair later on. Some of the exuded tissue fluid is also funnelled by lymphatics to the regional lymph nodes, flushing bacteria along to start the recognition and attack phase of the adaptive immune system.

대식세포와 비만세포(肥滿細胞, mastocytes )는 ​PAMP 와 접촉하게 되면 프로스타글란딘 E2 ( prostaglandin E2 ) 및 류코트리엔 B4 ( leukotriene B4 ) 같은 에이코사노이드( eicosanoids ) 외에 히스타민( histamine ) 및 세로토닌( serotonin )과 같은 혈관을 확장시키는 아민( amine )도 방출함으로써 국소 혈관계를 재조직한다. 대식세포와 상피세포는 산화질소를 방출한다. 이러한 매개체들은 혈관을 확장시키고 투과성을 유발하는데 그 결과 혈관으로부터 조직의 공간 속으로 혈장이 순(純)배분되게 된다. 체액이 조직 내로 들어가 모인 것이 축적되면 조직은 부풀어오른다(부종). 이렇게 삼출(渗出)된 조직의 체액에는 보 체( 補體, complement ), 리소자임( lysozyme ), 항체 와 같은 혈장의 다양한 항균 매개체가 포함되어 있는데, 이러한 매개체는 즉시 처리되어 세균에 손상을 가하며 세포 단계를 준비하면서 세균을 옵소닌화( opsonise )한다. 염증 자극이 열상(裂傷)이라면 삼출(渗出)된 혈소판, 응고제, 플라스 민( plasmin ) 및 키닌( kinin )이 상처부위를 응고시켜 우선적으로 지혈을 할 수 있다. 이러한 응고 매개체는 또한 식세포의 괴사조직 제거를 돕고 이후 상처를 복구하기 위해 - 공사장에서 공사용 비계를 만드는 것처럼 - 염증조직 부위에서 섬유소 격자( fibrin lattice )의 형태로 조직을 구성하는 틀도 제공한다. 삼출된 조직 체액의 일부는 또한 좁다란 림프관을 통과하 여 국소 림프절로 가면서 박테리아를 씻어냄으로써 적응면역계의 인식 및 공격단계를 개시한다 .

​ Acute inflammation is characterized by marked vascular changes, including vasodilation, increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation. Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood – a condition characterized by enlarged vessels packed with cells. Stasis allows leukocytes to marginate (move) along the endothelium, a process critical to their recruitment into the tissues. Normal flowing blood prevents this, as the shearing force along the periphery of the vessels moves cells in the blood into the middle of the vessel.

급성 염증 시에는 혈관확장, 투과성 증가 및 혈류량 증가 등 혈관의 뚜렷한 변화가 특징적으로 나타나는데 이러한 변화는 다양한 염증 매개체에 의해 유도된다. 혈관확장은 소동맥에서 일어나 모세혈관으로 진행되며 혈액량의 순증(純增)을 유발하고 염증의 발적(發赤) 및 발열을 일으킨다. 혈관의 투과성이 증가하면 혈장이 조직으로 이동하게 되며 그 결과 혈액 내 세포의 농도 증가로 인해 혈행(血行)이 정지되는데, 이 경우 혈관이 세포로 채워져 확대되는 것이 특징이다. 혈행이 정지( stasis )되면 백혈구는 내피세포를 따라 변연추향(邊緣趨向)할 수 있게 되는데, 이는 백혈구를 조직으로 소집하는 데 있어 극히 중요한 과정이다. 정상적인 혈행시에는 이러한 일이 일어나지 않게 되는데, 그 이유는 혈관의 가장자리를 따라 존재하는 전단력(剪斷力, shearing force )으로 인해 혈액 내의 세포가 혈관의 가운데로 이동하기 때문이다.

3-2. Plasma cascade systems

● The complement system, when activated, creates a cascade of chemical reactions that promotes opsonization, chemotaxis, and agglutination, and produces the MAC.

● The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.

● The coagulation system or clotting cascade, which forms a protective protein mesh over sites of injury.

● The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.

3-2. 혈장 다단계 시스템

● 보체 시 스템( complement system ). 활성화되면 옵소닌화, 주화성 및 응집반응, MAC 을 생산하는 다단계 화학반응을 유발한다.

● 키닌 시스템( kinin system ). 혈관확장을 유지할 수 있는 단백질 및 다른 물리적 염증 효과를 유발한다.

● 응고 시스템( coagulation system ), 또는 응괴 연쇄반응( clotting cascade ). 손상된 부위에 보호 단백질망를 형성한다.

● 섬유소분해 시스템( fibrinolysis system ). 응고시스템과는 반대로 작용하 여 응고를 중화시키고 몇 가지 다른 염증 매개체를 발생시킨다.​

3-3. Plasma-derived mediators

A vasoactive protein that is able to induce vasodilation, increase vascular permeability, cause smooth muscle contraction, and induce pain.

Cleaves to produce C3a and C3b. C3a stimulates histamine release by mast cells, thereby producing vasodilation. C3b is able to bind to bacterial cell walls and act as an opsonin, which marks the invader as a target for phagocytosis.

Stimulates histamine release by mast cells, thereby producing vasodilation. It is also able to act as a chemoattractant to direct cells via chemotaxis to the site of inflammation.

Factor XII (Hageman Factor)

A protein that circulates inactively, until activated by collagen, platelets, or exposed basement membranes via conformational change. When activated, it in turn is able to activate three plasma systems involved in inflammation: the kinin system, fibrinolysis system, and coagulation system.

A complex of the complement proteins C5b, C6, C7, C8, and multiple units of C9. The combination and activation of this range of complement proteins forms the membrane attack complex, which is able to insert into bacterial cell walls and causes cell lysis with ensuing bacterial death.

Able to break down fibrin clots, cleave complement protein C3, and activate Factor XII.

Cleaves the soluble plasma protein fibrinogen to produce insoluble fibrin, which aggregates to form a blood clot. Thrombin can also bind to cells via the PAR1 receptor to trigger several other inflammatory responses, such as production of chemokines and nitric oxide.

혈관확장을 유도할 수 있는 혈관작용단백질로서, 혈관의 투과성을 증가시키고 평활근의 수축 및 통증을 유발한다.

쪼개져 C3a 및 C3b 를 만들어낸다. C3a 는 비만세포를 통해 히스타민 방출을 자극하고, 이에 따라 혈관이 확장된다. C3b 는 박테리아의 세포벽에 결합할 수 있으며 옵소닌( opsonin )으로도 작용할 수있는데, 이것이 침입자를 식세포작용을 위한 표적으로 표지한다.

비만세포를 통해 히스타민 방출을 자극하고 , 이에 따라 혈관이 확장된다 . 이는 화학유인물질로 기능하여 주화성(走化性)을 통해 염증형성부위로 세포의 방향을 결정할 수 있다.

콜라겐, 혈소판에 의해 활성화되거나 구조변화에 따른 기저막 노출로 활성화될 때까지 비활성상태로 순환하는 단백질이다. 활성화되면 이는 다시 염증형성에 관여하는 3 개의 원형질시스템 ( 키닌시스템, 섬유소분해시스템, 응고시스템) 을 활성화시킬 수 있다.

보체단백질 복합체 및 복합단위체 C5b, C6, C7, C8 의 복합체 및 C9의 복합단위체. 이 범위의 성분 단백질이 결합하여 활성화되면 막공격 복합체( membrane attack complex )가 형성되는데, 이는 박테리아의 세포벽으로 삽입되어 세포용 혈 ( cell lysis ) 을 일으킴으로써 박테리아를 사망에 이르게 할 수 있다.

섬유소 응괴(凝塊)를 분해할 수 있고, 보체단백질 C3을 쪼갤 수 있으며 인자 XII 를 활성화시킬 수 있다.

수용성 혈장 단백질 피브리노 겐( fibrinogen )을 쪼 개어 불용성 섬유소를 만들어내는데, 이 섬유소는 응고되어 혈전을 형성한다. 트롬빈은 케모카인과 산화질소의 생산과 같은, 몇 가지 다른 염증반응을 촉발하는 질산 PAR1 수용체를 통해 세포와 결합할 수도 있다.

4. Cellular component

The cellular component involves leukocytes, which normally reside in blood and must move into the inflamed tissue via extravasation to aid in inflammation. Some act as phagocytes, ingesting bacteria, viruses, and cellular debris. Others release enzymatic granules that damage pathogenic invaders. Leukocytes also release inflammatory mediators that develop and maintain the inflammatory response. In general, acute inflammation is mediated by granulocytes, whereas chronic inflammation is mediated by mononuclear cells such as monocytes and lymphocytes.

세포성분은 백혈구를 포함하고 있는데, 이 백혈구는 일반적으로 혈액에 존재하며 혈관외유출( extravasation )을 통해 염증이 발생한 조직으로 들어가 염증반응을 돕는다. 어떤 백혈구는 식세포로 작용하여 박테리아, 바이러스 및 세포 부스러기를 섭취하며 어떤 것은 효소 과립을 방출하여 병을 일으키는 침입자에게 손상을 입힌다. 백혈구는 또한 염증형성 매개체도 방출하여 염증반응을 유발하고 이를 유지한다. 일반적으로 급성염증은 과립구에 의해 매개되지만 만성 염증은 단핵구 및 림프구와 같은 단핵세포 에 의해 매개된다.

4-1. Leukocyte extravasation

Various leukocytes, particularly neutrophils, are critically involved in the initiation and maintenance of inflammation. These cells must be able to move to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasation, and can be broadly divided up into a number of steps:

1.Leukocyte margination and endothelial adhesion: The white blood cells within the vessels which are generally centrally located move peripherally towards the walls of the vessels. Activated macrophages in the tissue release cytokines such as IL-1 and TNF α , which in turn leads to producti on of chemokines that bind to proteoglycans forming gradient in the inflamed tissue and along the endothelial wall . Inflammatory cytokines induce the immediate expression of P-selectin on endothelial cell surfaces and P-selectin binds weakly to carbohydrate ligands on the surface of leukocytes and causes them to "roll" along the endothelial surface as bonds are made and broken. Cytokines released from injured cells induce the expression of E-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of integrin ligands such as ICAM-1 and VCAM-1 on endothelial cells, which mediate the adhesion and further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue after signal transduction via respective G protein-coupled receptors that activates integrins on the leukocyte surface for firm adhesion. Such activation increases the affinity of bound integrin receptors for ICAM-1 and VCAM-1 on the endothelial cell surface, firmly binding the leukocytes to the endothelium.

​4-1. 백혈구의 혈관외 유출

다양한 백혈구, 특히 중성구는 염증반응의 개시 및 유지에 결정적으로 관여한다. 이 세포는 혈액 내에 통상 존재하고 있는 장소에서 손상 부위로 이동할 수 있어야 하므로 백혈구를 적절한 장소로 소집하고 이끄는 여러 메커니즘이 존재한다. 백혈구가 혈관을 통해 혈액으로부터 조직으로 이동하는 과정은 혈관외유출( extravasation )이라고 알려져 있으며 수많은 단계로 대별할 수 있다.

1. 백혈구 ​변연추향(邊緣趨向)( leukocyte margination ) 및 내피 부착 : 일반적으로 혈관의 중앙부에 모여 있는 백혈구는 혈관벽을 향해 주변부로 이동한다. 이 조직의 활성화된 대식세포는 IL-1 및 TNF α 와 같은 시토카인( cytokines )을 방출하는데, 이들은 케모카인( chemokines )의 생산을 유발하고 이 케모카인은 프로테오글리칸( proteoglycans )에 결합하여 염증이 발생한 조직에, 그리고 내피의 벽을 따라, 구배를 형성하는 프로테오글리칸에 결합한다. 염증성 시토카인은 즉각적으로 P- 셀렉틴( P-selectin )을 내피세포 표면에 발현시키며, P- 셀렉틴은 백혈구의 표면에서 탄수화물 리간드와 약하게 결합하여, 결합이 형성되고 끊어질 때 이 리간드들이 내피의 표면을 따라 "굴러가도록" 한다. 손상된 세포로부터 방출된 시토카인은 내피세포 위에서 E- 셀렉틴 ( E -selectin ) 의 발현을 유도하는데, 이 E- 셀렉틴은 P- 셀렉틴과 기능이 유사하다. 시토카인은 내피세포 위에서 ICAM-1 및 VCAM-1 와 같은 인테그린 리간드( integrin ligands )의 발현도 유도하는데, 이 리간드는 부착을 매개하며 나아가 백혈구의 속도를 늦춘다. 이처럼 약하게 결합된 백혈구는 백혈구의 표면에서 인테그린( integrin )을 활성화시키는 각각의 G 단백질 결합 수용체( G protein-coupled receptors )를 통해 신호변환된 후 손상된 조직에서 생산되는 케모카인에 의해 활성화되어 강하게 부착되지 않으면 자유롭게 떨어져 나간다. 이런 활성화가 일어나면 내피세포 표면에 있는, 결합되어 있는 ICAM-1 및 VCAM-1 인테그린 수용체의 친화력이 증가하고 백혈구는 내피에 강하게 결합된다.

​ 2. Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between adjacent endothelial cells. The endothelial cells retract and the leukocytes pass through the basement membrane into the surrounding tissue using adhesion molecules such as ICAM-1.

​ 3.Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrix proteins via expressed integrins and CD44 to prevent them from leaving the site. A variety of molecules behave as chemoattractants, for example, C3a or C5, and cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.

2. 혈구누출( diapedesis ) 과정을 통한 내피횡단 이동(이행이라고 한다) : 부착된 백혈구는 케모카인 구배에 자극을 받아 인접한 내피세포 사이로 이동한다. 이 내피세포는 수축되고 백혈구는 ICAM-1 과 같은 부착분자를 이용, 기저막을 통과하여 주변 조직으로 들어간다. ​

3. 주화성(走化性, chemotaxis )을 이용한 조직내에서의 백혈구 이동 : 조직의 간질(間質, interstitium )에 도착하는 백혈구는 ​발현된 인테그린( integrin ) 및 CD44 를 통해 세포외 기질 단백질에 결합하여 단백질이 그 부위에서 떠나지 못하도록 한다. 다양한 분자는 C3a 나 C5 와 같은 다양한 화학 유인물질로 작용하며 백혈구가 염증원(炎症源)을 향해 주화구배(走化勾配, chemotactic gradient )를 따라 이동하도록 한다.

​4-2. Phagocytosis

Extravasated neutrophils in the cellular phase come into contact with microbes at the inflamed tissue. Phagocytes express cell-surface endocytic pattern recognition receptors (PRRs) that have affinity and efficacy against non-specific microbe-associated molecular patterns (PAMPs). Most PAMPs that bind to endocytic PRRs and initiate phagocytosis are cell wall components, including complex carbohydrates such as mannans and β -glucans, lipopolysaccharides (LPS), peptidoglycans, and surface proteins. Endocytic PRRs on phagocytes reflect these molecular patterns, with C-type lectin receptors binding to mannans and β -glucans, and scavenger receptors binding to LPS.

세포단계에서 세포 밖으로 유출된 중성구는 ​염증이 일어난 조직에서 세균과 접촉하게 된다. 식세포는 친화력 및 비특이적 병원체관련 분자형(( pathogen-associated molecular patterns, PAMPs )에 대항하는 효능이 있는 세포표면의 식균성 패턴인식 수용체( pattern recognition receptors, PRRs )를 발현시킨다. 식균성 PRR 에 결합하여 식세포작용을 개시하는 PAMP 는 대부분 세포벽 성분으로서, 이에는 만난( mannans ) 및 베타글루칸( β -glucans ), 지질다당류( lipopolysaccharides, LPS ), 펩티도글리칸( peptidoglycans ) 및 표면 단백질과 같은 복합 탄수화물이 있다. 식세포 위에 있는 식균성 PRR 은 이러한 분자 패턴을 반영하고 있으며 C 형 렉틴 수용체는 만난 및 베타 글루칸과 결합하고 스캐빈저 수용체( scavenger receptors )는 LPS 과 결합한다.

​ Upon endocytic PRR binding, actin-myosin cytoskeletal rearrangement adjacent to the plasma membrane occurs in a way that endocytoses the plasma membrane containing the PRR-PAMP complex, and the microbe. Phosphatidylinositol and Vps34-Vps15-Beclin1 signalling pathways have been implicated to traffic the endocytosed phagosome to intracellular lysosomes, where fusion of the phagosome and the lysosome produces a phagolysosome. The reactive oxygen species, superoxides and hypochlorite bleach within the phagolysosomes then kill microbes inside the phagocyte.

​ Phagocytic efficacy can be enhanced by opsonization. Plasma derived complement C3b and antibodies that exude into the inflamed tissue during the vascular phase bind to and coat the microbial antigens. As well as endocytic PRRs, phagocytes also express opsonin receptors Fc receptor and complement receptor 1 (CR1), which bind to antibodies and C3b, respectively. The co-stimulation of endocytic PRR and opsonin receptor increases the efficacy of the phagocytic process, enhancing the lysosomal elimination of the infective agent.

식균성 PRR 결합시에는 PRR-PAMP 복합체 및 세균을 포함하여 원형질막을 흡수하는 방식으로 원형질막 인접부위에 액틴-미오신 세포골격 재배열( actin-myosin cytoskeletal rearrangement )이 일어난다. ​ 포스파티딜이노시톨( p hosphatidylinositol ) 및 Vps34-Vps15-Beclin1 신호전달 경로는 흡수된 파고솜( phagosome )을 세포내 리소솜( lysosome )으로 운반하는 일에 관여하는데, 파고솜과 리소솜은 융합되어 파고리소솜( phagolysosome )을 만든다. 반응성 산소종인 초과산 화물( superoxides ) 및 차아염소산염( hypochlorite )은 파고리소솜 안에서 표백된 후 식세포 안에서 세균을 죽인다.

식세포의 효능은 옵소닌화( opsonization )를 통해 향상될 수 있다. 혈관단계에서 혈장에서 유도된 보체 C3b 및 항체는 염증발생 조직 안으로 삼출되고 세균성 항원에 결합하여 외피를 입힌다. 식균성 PRR 뿐만 아니라 식세포도 옵소닌 수용체인 Fc 수용체 및 보체수용체 1(CR1) 을 발현시키는데, 이 수용체들은 각각 항체 및 C3b 와 결합한다. 식균성 PRR 및 옵소닌 수용체의 공동 자극이 있으면 식세포작용의 효능 및 리소솜의 감염체 제거가 증가한다.

4-3. Cell-derived mediators

These cells contain a large variety of enzymes that perform a

number of functions. Granules can be classified as either

specific or azurophilic depending upon the contents, and are

able to break down a number of substances, some of which

may be plasma-derived proteins that allow these enzymes to

act as inflammatory mediators.

Stored in preformed granules, histamine is released in response to a number of stimuli. It causes arteriole dilation, increased

venous permeability, and a wide variety of organ-specific effects.

Antiviral, immunoregulatory, and anti-tumour properties. This

interferon was originally called macrophage-activating factor,

and is especially important in the maintenance of chronic inflammation.

Activation and chemoattraction of neutrophils, with a weak

effect on monocytes and eosinophils.

Able to mediate leukocyte adhesion and activation, allowing

them to bind to the endothelium and migrate across it. In

neutrophils, it is also a potent chemoattractant, and is able to

induce the formation of reactive oxygen species and the release of lysosomal enzymes by these cells.

These three Cysteine-containing leukotrienes contract lung

airways, increase micro-vascular permeability, stimulate mucus secretion, and promote eosinophil-based inflammation in the

lung, skin, nose, eye, and other tissues.

Potent stimulator of neutrophil chemotaxis, lysosome enzyme

release, and reactive oxygen species formation monocyte

chemotaxis and with even greater potency eosinophil chemotaxis, lysosome enzyme release, and reactive oxygen species formation.

Metabolic precursor to 5-Oxo-eicosatetraenoic acid, it is a less potent stimulator of neutrophil chemotaxis, lysosome enzyme

release, and reactive oxygen species formation monocyte

chemotaxis and eosinophil chemotaxis, lysosome enzyme

release, and reactive oxygen species formation.

A group of lipids that can cause vasodilation, fever, and pain.

endothelial cell s , some neurons

Potent vasodilator, relaxes smooth muscle, reduces platelet

aggregation, aids in leukocyte recruitment, direct antimicrobial

activity in high concentrations.

Both affect a wide variety of cells to induce many similar inflammatory reactions: fever, production of cytokines, endothelial

gene regulation, chemotaxis, leukocyte adherence, activation of fibroblasts. Responsible for the systemic effects of inflammation, such as loss of appetite and increased heart rate. TNF- α inhibits osteoblast differentiation.

This serine protease is believed to be exclusively stored in mast cells and secreted, along with histamine, during mast cell activation.

이 세포는 수많은 기능을 수행하는 매우 다양한 효소를 포함하고 있다. 과립은 그 내용물에 따라 특이적 과립 또는 아주르친화성 과립으로 분류할 수 있으며 많은 물질을 분해할 수 있는데, 그 물질 중 일부는 이 효소가 염증반응 매개체로서 기능할 수 있도록 해 주는 원형질 유도성 단백질일 수 있다.

전(前)형성 과립에 저장되어 있는 히스타민은 많은 자극에 대한 반응으로 방출된다. 이는 세동맥확장, 정맥의 투과성 증가, 매우 다양한 기관특이적(organ-specific) 염증을 일으킨다.

항바이러스, 면역조절 및 항종양 성질을 가짐. 이 인터페론은 처음에는 대식세포 활성화 인자라고 불렀으며 특히 만성 염증형성의 유지에 중요하다.

백혈구 부착 및 활성화를 매개할 수 있으며 , 이들이 내피에 결합하여 이를 가로질러 이동할 수 있도록 한다. 중성구의 경우 이것은 강력한 화학유도물질이기도 하며 반응성산소종을 형성시킬 수 있고 이 세포들에 의한 리소솜 효소를 방출시킬 수 있다.

시스테인을 함유하고 있는 이 3가지 류코트리엔은 폐기도를 감염시켜 미세혈관 투과성을 증가시키고 점액분비를 자극하며 폐, 피부, 코, 눈 및 기타 조직에서 호산구 기반 염증형성을 촉진한다.

중성구 주화성, 리소솜 효소방출 및 활성산소종 형성의 강력한 자극제 단핵구 주화성 훨씬 더 강력한 호산구 주화성, 리소솜 효소 방출, 반응성산소종의 형성

5-옥소-에이코사테트라엔산의 대사 전구체로서 호중구 주화성, 리소솜 효소방출 및 반응성산소종 형성의 덜 강력한 자극제 단핵구 주화성 호산구 주화성, 리소솜 효소방출 및 반응성산소종 형성

혈관확장, 발열 및 통증을 유발할 수 있는 지질 그룹

강력한 혈관확장제로서 평활근을 완화시키고 혈소판 응고를 감소시켜 백혈구 소집을 돕고 고농도 시에는 항균활동의 방향을 설정한다.

두 가지 모두 많은 유사염증반응(발열, 시토카인 생산, 내피 유전자 조절, 주화성, 백혈구 부착, 섬유아세포 활성화)을 유도하는 매우 다양한 세포에 영향을 미친다.

식욕상실 및 심방동속도 증가와 같은 염증의 전신 효과를 담당한다. 종양괴사인자-알파는 조골세포 분화를 억제한다.

이 세린단백질가수분해효소는 단독적으로 비만세포에 저장되어 비만세포가 활성화되는 동안 히스타민과 함께 분비되는 것으로 생각된다.

5. Morphologic patterns

​ Specific patterns of acute and chronic inflammation are seen during particular situations that arise in the body, such as when inflammation occurs on an epithelial surface, or pyogenic bacteria are involved.

● Granulomatous inflammation: Characterised by the formation of granulomas, they are the result of a limited but diverse number of diseases, which include among others tuberculosis, leprosy, sarcoidosis, and syphilis.

● Fibrinous inflammation: Inflammation resulting in a large increase in vascular permeability allows fibrin to pass through the blood vessels. If an appropriate procoagulative stimulus is present, such as cancer cells, a fibrinous exudate is deposited. This is commonly seen in serous cavities, where the conversion of fibrinous exudate into a scar can occur between serous membranes, limiting their function. The deposit sometimes forms a pseudomembrane sheet. During inflammation of the intestine (Pseudomembranous colitis), pseudomembranous tubes can be formed.

특수한 패턴의 급성 및 만성 염증 은 ​염증이 상피 표면에서 일어난다거나 화농균이 관여하고 있는 경우와 같이 체내에서 특수한 상황이 발생하는 동안 볼 수 있다.

● 육아종성 염증 : 이 염증의 특징은 육아종(肉芽腫, granuloma )이 형성된다는 점으로, 이 육아종은 숫적으로 제한적이지만 다양한 질병, 특히 결핵, 한센병, 사르코이드증( sarcoidosis ), 매독과 같은 질병 으로 인해 발생한다.

​ ​ ● 섬유소성 염증 : 염증으로 인해 혈관의 투과도가 크게 증가하면 섬유소는 혈관을 통과할 수 있게 된다. 만약 암세포와 같은 적절한 응고촉진 자극이 존재하면 섬유성 삼출물이 침착된다. 이는 대체로 장막강( 漿膜腔, serous cavities )에서 볼 수 있는데, 이때 섬유성 삼출물은 장막( 漿膜) 사이 에서 반흔(斑痕)으로 전환되고 이로 인해 기능이 제한 된다. 이 침착물은 때로 가성막(假性膜, pseudomembrane sheet )을 형성한다. 장에 염증이 생기면(가막성 대장염, Pseudomembranous colitis ) 가막성관( 假膜性管, pseudomembranous tubes )이 형성될 수 있다.

● Purulent inflammation: Inflammation resulting in large amount of pus, which consists of neutrophils, dead cells, and fluid. Infection by pyogenic bacteria such as staphylococci is characteristic of this kind of inflammation. Large, localised collections of pus enclosed by surrounding tissues are called abscesses.

● Serous inflammation: Characterised by the copious effusion of non-viscous serous fluid, commonly produced by mesothelial cells of serous membranes, but may be derived from blood plasma. Skin blisters exemplify this pattern of inflammation.

​ ● Ulcerative inflammation: Inflammation occurring near an epithelium can result in the necrotic loss of tissue from the surface, exposing lower layers. The subsequent excavation in the epithelium is known as an ulcer.

​ ​ ● 화농성 염증 : 많은 양의 화농(化濃)을 유발하는 염증으로서 화농은 중성구, 죽은 세포 및 체액으로 구성되어 있다. 포도상구균과 같은 화농균은 이러한 종류의 염증에 특징적으로 나타난다. 주변조직에 갇혀 있는 다량의 국소 화농을 농양( 膿瘍, abscess es )이라고 한다.

● 장액성 염증 : ​비점성(非粘性) 장액의 방대한 유출이 특징적으로 나타나며, 일반적으로 장막의 중피세포( mesothelial cells )에 의해 유발되지만 혈장으로부터 유래하기도 한다. 피부의 수포는 이러한 염증의 사례이다.

● 궤양성 염증 : 내피 근처에 염증이 발생하면 조직은 표면부터 괴사적(壞死的)으로 상실되어 저층부가 노출될 수 있다. 이후 상피에 생긴 강와(腔窩, excavation )를 궤양이라고 한다.

6. Inflammatory disorders

Inflammatory abnormalities are a large group of disorders that underlie a vast variety of human diseases. The immune system is often involved with inflammatory disorders, demonstrated in both allergic reactions and some myopathies, with many immune system disorders resulting in abnormal inflammation. Non-immune diseases with causal origins in inflammatory processes include cancer, atherosclerosis, and ischemic heart disease.

염증성 이상이란 매우 다양한 인간의 질병 기저에 있는 대규모 장애집단이다. 면역계는 종종 염증성 질환과 관련이 있는데, 알러지 반응 및 일부 근위축증( myopathies )에서 보듯 많은 면역계 질환은 비정상적 염증을 유발한다. 염증형성 과정 때문에 일어나는 비면역성 질환으로는 암, 죽상동맥경화증 및 허혈성 심장질환이 있다.

​ Examples of disorders associated with inflammation include:

● Inflammatory bowel diseases

● Mast Cell Activation Syndrome

● Pelvic inflammatory disease

염증과 관련되어 있는 질환으로는 다음과 같은 것이 있다.

6-1. Atherosclerosis

Atherosclerosis, formerly considered a bland lipid storage disease, actually involves an ongoing inflammatory response. Recent advances in basic science have established a fundamental role for inflammation in mediating all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis. These new findings provide important links between risk factors and the mechanisms of atherogenesis. Clinical studies have shown that this emerging biology of inflammation in atherosclerosis applies directly to human patients. Elevation in markers of inflammation predicts outcomes of patients with acute coronary syndromes, independently of myocardial damage. In addition, low-grade chronic inflammation, as indicated by levels of the inflammatory marker C-reactive protein, prospectively defines risk of atherosclerotic complications , thus adding to prognostic in formation provided by traditional risk factors. Moreover, certain treatments that reduce coronary risk also limit inflammation. In the case of lipid lowering with statins, this anti-inflammatory effect does not appear to correlate with reduction in low-density lipoprotein levels. These new insights into inflammation in atherosclerosis not only increase our understanding of this disease but also have practical clinical applications in risk stratification and targeting of therapy for this scourge of growing worldwide importance.

죽상동맥경화증( a therosclerosis ) 은 이전에는 서행성(徐行性) 지방침착질환으로 생각되었는데, 실제로는 진행 성 염증반응을 수반하고 있다. 최근 기초과학의 진보로 인해 시작 단계부터 진행단계를 거쳐 궁극적으로는 죽상동맥경화증의 혈소판 합병증에 이르기까지 이 질환의 모든 단계를 매개하는 염증의 근본적인 역할이 증명되었다. 이 새로운 발견으로 인해 죽상동맥경화증의 위험요인 및 메커니즘 사이에 중요한 관련성이 존재하는 것으로 밝혀졌다. 임상연구 결과 죽상동맥경화증에서 최근 알려지고 있는 이러한 염증형성 생리는 인간 환자에게 직접 적용되는 것으로 밝혀졌 다. 염증 표지의 상승은 심근 손상과는 별개로, 급성 관상동맥증후군 환자의 결과를 예측한다. 또한 저수준의 만성염증은, 염증 표지인 C 반응성단백질( C-reactive protein )의 수준을 통해 알 수 있는 것처럼, 장래의 죽상동맥경화증 합병증 위험을 규정하며 이렇게 전통적인 위험요인이 제공하는 예후적 정보에 추가될 수 있다. 또한 관상동맥 위험을 줄여주는 특정 치료제도 염증형성을 제한한다. 스타틴( statin )을 이용하여 지질을 저감시키는 경우 이 항염 효과와 저밀도 지단백질 농도의 감소는 상관관계가 없는 것으로 보인다. 죽상동맥경화증에서 염증에 대한 이 새로운 통찰력은 이 질환에 대한 우리의 이해를 높여 주고 있을 뿐만 아니라 위험수준 평가( risk stratification ) 및 세계적으로 중요성이 높아지고 있는 이 두통거리에 대한 치료의 표적 설정 에 실제적, 임상적으로 적용되고 있다.

6-2. ​ Allergy

An allergic reaction, formally known as type 1 hypersensitivity, is the result of an inappropriate immune response triggering inflammation, vasodilation, and nerve irritation. A common example is hay fever, which is caused by a hypersensitive response by mast cells to allergens. Pre-sensitised mast cells respond by degranulating, releasing vasoactive chemicals such as histamine. These chemicals propagate an excessive inflammatory response characterised by blood vessel dilation, production of pro-inflammatory molecules, cytokine release, and recruitment of leukocytes. Severe inflammatory response may mature into a systemic response known as anaphylaxis.

알러지 반응은 이전에는 제 1 형 과민감 성( hypersensitivity )이라고 알려져 있었는데, 이는 부적절한 면역반응 때문에 일어나는 것으로, 염증, 혈관확장 및 신경자극을 촉발한다. 흔한 사례로 건초열( hay fever )이 있는데, 이는 알러지원에 대한 비만세포의 과민반응으로 인해 유발된다. 감작(感作) 전의 비만세포는 탈과립화 (脫顆粒化)되어 히스타민과 같은 혈관 활성화 화학물질을 방출한다. 이러한 화학물질은 혈관 확장, 염증촉진 분자의 생산, 시토카인 방출 및 백혈구의 소집으로 특징되는 과도한 염증반응을 촉진한다. 심한 염증반응은 충분히 진행되면 아나필락시스( anaphylaxis )라고 하는 전신반응으로 이어질 수 있다.

6-3. Myopathies

Inflammatory myopathies are caused by the immune system inappropriately attacking components of muscle, leading to signs of muscle inflammation. They may occur in conjunction with other immune disorders, such as systemic sclerosis, and include dermatomyositis, polymyositis, and inclusion body myositis.

염증성 근위축증은 면역계가 근육의 성분을 부적절하게 공격함으로써 유발되는데, 그 결과 근육 염증 증후가 발생한다. 이 근위축증은 전신 경화증과 같은 다른 면역질환과 함께 발생할 수 있는데, 이에는 피부근염( dermatomyositis ), 다발성근염( polymyositis ), 포함체근염(包含體筋炎, inclusion body myositis )이 있다.

6-4. Leukocyte defects

Due to the central role of leukocytes in the development and propagation of inflammation, defects in leukocyte functionality often result in a decreased capacity for inflammatory defense with subsequent vulnerability to infection. Dysfunctional leukocytes may be unable to correctly bind to blood vessels due to surface receptor mutations, digest bacteria (Chédiak – Higashi syndrome), or produce microbicides (chronic granulomatous disease). In addition, diseases affecting the bone marrow may result in abnormal or few leukocytes.

백혈구의 기능성에 결함이 생기면 감염에 취약해지면서 종종 염증 방어능력이 감소하게 되는데, 이는 염증의 발생 및 전파에 있어 백혈구가 중추적인 역할을 하기 때문이 다.​ 기능이 부전된 백혈구는 표면 수용체 돌연변이로 인해 혈관에 정확히 결합할 수 없고 세균을 소화하지 못하거나(체디악-히가시 증후군) 살균물질을 생산하지 못할 수 있다(만성육아종증). 또한 골수에 영향을 미치는 질환은 백혈구 비정상이나 백혈구 부족을 유발할 수 있다.

6-5. ​ Pharmacological

Certain drugs or exogenous chemical compounds are known to affect inflammation. Vitamin A deficiency causes an increase in inflammatory responses, and anti-inflammatory drugs work specifically by inhibiting the enzymes that produce inflammatory eicosanoids. Certain illicit drugs such as cocaine and ecstasy may exert some of their detrimental effects by activating transcription factors intimately involved with inflammation (e.g. NF- κ B).

특정 약물이나 외생적 화합물은 염증에 영향을 미치는 것으로 알려져 있다. 비타민 A 가 결핍​되면 염증반응이 증가하며 항염증 약물은 특히 염증을 유발하는 에이코사노이드( eicosanoids ) 생산 효소를 억제하는 작용을 한다. 코카인과 같은 특정 불법 약물이나 엑스터시는 염증에 밀접하게 관여하고 있는 전사요소(예컨대 NF- κ B ) 를 활성화함으로써 일부 유해한 효과를 유발한다.

6-6. ​ Cancer

Inflammation orchestrates the microenvironment around tumours, contributing to proliferation, survival and migration. Cancer cells use selectins, chemokines and their receptors for invasion, migration and metastasis. On the other hand, many cells of the immune system contribute to cancer immunology, suppressing cancer. Molecular intersection between receptors of steroid hormones, which have important effects on cellular development, and transcription factors that play key roles in inflammation, such as NF- κ B, may mediate some of the most critical effects of inflammatory stimuli on cancer cells. This capacity of a mediator of inflammation to influence the effects of steroid hormones in cells, is very likely to affect carcinogenesis on the one hand on the other hand, due to the modular nature of many steroid hormone receptors, this interaction may offer ways to interfere with cancer progression, through targeting of a specific protein domain in a specific cell type. Such an approach may limit side effects that are unrelated to the tumor of interest, and may help preserve vital homeostatic functions and developmental processes in the organism.

​ According to a review of 2009, recent data suggests that cancer-related inflammation (CRI) may lead to accumulation of random genetic alterations in cancer cells.

염증은 종양 주변의 미세환경을 조직화하여 증식, 생존, 이동에 기여한다. 암세포는 셀렉틴( selectin ), 케모카인( chemokine ) 및 이들의 수용체를 이용하여 침입하고 이동하고 대사한다. 한편, 면역계의 많은 세포들은 암의 면역에 기여하고 암을 억제한다. 스테로이드 호르몬은 세포의 발생, NF- κ B 와 같이 염증형성에 핵심적인 역할을 하는 전사인자( transcription factor )에 중 요한 역할을 하는데, 이 호르몬 수용체 간의 분자교차( m olecular intersection )는 암세포에 대한 염증형성 자극 에 가장 중요한 몇 가지 효과를 매개할 수 있다. 세포 내에서 스테로이드 호르몬의 효과에 영향을 미치는 염증형성 매개체의 이러한 능력은 한편으로는 암발생에도 영향을 미칠 가능성이 매우 높다. 한편, 이러한 상호작용은 많은 스테로이드 호르몬 수용체의 단위적 특성으로 인해 특정 세포 타입의 특정 단백질 영역을 표적으로 함으로써 암의 진행을 방해하는 여러 방법을 제공할 수 있다. 그러한 접근방법은 관심의 대상인 종양과 관련이 없는 부작용을 제한할 수 있으며 유기체의 중요한 항상성 기능 및 발생 과정을 보존하는 데 도움을 줄 수 있다.

2009 년의 한 비평에 따르면 최근의 데이터는 암 관련 염증( cancer-related inflammation, CRI )이 있으면 암세포 유전자의 임의적 변형이 축적될 수 있음을 시사하고 있다.

6-7. ​ HIV and AIDS

It has long been recognized that infection with HIV is characterized not only by development of profound immunodeficiency but also by sustained inflammation and immune activation. A substantial body of evidence implicates chronic inflammation as a critical driver of immune dysfunction, premature appearance of aging-related diseases, and immune deficiency. Many now regard HIV infection not only as an evolving virus-induced immunodeficiency but also as chronic inflammatory disease. Even after the introduction of effective antiretroviral therapy (ART) and effective suppression of viremia in HIV-infected individuals, chronic inflammation persists. Animal studies also support the relationship between immune activation and progressive cellular immune deficiency: SIVsm infection of its natural nonhuman primate hosts, the sooty mangabey, causes high-level viral replication but limited evidence of disease. This lack of pathogenicity is accompanied by a lack of inflammation, immune activation and cellular proliferation. In sharp contrast, experimental SIVsm infection of rhesus macaque produces immune activation and AIDS-like disease with many parallels to human HIV infection.

​6-7. HIV 및 AIDS

​HIV 에 감염되면 심각한 면역결핍 뿐만 아니라 지속적인 염증 및 면역계 활성화가 특징적으로 나타난다. 상당량의 증거는 면역부전, 노화관련 질환 및 면역결핍이 때이르게 나타나게 하는 결정적 추동체가 만성 염증임을 암시하고 있다. 많은 사람들은 이제 HIV 감염이 진화하는 바이러스성 면역결핍 뿐만 아니라 만성 염증질환이기도 하다고 생각하고 있다. HIV 환자에게 효과적인 항레트로바이러스요법( antiretroviral therapy, ART )을 도입하고 바이러스혈증( viremia )을 효과적으로 억제한 후에도 만성 염증은 지속된다. 동물 연구 결과도 면역 활성화와 누적적 세포면역 결핍 사이의 관련성을 뒷받침하고 있다 : SIVsm 의 천연 비영장류 숙주인 검댕망가베이( sooty mangabey )가 이 바이러스( SIVsm )에 감염되면 이 바이러스는 매우 높은 수준으로 복제되지만 질병이 유발된다는 증거는 제한되어 있다. 염증, 면역계 활성화 및 세포증식의 결핍은 병원성의 결핍을 동반한다. 매우 대조적인 경우로서 실험적으로 붉은털원숭이에 SIVsm 을 실험적으로 감염시키면 면역 활성화 및 AIDS 유사 질병이 발생하는데 이는 인간 HIV 감염과 많은 점에서 동일하다.

​ Delineating how CD4 T cells are depleted and how chronic inflammation and immune activation are induced lies at the heart of understanding HIV pathogenesis –– one of the top priorities for HIV research by the Office of AIDS Research, National Institutes of Health. Recent studies demonstrated that caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death, drives CD4 T-cell depletion and inflammation by HIV. These are the two signature events that propel HIV disease progression to AIDS. Pyroptosis appears to create a pathogenic vicious cycle in which dying CD4 T cells and other immune cells (including macrophages and neutrophils) release inflammatory signals that recruit more cells into the infected lymphoid tissues to die.

The feed-forward nature of this inflammatory response produces chronic inflammation and tissue injury. Identifying pyroptosis as the predominant mechanism that causes CD4 T-cell depletion and chronic inflammation, provides novel therapeutic opportunities, namely caspase-1 which controls the pyroptotic pathway. In this regard, pyroptosis of CD4 T cells and secretion of pro-inflmammatory cytokines such as IL-1 β and IL-18 can be blocked in HIV-infected human lymphoid tissues by addition of the caspase-1 inhibitor VX-765, which has already proven to be safe and well tolerated in phase II human clinical trials. These findings could propel development of an entirely new class of “anti-AIDS” therapies that act by targeting the host rather than the virus. Such agents would almost certainly be used in combination with ART. By promoting “tolerance” of the virus instead of suppressing its replication, VX-765 or related drugs may mimic the evolutionary solutions occurring in multiple monkey hosts (e.g. the sooty mangabey) infected with species-specific lentiviruses that have led to a lack of disease, no decline in CD4 T-cell counts, and no chronic inflammation.

CD4 T 세포가 어떻게 고갈되는가, 그리고 만성 염증 및 면역 활성화가 어떻게 유발되는가를 파악하는 것은 HIV 발병을 이해하는 핵심으로서 미국 국립보건원 AIDS 연구소의 HIV 연구를 위한 최우선 사항 중 하나이다. 최근의 여러 연구는 카스파제 -1 매개 파이로토시스( pyrotopsis, ​ 죽어가는 세포가 강한 염증 반응을 나타내고 사멸하는 것) - 세포예정사의 고염증성 형태 - 가 HIV 에 의한 CD4 T 세포 고갈 및 염증반응을 유발함을 보여주었다. 이는 HIV 질환이 AIDS 로 진행되도록 하는 2 가지 특징적 사건이다. 파이로토시스는 사망하고 있는 CD4 T 세포와 다른 면역세포(대식세포 및 중성구를 포함하여)가 염증형성 신호를 발하여 감염된 림프조직으로 더 많은 세포를 소집하여 사망케 하는 발병성 악순환을 유발하는 것으로 보인다.

이러한 염증반응의 피드포워드 ( feed-forward, 예기효과 ) 특성은 만성 염증과 조직 손상을 일으킨다. 파이로토시스를 CD4 T 세포 고갈 및 만성염증 을 유발하는 주된 메커니즘으로 이해하는 것은 새로운 치료적 기회, 다시 말하면 파이로토시스 경로를 조절하는 카스파제- 1 ( caspase1 ) 을 제공한다. 이와 관련하여, HIV 에 감염된 인간의 염증형성 조직에서는 카스파제 1 억제제 VX-765 에 의해 CD4 T 세포의 파이 로토시스, 인터류킨 - 1 β ( IL-1 β ) 및 인터류킨- 18 ( IL-18 )의 분비가 차단되는데, 이 억제제는 안전하며 제 2 상 인간 임상실험에서 잘 수용되는 것으로 이미 증명된 바 있다. 이러한 연구결과로 인해 바이러스보다는 숙주를 표적으로 함으로써 작용하는 전혀 새로운 종류의 "항 AIDS " 치료법 개발을 추진할 수 있을 것이다. 그러한 약물이라면 거의 확실히 ART 와 함께 사용할 수 있을 것이다. VX-765 나 그 관련 약물은 바이러스의 복제를 억제하는 것이 아니라 바이러스에 대한 "내성( tolerance )"을 향상시킴으로써 질병, CD4 T 세포의 수의 감소 및 만성염증을 유발하지 않도록 하는, 종특이적 렌티바이러스( lentiviruses )에 감염된 다양한 원숭이(숙주)(예컨대 검댕이망가비)의 진화적 해결책을 모방할 수 있을 것이다.

​6-8. Resolution of inflammation

The inflammatory response must be actively terminated when no longer needed to prevent unnecessary "bystander" damage to tissues. Failure to do so results in chronic inflammation, and cellular destruction. Resolution of inflammation occurs by different mechanisms in different tissues. Mechanisms that serve to terminate inflammation include:

● Short half-life of inflammatory mediators in vivo.

● Production and release of transforming growth factor (TGF) beta from macrophages

● Production and release of interleukin 10 (IL-10)

● Production of anti-inflammatory specialized proresolving mediators, i.e. lipoxins, resolvins, maresins, and neuroprotectins

● Downregulation of pro-inflammatory molecules, such as leukotrienes.

● Upregulation of anti-inflammatory molecules such as the interleukin 1 receptor antagonist or the soluble tumor necrosis factor receptor (TNFR)

● Apoptosis of pro-inflammatory cells

● Desensitization of receptors.

● Increased survival of cells in regions of inflammation due to their interaction with the extracellular matrix (ECM)

● Downregulation of receptor activity by high concentrations of ligands

● Cleavage of chemokines by matrix metalloproteinases (MMPs) might lead to production of anti-inflammatory factors.

염증반응은 조직에 대한 불필요한 "방관자( bystander )" 손상​을 예방할 필요가 없을 때 반드시 능동적으로 종결되어야 한다. 그렇게 되지 못하면 만성 염증이 발생하고 세포가 파괴된다. 염증은 다양한 조직의 다양한 메커니즘에 의해 해소된다. 염증을 종결하는 데 일조하는 메커니즘으로는 다음과 같은 것이 있다.

● 대식세포로부터 변형생장인자​( transforming growth factor, TGF ) 베타의 생산 및 방출

● 분화된 항염성 소염촉진 매개체, 즉 리폭신( lipoxins ), 레졸빈( resolvins ), 마레신( maresins ) 및 뉴로프로텍신

● 류코트리엔( leukotrienes )과 같은 염증촉진 분자의 하향조절​

● 인터류킨 1 수용체 길항제나 수용성 종양괴사인자수용체( TNFR )와 같은 항염증 분자의 상향조절​

● 세포외 기질( ECM )과의 상호작용으로 인한 염증형성 구역에 있는 세포의 생존 증가

● 기질금속단백분해효소( matrix metalloproteinases,MMPs )에 의해 케모카인이 쪼개지면 항염증 인자가 생성될 수 있다.

“ Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes promote the switch of arachidonic acid – derived prostaglandins and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3 polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. As a consequence, apoptotic neutrophils undergo phagocytosis by macrophages, leading to neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor- β 1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics. ”

​"일반적으로 급성 염증은 지금까지도 다소 미묘한 상태로 남아 있는 여러 메커니즘에 의해 해소된다. 현재 새로운 증거는 활동적인 소염 조정 프로그램이 염증반응이 시작된 지 최초 수 시간 후에 시작됨을 시사하고 있다. 조직 안으로 들어간 후 과립구는 아라키돈산(arachidonic acid)에서 유도된 프로스타글란딘( prostaglandins ) 및 류코트리엔( leukotrienes )이 리폭신( lipoxins )으로 전환되도록 촉진하는데, 이 리폭신은 순서 진행과정의 종결을 개시한다. 중성구 호출은 이렇게 하여 멈추고 세포자살로 인한 세포 예정사( programmed death )가 시작된다. 이러한 일은 오메가3 다중불포화 지방산으로부터 레졸빈( resolvins ) 및 프로텍틴( protectins )의 생합성과 동시에 일어나는데, 이 생합성 결과 세포자살을 개시함으로써 중성구의 침투 기간이 결정적으로 축소된다. 그 결과 세포자살하는 중성구는 대식세포에 의한 식세포작용을 겪게 되고 이에 따라 중성구가 제거되고 변형생장인자 -베타1( transforming growth factor- β 1 )과 같은 항염증성 및 회복성 시토카인의 방출이 일어난다. 이 항염증 프로그램은 대식세포가 림프관을 통과하여 이탈되면서 종결된다."

6-9. Connection to depression

There is evidence for a link between inflammation and depression. Inflammatory processes can be triggered by negative cognitions or their consequences, such as stress, violence, or deprivation. Thus, negative cognitions can cause inflammation that can, in turn, lead to depression.[dubious – discuss] In addition there is increasing evidence that inflammation can cause depression because of the increase of cytokines, setting the brain into a "sickness mode". Classical symptoms of being physically sick like lethargy show a large overlap in behaviors that characterize depression. Levels of cytokines tend to increase sharply during depressive episodes in manics and drop off during remission. Furthermore, it has been shown in clinical trials that anti-inflammatory medicines taken in addition to antidepressants not only significantly improves symptoms but also increases the proportion of subjects positively responding to treatment. Inflammations that lead to serious depression could be caused by common infections such as those caused by a virus, bacteria or even parasites.

6-9. 우울증과의 관련성

염증과 우울증 사이에 연결고리가 존재한다는 증거가 있다. 염증 과정은 스트레스, 폭력 또는 박탈감과 같은​ 부정적 인식이나 그 결과에 의해 촉발될 수 있다. 이처럼 부정적 인식은 염증을 유발할 수 있으며, 이로 인해 우울증이 유발될 수 있다. 또한 염증이 발생하면 시토카인( cytokine )이 증가하여 우울증이 유발되고 뇌가 "질병 모드"로 설정될 수 있다는 증거가 늘어나고 있다. 혼수상태와 같은, 육체적으로 아픈 고전적인 증상은 작용 면에서 우울증에 특징적으로 나타나는 증상과 많이 겹친다. 시토카인의 농도는 조병(躁病) 환자의 우울증 기간 동안 대체로 급격히 증가하며 회복기에는 떨어진다. 또한 임상실험에서 항우울제와 함께 복용한 항염증 약물은 증상을 유의미한 수준으로 개선시킴과 동시에 치료에 긍정적으로 반응하는 환자의 비율을 증가시키는 것으로 밝혀졌다. 심각한 우울증을 유발하는 염증은 바이러스, 박테리아, 심지어는 기생충 감염과 같은 일반적 감염에 의해서도 유발될 수 있다.

7. ​ Systemic effects

An infectious organism can escape the confines of the immediate tissue via the circulatory system or lymphatic system, where it may spread to other parts of the body. If an organism is not contained by the actions of acute inflammation it may gain access to the lymphatic system via nearby lymph vessels. An infection of the lymph vessels is known as lymphangitis, and infection of a lymph node is known as lymphadenitis. When lymph nodes cannot destroy all pathogens, the infection spreads further. A pathogen can gain access to the bloodstream through lymphatic drainage into the circulatory system.

When inflammation overwhelms the host, systemic inflammatory response syndrome is diagnosed. When it is due to infection, the term sepsis is applied, with the terms bacteremia being applied specifically for bacterial sepsis and viremia specifically to viral sepsis. Vasodilation and organ dysfunction are serious problems associated with widespread infection that may lead to septic shock and death.

7. 전신에 미치는 효과

감염성이 있는 생물은 순환계나 림프계를 통해 이웃한 조직 테두리에서 탈출하여 신체의 다른 부위로 퍼져나갈 수 있다. 한 생물체가 이러한 급성 염증의 작용을 통해 제한을 받지 않으면 인근 림프관을 통해 림프계로 접근할 수 있다. 림프관의 감염은 림프관염( lymphangitis )이라고 하며 림프절의 감염을 림프절염( lymphadenitis )이라고 한다. 림프절이 모든 병원체를 파괴할 수 없으면 감염은 더욱 퍼지게 된다. 림프액이 순환계로 흘러나감에 따라 병원체는 혈류 안으로 접근할 수 있다.

염증이 숙주를 압도하게 되면 전신성 염증반응 증상이 진단된다. 이 반응이 감염으로 인한 것일 경우 패혈(敗血, sepsis )이라는 용어가 사용되는데 균혈증(菌血症, bacteremia )이라는 용어는 특히 박테리아성 패혈증의 경우에 사용되며 바이러스혈증( viremia )이라는 용어는 특히 바이러스성 패혈증에 사용된다. 혈관확장 및 조직의 기능부전은 광범위한 감염과 관련되어 있는 심각한 문제로서​ 패혈성 쇼크 및 사망을 유발할 수 있다.

7-1. ​ Acute-phase proteins

Inflammation also induces high systemic levels of acute-phase proteins. In acute inflammation, these proteins prove beneficial however, in chronic inflammation they can contribute to amyloidosis. These proteins include C-reactive protein, serum amyloid A, and serum amyloid P, which cause a range of systemic effects including:

7-1. 급성기(急性期) 단백질

염증은 높은 수준의 전신성(全身性) 급성기 단백질을 유발하기도 한다. 급성 염증의 경우 이러한 단백질은 잇점이 있는 것으로 판명되었다 그러나 만성 염증의 경우 이 단백질은 ​아밀로이드증( amyloidosis )에 일조할 수 있다. 이러한 단백질로는 C 반응성단백질, 혈청아밀로이드 A 및 혈청아밀로이드 P 가 있는데, 이들은 다음과 같은 다양한 전신성 효과를 유발한다.

7-2. Leukocyte numbers

Inflammation often affects the numbers of leukocytes present in the body:

● Leukocytosis is often seen during inflammation induced by infection, where it results in a large increase in the amount of leukocytes in the blood, especially immature cells. Leukocyte numbers usually increase to between 15 000 and 20 000 cells per microliter, but extreme cases can see it approach 100 000 cells per microliter. Bacterial infection usually results in an increase of neutrophils, creating neutrophilia, whereas diseases such as asthma, hay fever, and parasite infestation result in an increase in eosinophils, creating eosinophilia.

● Leukopenia can be induced by certain infections and diseases, including viral infection, Rickettsia infection, some protozoa, tuberculosis, and some cancers.

염증은 종종 체내에 존재하는 백혈구의 수에 영향을 미친다.

​ ● 백혈구증가증( l eukocytosis )은 종종 감염으로 인한 염증 시에 보이는데, 이 경우 이로 인해 혈중 백혈구, 특히 미성숙 세포의 양이 크게 증가하게 된다. ​백혈구의 수는 보통 마이크로리터당 15,000

20,000 개가 증가하지만 극단적인 경우에는 마이크로리터당 10 만개가 증가하기도 한다. 박테리아에 감염되면 대개는 중성구가 증가하고 호중구증가증이 유발되는 반면, 천식, 건초열 및 기생충 창궐과 같은 질환의 경우에는 호산구가 증가하며 호산구증가증이 유발된다.

● 백혈구감소증 ( l eukopenia )은 바이러스 감염, 리케챠( Rickettsia ) 감염, 몇몇 원생동물, 결핵 및 몇몇 암과 같은 특정 감염 및 질환에 의해 유발될 수 있다.​

7-3. Systemic inflammation and obesity

With the discovery of interleukins (IL), the concept of systemic inflammation developed. Although the processes involved are identical to tissue inflammation, systemic inflammation is not confined to a particular tissue but involves the endothelium and other organ systems.

Chronic inflammation is widely observed in obesity. The obese commonly have many elevated markers of inflammation, including:

● TNF- α (Tumor necrosis factor-alpha)

7-3. 전신성 염증 및 비만

​인터류킨( interleukins, IL )의 발견으로 전신성 염증의 개념이 생겨났다. 이와 관련된 과정은 조직 염증과 동일하며 전신성 염증은 특정한 조직에 한정되어 있지 않으며 상피 및 다른 기관계를 포함하고 있다.

만성 염증은 비만에서 널리 관찰되고 있다.​ 비만한 사람은 일반적으로 다음과 같은 염증관련 많은 지표가 상승해 있다.

​ Low-grade chronic inflammation is characterized by a two- to threefold increase in the systemic concentrations of cytokines such as TNF- α , IL-6, and CRP. Waist circumference correlates significantly with systemic inflammatory response. A predominant factor in this correlation is due to the autoimmune response triggered by adiposity, whereby immune cells may mistake fatty deposits for intruders. The body attacks fat similar to bacteria and fungi. When expanded fat cells leak or break open, macrophages mobilize to clean up and embed into the adipose tissue. Then macrophages release inflammatory chemicals, including TNF- α and IL-6. TNF's primary role is to regulate the immune cells and induce inflammation. White blood cells then assist by releasing more cytokines. This link between adiposity and inflammation has been shown to produce 10

35% of IL-6 in a resting individual, and this production increases with increasing adiposity.

​ Loss of white adipose tissue reduces levels of inflammation markers. The association of systemic inflammation with insulin resistance and atherosclerosis is the subject of intense research.

​저수준의 염증이 만성적으로 존재하면 종양괴사인자 -알파( TNF- α ), 인터류킨 -6 ( IL-6 ) 및 C 반응성단백질( CRP )과 같은 시토카인 ( cytokine ) 의 전신 농도가 2

3 배 증가한다. 허리둘레는 전신 염증반응과 의미있는 수준으로 상관관계가 있다. 이러한 상관관계의 주된 요인은 비만증에 의해 촉발된 자가면역 반응 때문으로, 이 자가면역으로 인해 면역세포는 침착된 지방을 침입자로 오해하게 될 수 있다. 신체는 박테리아나 곰팡이와 유사한 지방을 공격한다. 팽창된 지방세포가 누출되거나 파괴되어 열리게 되면 대식세포가 동원되어 이를 청소하여 지방조직에 박아넣게 된다. 이후 대식세포는 종양괴사인자알파( TNF- α ) 및 인터류킨 6 ( IL-6 ) 과 같은 염증성 화학물질을 방출한다. 종양괴사인자의 주된 역할은 면역세포를 조절하고 염증을 유도하는 것이다. 백혈구는 이후 시토카인 을 더 많이 방출함으로써 지원한다. 휴식을 취하고 있는 사람의 경우 10

35% 의 인터류킨 6 은 비만증과 염증 사이의 이러한 관련성으로 인해 만들어지는 것으로 밝혀졌으며 이러한 생산량은 비만증이 증가할수록 증가하게 된다.

백색 지방조직이 상실되면 염증 지표의 농도가 감소한다. 전신 염증과 인슐린 저항성 및 죽상동맥경화증과의 연관성은 심도있게 연구가 진행되고 있다. ​

​ In the obese mouse models, inflammation and macrophage-specific genes are upregulated in white adipose tissue (WAT). There were also signs of dramatic increase in circulating insulin level, adipocyte lipolysis and formation of multinucleate giant cells. The fat-derived protein called angiopoietin-like protein 2 (Angptl2) elevates in fat tissues. Higher than normal Angptl2 level in fat tissues develop inflammation as well as insulin and leptin resistance. Stored fat secretes Leptin to signal satiety. Leptin resistance plays a role in the process where appetite overrules the message of satiety. Angptl2 then starts an inflammatory cascade causing blood vessels to remodel and attract macrophages. Angptl2 is an adipocyte-derived inflammatory mediator linking obesity to systemic insulin resistance. It is possible that, as an inflammatory marker, leptin responds specifically to adipose-derived inflammatory cytokines.

C-reactive protein (CRP) is generated at a higher level in obese people. It raises when there is inflammation throughout the body. Mild elevation in CRP increase risk of heart attacks, strokes, high blood pressure, muscle weakness and fragility.

비만한 생쥐의 경우, 백색지방조직( white adipose tissue, WAT )에서는 염증형성 및 대식세포 특이적 유전자가 상향조절되어 있다. 또한 순환계의 인슐린 농도, 지방세포 지질분해 및 다세포 거대세포의 형성이 극적으로 증가한다는 여러 징후도 있었다. 지방조직에서는 안지오포이에틴 유사 단백질 2 ( angiopoietin-like protein 2, Angptl2 )이라고 하는, 지방으로부터 유도된 단백질​이 증가한다. 지방조직의 Angptl2 농도가 정상치 이상이면 인슐린 저항성 및 렙틴 저항성 외에 염증도 발생한다. 저장된 지방은 렙틴을 분비하여 포만상태라는 신호를 보낸다. 렙틴 저항성은 식욕이 포만상태라는 메시지를 능가하도록 하는 과정에서 역할을 한다. Angptl2 는 지방세포에서 유도된 염증형성 매개체로서 비만을 전신성(全身性) 인슐린 저항성과 연결시킨다. 염증형성 표지로서의 렙틴은 특히 지방에서 유도된 염증형성 시토카인에 반응한다.

C 반응성 단백 질( C-reactive protein, CRP )은 비만한 사람들에게서 고농도로 발생하며 전신(全身)에 염증이 존재할 경우 증가한다. C 반응성 단백질이 약간 증가하면 심장발작, 뇌졸중, 고혈압, 근력저하 및 근육의 취약성이 증가한다. ​

7-4. Systemic inflammation and overeating

Hyperglycemia induces IL-6 production from endothelial cells and macrophages. Meals high in saturated fat, as well as meals high in calories have been associated with increases in inflammatory markers. In addition, interstitial abdominal adiposity (also referred to as accumulated intra-abdominal fat) may be a factor in increasing systemic risk for multiple inflammatory diseases. Although the exact mechanisms are still being investigated, a review published in 2010 suggested that significant growth of adipose tissue in response to overeating can evoke a chronic inflammatory response.

7-4. 전신 염증 및 과식

고혈당증이 있으면 내피세포 및 대식세포로부터 인터류킨 6​ 생산이 증가하게 된다. 고칼로리 음식 외에 포화지방 함량이 높은 음식도 염증표지의 증가와 관련이 있었다. 또한, 간질성(間質性) 복부비만(복부축적지방이라고도 한다)도 다발성 염증 질환이 전신에 발생할 위험을 증가시키는 한 요인이 될 수 있다. 정확한 메커니즘은 아직도 연구 중이지만, 2010 년 발표된 한 평론은 과식으로 인한 지방조직의 유의미한 증식은 만성 염증반응을 유발할 수 있음을 시사하였다.

The outcome in a particular circumstance will be determined by the tissue in which the injury has occurred and the injurious agent that is causing it. Here are the possible outcomes to inflammation:

​a . Resolution

The complete restoration of the inflamed tissue back to a normal status. Inflammatory measures such as vasodilation, chemical production, and leukocyte infiltration cease, and damaged parenchymal cells regenerate. In situations where limited or short-lived inflammation has occurred this is usually the outcome.

특정한 상황에서 염증의 결과는 손상이 발생한 조직 및 그 손상을 일으키는 유해한 인자에 의해 결정된다. 염증 이후의 일어날 수 있는 결과는 다음과 같다.

염증이 발생한 조직이 완전히 정상적인 상태로 회복되는 것. 혈관확장, 화학물질 생산 및 백혈구 침투와 같은 염증​형성 수단은 중단되고 손상된 실질(實質) 세포는 재생된다. 염증이 한정된 기간 또는 단기간 동안 발생하는 상황에서는 그 결과는 보통 이런 것이다.

Large amounts of tissue destruction, or damage in tissues unable to regenerate, cannot be regenerated completely by the body. Fibrous scarring occurs in these areas of damage, forming a scar composed primarily of collagen. The scar will not contain any specialized structures, such as parenchymal cells, hence functional impairment may occur.

c. Abscess formation

A cavity is formed containing pus, an opaque liquid containing dead white blood cells and bacteria with general debris from destroyed cells.

d. Chronic inflammation

In acute inflammation, if the injurious agent persists then chronic inflammation will ensue. This process, marked by inflammation lasting many days, months or even years, may lead to the formation of a chronic wound. Chronic inflammation is characterised by the dominating presence of macrophages in the injured tissue. These cells are powerful defensive agents of the body, but the toxins they release (including reactive oxygen species) are injurious to the organism's own tissues as well as invading agents. As a consequence, chronic inflammation is almost always accompanied by tissue destruction.

재생이 불가능할 정도로 조직이 많이 파괴되거나 손상을 입으면 신체는 이를 완전히 재생할 수 없다. 이러한 손상 부위에는 섬유성 반흔이 발생하며 이 반흔은 주로 콜라겐으로 이루어져 있다. 이 반흔은 실질세포( parenchymal cells )와 같은 그 어떤 분화된 조직도 포함하고 있지 않으며 따라서 기능상의 장애는 발생하지 않는다.

강(腔, cavity )은 농양을 포함한 채로 형성되는데 이 농양은​ 파괴된 세포의 전체 잔사(殘渣)와 함께 죽은 백혈구 및 박테리아를 포함하고 있는 불투명한 액체이다.

급성 염증 시 유해한 인자가 없어지지 않으면 만성 염증​이 뒤따른다. 이러한 과정은 수 일, 수 개월 심지어 수년간 지속되는 염증으로 특징되며, 만성적 상처가 형성될 수 있다. 만성 염증은 손상된 조직에 대식세포가 우세하게 나타난다는 점이 특징이다. 이 대식세포는 신체의 강력한 방어체지만 이들이 방출하는 독소(반응성 산소종을 포함)는 침입하는 병원체 뿐만 아니라 생물체 자신의 조직에도 유해하다. 그 결과 만성염증은 거의 항상 조직 파괴를 동반한다.

Inflammation is usually indicated by adding the suffix "itis", as shown below. However, some conditions such as asthma and pneumonia do not follow this convention. More examples are available at list of types of inflammation.

아래에서 보는 바와 같이 염증은 대 개 접미사 " itis "를 부가하여 표시한다. 그러나 천 식( asthma ) 및 폐렴( pneumonia )과 같은 일부 질환은 이러한 관행을 따르지 않는다. 더 많은 사례는 염증 의 유형 목록에서 볼 수 있다.

​ 10. Diet and inflammation

The Dietary Inflammatory Index (DII) is a score (number) that describes the potential of diet to modulate systemic inflammation within the body. As stated chronic inflammation is linked to most chronic diseases including arthritis, many types of cancer, cardiovascular diseases, inflammatory bowel diseases, and diabetes.

식이염증지수( Dietary Inflammatory Index, DII )란 식단의 체내 전신 염증 조절 가능성을 표시해 주는 점수(숫자)를 말한다.​ 언급한 바와 마찬가지로 관절염, 많은 종류의 암, 심혈관계질환, 염증성 장질환 및 당뇨병을 포함하여 만성염증은 대부분의 만성 질환과 관련되어 있다.

11. Exercise and inflammation

11-1. Exercise-induced acute inflammation

Acute inflammation of the muscle cells, as understood in exercise physiology, can result after induced eccentric and concentric muscle training. Participation in eccentric training and conditioning, including resistance training and activities that emphasize eccentric lengthening of the muscle including downhill running on a moderate to high incline can result in considerable soreness within 24 to 48 hours, even though blood lactate levels, previously thought to cause muscle soreness, were much higher with level running. This delayed onset muscle soreness (DOMS) results from structural damage to the contractile filaments and z-disks, which has been noted especially in marathon runners whose muscle fibers revealed remarkable damage to the muscle fibers after both training and marathon competition[citation needed]. The onset and timing of this gradient damage to the muscle parallels the degree of muscle soreness experienced by the runners.

11. 신체운동과 염증

​11-1. 신체운동으로 인한 급성 염증

운동생리학에서 이해되어 있는 바와 마찬가지로 근육세포의 급성염증​은 신체운동으로 인한 단축성 근육 트레이닝 및 신장성 근육 트레이닝의 결과로 발생할 수 있다. 평지를 달림에 따라 혈중 젖산 농도(종전에는 근육통을 유발한다고 생각되었다)가 훨씬 더 높아짐을 감안한다 하더라도 보통

높은 경사지에서의 다운힐 런닝( downhill running )과 같은 근육의 원심성 신장을 중시하는 저항성 훈련 및 활동을 포함하여 원심성 훈련 및 조건화 훈련을 하게 되면 24

48 시간 이내에 상당한 통증이 유발될 수 있다. 이러한 지연발생 근육통은 수축성 미세섬유 및 z 판에 가해지는 구조적 손상 때문으로, 훈련 및 마라톤 경주 후 근섬유에 뚜렷한 손상을 입는 마라톤 선수의 경우에게서 특히 주목되었다. 근육에 대한 이러한 구배손상의 시작 및 시점은 선수가 겪는 근육통의 정도와 대응한다.

​ Z-disks are the point of contact for the contractile proteins. They provide structural support for transmission of force when muscle fibers are activated to shorten. However, in marathon runners and those who subscribe to the overload principle to enhance their muscles, show moderate Z-disk streaming and major disruption of thick and thin filaments in parallel groups of sarcomeres as a result of the force of eccentric actions or stretching of tightened muscle fibers.

​ ​ This disruption of muscle fibers triggers white blood cells to increase following induced muscle soreness, leading to the inflammatory response observation from induced muscle soreness. Elevations in plasma enzymes, myoglobinemia, and abnormal muscle histology and ultrastructure are concluded to be associated with inflammatory response. High tension in the contractile-elastic system of muscle results in structural damage to the muscle fiber and p lasmalemma and its epimysium, perimysium, and/or endomysium. The mysium damage disrupts calcium homeostasis in injured fibers and fiber bundles, resulting in necrosis that peaks about 48 hours after exercise. The products of macrophage activity and intracellular contents (such as histamines, kinins, and K+) accumulate outside cells. These substances then stimulate free nerve endings in the muscle a process that appears accentuated by eccentric exercise, in which large forces are distributed over a relatively small cross-sectional area of the muscle.

Z 판( Z-disk )은 수축성 단백질이 접촉하는 지점이다. 이 판은 근섬유가 활성화되어 짧아질 때 힘의 전달을 구조적으로 지원한다. 그러나, 마라톤 선수와 근육을 강화시킬 목적으로 ​부하원칙( overload principle )에 동의하는 사람들의 Z 판은 팽팽해진 근섬유의 원심력이나 신장력으로 인해 그 배열이 완만한 수준으로 불규칙 하며 ( Z-disk st reaming ) , 평행한 근섬유분절군(群)의 가는 미세섬유 및 굵은 미세섬유가 주로 파열되어 있다.

근섬유가 파열되면 이로 인한 근육통 후에 백혈구가 증가하게 되며, 그 결과 이 근육통으로 인한 염증형성 반응이 발생하게 된다. 혈장효소의 증가, 미오글로빈혈증( myoglobinemia ), 비정상적 근육 조직 및 초미세구조는 염증반응과 관련되어 있는 것으로 결론이 내려졌다. 근육의 수축-탄성계에 긴장상태가 높아지면 근섬유, 그리고 원 형 질막( p lasmalemma ) 및 그 근외막(筋外膜, epimysium ), 근주막(筋周膜, perimysium ) 및/또는 근내막(筋內膜, endomysium )에 구조적인 손상이 발생한다. 근막( mysium )이 손상되면 손상된 섬유 및 섬유다발의 칼슘항상성이 파괴되며 그 결과 괴사가 일어나는데, 이는 운동 후 약 48 시간 후에 최대가 된다. 대식세포 활동의 산물 및 (히스타민, 키닌, K+ 과 같은) 세포 내용물은 세포의 밖에 축적된다. 이러한 물질은 이후 근육의 자유신경말단( free nerve endings )을 자극한다 이 과정은 원심성 운동에 의해 악화되는 것으로 보이는데, 이 경우 큰 힘이 상대적으로 작은 근육횡단면 영역에 걸쳐 배분된다.

​11-2. Post-inflammatory muscle growth and repair

There is a known relationship between inflammation and muscle growth. For instance, high doses of anti-inflammatory medicines (e.g., NSAIDs) are able to blunt muscle growth. Cold therapy has been shown to negatively affect muscle growth as well. Reducing inflammation results in decreased macrophage activity and lower levels of IGF-1. Acute effects of cold therapy on training adaptations show reduced satellite cell proliferation. Long term effects include less muscular hypertrophy and an altered cell structure of muscle fibers.

​ It has been further theorized that the acute localized inflammatory responses to muscular contraction during exercise, as described above, are a necessary precursor to muscle growth. As a response to muscular contractions, the acute inflammatory response initiates the breakdown and removal of damaged muscle tissue. Muscles can synthesize cytokines in response to contractions, such that the cytokines interleukin-1 beta (IL-1 β ), TNF- α , and IL-6 are expressed in skeletal muscle up to 5 days after exercise.

​ 11-2. 염증 후 근육비대 및 수선

염증은 근육 비대와 관계가 있는 것으로 알려져 있다. 예컨대 항염증 약물(예컨대 NSAID 류)을 많이 복용하면 근육 성장이 제한될 수 있다. 한랭요법( c old therapy )도 근육 성장을 제한하는 것으로 밝혀졌다. 염증이 감소하면 그 결과 대식세포의 활성이 감소하고 IGF-1 의 농도가 낮아지게 된다. 한랭요법은 운동적응( training adaptations )에 대한 급성 효과로서 위성 세포( satellite cell )의 증식을 감소시킴을 보여주고 있다. 장기적 효과로는 근육성장의 감소 및 근섬유의 세포구조 변화가 있다.

위에서 언급한 바와 마찬가지로, ​운동 중 근육 수축에 대한 급성 국소 염증 반응이 근육성장에 필요한 전구적(前驅的) 사건이라는 점은 더 잘 이론화되어 있다. 근육수축에 대한 반응으로 급성 염증 반응이 일어나면 손상된 조직이 파괴되고 제거되기 시작한다. 근육은 수축에 대한 반응으로 시토카인을 합성할 수 있으며 그 결과 운동을 한 지 최대 5 일 후에는 골격근에서 시토카인인 인터류킨 -1 베타( IL-1 β ), TNF- α 및 IL-6 이 발현된다.

​ ​ In particular, the increase in levels of IL-6 (interleukin 6), a myokine, can reach up to one hundred times that of resting levels. Depending on volume, intensity, and other training factors, the IL-6 increase associated with training initiates about 4 hours after resistance training and remains elevated for up to 24 hours.

​ These acute increases in cytokines, as a response to muscle contractions, help initiate the process of muscle repair and growth by activating satellite cells within the inflamed muscle. Satellite cells are crucial for skeletal muscle adaptation to exercise. They contribute to hypertrophy by providing new myonuclei and repair damaged segments of mature myofibers for successful regeneration following injury- or exercise-induced muscle damage high-level powerlifters can have up to 100% more satellite cells than untrained controls.

​특히, IL-6 (인터류킨 6 ), 미오카인( myokine )의 농도는 휴식시의 수준보다 최대 100 배까지 증가할 수 있다. 부피, 강도 및 다른 운동 요인에 따라 다르지만, 저항운동 약 4 시간 후에는 운동과 관련된 인터류킨 6 이 상승하기 시작하며 최대 24 시간 동안 상승된 상태를 유지한다.

이처럼 근육 수축에 반응하여 시토카인이 급격하게 증가하면 염증이 발생한 근육 내의 위성세포가 활성화됨으로써 근육의 수선 및 생장 과정이 개시되는 데 도움이 된다. 위성세포는 운동에 대한 골격근 적응에 극히 중요하다. 이 위성세포는 새로운 근핵(筋核, myonuclei )을 제공함으로써 부상 또는 운동으로 인해 근육이 손상된 후 성숙한 근섬유의 손상된 조각을 수선하여 근육이 성공적으로 재생되도록 함으로써 근육비대에 기여한다 높은 수준의 바벨 들어올리기 전문가는 훈련받지 않은 대조군 집단보다 위성세포가 최대 100% 더 많을 수 있다.

​ ​ A rapid and transient localization of the IL-6 receptor and increased IL-6 expression occurs in satellite cells following contractions. IL-6 has been shown to mediate hypertrophic muscle growth both in vitro and in vivo. Unaccustomed exercise can increase IL-6 by up to sixfold at 5 hours post-exercise and threefold 8 days after exercise. Also telling is the fact that NSAIDs can decrease satellite cell response to exercise, thereby reducing exercise-induced protein synthesis.

​ The increase in cytokines (myokines) after resistance exercise coincides with the decrease in levels of myostatin, a protein that inhibits muscle differentiation and growth. The cytokine response to resistance exercise and moderate-intensity running occur differently, with the latter causing a more prolonged response, especially at the 12 – 24 hour mark.

​ Developing research has demonstrated that many of the benefits of exercise are mediated through the role of skeletal muscle as an endocrine organ. That is, contracting muscles release multiple substances known as myokines, including but not limited to those cited in the above description, which promote the growth of new tissue, tissue repair, and various anti-inflammatory functions, which in turn reduce the risk of developing various inflammatory diseases. The new view that muscle is an endocrine organ is transforming our understanding of exercise physiology and with it, of the role of inflammation in adaptation to stress.

IL-6 수용체의 빠르고 일시적으로 국소화( localization ) 및 IL-6 의 발현 증가는 위성세포( satellite cells )가 수축된 후 그 안에서 일어난다. IL-6 은 생체 내 및 시험관 모두에서 비대성 근육성장( hypertrophic muscle growth )을 매개하는 것으로 밝혀졌다. 간헐적 신체운동 시에는 운동을 한 지 최대 5 시간 후 IL-6 이 최대 6 배까지, 운동 8 일 후 3 배까지 증가할 수 있다. NSAID 류가 신체운동에 대한 위성세포 반응을 감소시키고 이로써 신체운동으로 인한 단백질 합성이 감소할 수 있다는 사실도 언급되고 있다.

저항성 운동 후에는 ​근육의 분화 및 생장을 억제하는 단백질인 미오스타틴( myostatin ) 농도의 감소와 동시에 시토카인(미오카인)이 증가한다. 저항성 운동 및 중간강도의 달리기에 대한 시토카인 반응은 다르게 일어나는데, 중간 강도의 달리기를 할 경우에는 반응이 더 장시간에 걸쳐, 특히 12

개발연구 결과 신체운동의 잇점 중 많은 것이 골격근이 내분비 기관으로 역할을 함으로써 매개된다는 사실이 증명되었다. ​다시 말하면, 근육이 수축되면 미 오카인( myokines )이라고 알려진 많은 물질이 방출되는데, 이 물질은 위에서 기술한 것을 포함하며 거기에 한정되지 않는다. 미오카인은 새로운 조직의 생장, 조직 수선 및 다양한 항염기능을 촉진하며 이는 다시 다양한 염증성 질환이 발생할 위험을 감소시킨다. 근육이 내분비 기관이라는 새로운 견해로 인해 신체운동 생리에 대한 우리의 이해는 변화하고 있으며, 이와 함께 스트레스에 대한 적응에 있어 염증의 역할에 대한 이해도 변하고 있다.

​ ​ 11-3. Chronic inflammation and muscle loss

Both chronic and extreme inflammation are associated with disruptions of anabolic signals initiating muscle growth. Chronic inflammation has been implicated as part of the cause of the muscle loss that occurs with aging. Increased protein levels of myostatin have been described in patients with diseases characterized by chronic low-grade inflammation. Increased levels of TNF- α can suppress the AKT/mTOR pathway, a crucial pathway for regulating skeletal muscle hypertrophy, thereby increasing muscle catabolism. Cytokines may antagonize the anabolic effects of insulin-like growth factor 1 (IGF-1). In the case of sepsis, an extreme whole body inflammatory state, the synthesis of both myofibrillar and sarcoplasmic proteins are inhibited, with the inhibition taking place preferentially in fast-twitch muscle fibers. Sepsis is also able to prevent leucine from stimulating muscle protein synthesis. In animal models, when inflammation is created, mTOR loses its ability to be stimulated by muscle growth.

11-3. 만성 염증 및 근육 상실

만성 염증 및 극심한 염증은 둘 다 근육 생장이 시작되도록 하는 동화작용 신호를 파괴한다. 만성 염증은 노화성 근육 상실의 일부 원인이다. 미오스타틴( myostatin )의 단백질 증가는 저수준의 만성염증이 특징적으로 나타나는 질환을 가진 환자에서 기술되었다. TNF- α 농도가 증가하면 골격근 비대를 조절하는 매우 중요한 경로인 ​ AKT/mTOR 경로가 억제될 수 있으며 이로 인해 근육 이화작용이 증가할 수 있다. 시토카인은 인슐린 유사 생장인자 -1 ( IGF-1 )의 동화 효과를 상쇄할 수 있다. 극심한 전신염증 상태인 패혈증의 경우에는 근원섬유 단백질 및 근장단백질의 합성이 억제되며 이러한 일은 속근섬유(速筋纖維, fast-twitch muscle fibers )에서 더 잘 일어난다. 패혈증의 경우에도 류신( leucine )이 근단백질 합성을 자극하지 못하도록 할 수 있다. 실험동물의 경우 염증이 발생하면 mTOR 은 근육생장으로 인해 자극받는 능력을 상실한다.

11-4. ​​ Exercise as a treatment for inflammation

Regular physical activity is reported to decrease markers of inflammation, although the correlation is imperfect and seems to reveal differing results contingent upon training intensity. For instance, while baseline measurements of circulating inflammatory markers do not seem to differ greatly between healthy trained and untrained adults, long-term training may help reduce chronic low-grade inflammation.

On the other hand, levels of the anti-inflammatory myokine IL-6 (interleukin 6) remained elevated longer into the recovery period following an acute bout of exercise in patients with inflammatory diseases, relative to the recovery of healthy controls. It may well be that low-intensity training can reduce resting pro-inflammatory markers (CRP, IL-6), while moderate-intensity training has milder and less-established anti-inflammatory benefits. There is a strong relationship between exhaustive exercise and chronic low-grade inflammation. Marathon running may enhance IL-6 levels as much as 100 times over normal and increases total leuckocyte count and neturophil mobilization.

​11-4. 염증치료방법으로서의 신체운동

그 상관관계는 불완전하고 훈련의 강도에 따라 결과가 다른 것으로 생각되지만, 규칙적인 신체활동은 염증의 표지를 감소시키는 것으로 알려져 있다.​ 예컨대 염증 표지의 기준 측정값은 훈련받은 건강한 성인과 훈련받지 않은 성인 사이에 별로 차이가 없는 것 같지 만 장기적인 훈련을 하면 저수준의 만성 염증을 줄이는 데 도움이 된다.

한편, 염증성 질환이 있는 환자의 경우 항염성 미오카인 IL-6 (인터류킨 6 )의 수준은 1 회의 급격한 신체운동 이후 회복기간까지 건강한 대조군에 비해 더 오랫동안 증가된 상태를 유지하였다. 저강도 훈련을 하면 휴식 중의 염증촉진 표지( CRP, IL-6 )가 감소하지만 보통 수준의 훈련은 항염 잇점이 더 약하고 덜 확실성도 떨어질 수 있다. 소모성 운동과 저수준의 만성염증은 상관관계가 높다. 마라톤 경주를 하면 IL-6 농도가 정상치의 100 배 수준으로 상승할 수 있으며 총 백혈구 수와 중성구 동원량이 증가한다.

​ Regarding the above, IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage. However, it has become evident that eccentric exercise is not associated with a larger increase in plasma IL-6 than exercise involving concentric “nondamaging” muscle contractions.

This finding clearly demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.

​ Recent work has shown that both upstream and downstream signalling pathways for IL-6 differ markedly between myocytes and macrophages. It appears that unlike IL-6 signalling in macrophages, which is dependent upon activation of the NF κ B signalling pathway, intramuscular IL-6 expression is regulated by a network of signalling cascades, including the Ca2+/NFAT and glycogen/p38 MAPK pathways. Thus, when IL-6 is signalling in monocytes or macrophages, it creates a pro-inflammatory response, whereas IL-6 activation and signalling in muscle is totally independent of a preceding TNF-response or NF κ B activation, and is anti-inflammatory.

​위에 언급한 사항과 관련하여 IL-6 은 종전에는 염증촉진 시토카인으로 분류되었었다. 그러므로 처음에는 신체운동으로 인한 IL-6 반응은 근육손상과 관련이 있을 거라고 생각되었다. 그러나 원심 성 운동 ( eccentric exercise )이 "비손상적" 근육수축을 수반하는 구심성 운동( conc entri c exercise ) 보다 혈장 IL-6 을 더 크게 증가시키지는 않는다는 사실이 명백해졌다.

이러한 연구결과는 신체운동 시의 근육손상이 혈장 IL-6 의 증가에 필요하지 않다는 점을 명백히 보여주고 있다. 사실 원심성 운동은 그 결과 지연정점( delayed peak )이 유발될 수 있고 회복 중 혈장 IL-6 은 훨씬 더 느리게 감소할 수 있다.

최근의 연구 결과 IL-6 상향 및 하향 신호전달 경로는 둘 다 근육세포 및 대식세포 사이에 ​현저한 차이가 있다는 사실이 밝혀졌다. 대식세포에서의 IL-6 신호전달은 NF κ B 신호전달경로의 활성화에 의존하는데, 이와 달리 근육내 IL-6 발현은 Ca2+/NFAT 및 포도당 /p38 MAPK 를 포함하는 신호전달 연쇄체계망에 의해 조절된다. 이처럼 IL-6 는 단핵구나 대식세포에서 신호가 전달될 때 염증촉진 반응을 만들어내는 반면, 근육에서의 IL-6 활성화 및 신호전달은 TNF- 반응 또는 NF κ B 활성화와는 전혀 별개이며 항염증성이다.

​ Several studies show that markers of inflammation are reduced following longer-term behavioural changes involving both reduced energy intake and a regular program of increased physical activity, and that, in particular, IL-6 was miscast as an inflammatory marker. For example, the anti-inflammatory effects of IL-6 have been demonstrated by IL-6 stimulating the production of the classical anti-inflammatory cytokines IL-1ra and IL-10. As such, individuals pursuing exercise as a means to treat the causal factors underlying chronic inflammation are pursuing a course of action strongly supported by current research, as an inactive lifestyle is strongly associated with the development and progression of multiple inflammatory diseases. Note that cautions regarding over-exertion may apply in certain cases, as discussed above, though this concern rarely applies to the general population.

몇가지 연구 결과 에너지 흡수량을 감소시키고 신체활동을 증가시키는 정규 프로그램을 수반하는 더 장기적인 행동변화 이후 염증의 표지는 감소하며, 특히 IL-6 은 염증촉진 표지로 잘못 선택된 것으로 밝혀졌다. ​예컨대 IL-6 의 항염 효과는 고전적인 항염성 시토카인 IL-1ra 및 IL-10 의 생산을 자극하는 IL-6 에 의해 입증되었다. 이처럼 만성염증의 기저에 있는 인과요인을 치료하기 위해 신체운동을 하는 사람은 현행 연구에 의해 강력히 뒷받침되는 작용경로를 추구하고 있다. 왜냐하면 비활동적 생활방식은 많은 염증성 질환의 발생 및 진행과 강한 관련이 있기 때문이다. 위에 언급한 바와 마찬가지로, 지나친 노력과 관련한 주의사항이 특정한 경우에 적용될 수 있다는 점에는 유의하여야 하지만, 이것이 일반 대중에게 적용되는 일은 드물다.

11-5. Signal-to-noise theory

Given that localized acute inflammation is a necessary component for muscle growth, and that chronic low-grade inflammation is associated with a disruption of anabolic signals initiating muscle growth, it has been theorized that a signal-to-noise model may best describe the relationship between inflammation and muscle growth. By keeping the "noise" of chronic inflammation to a minimum, the localized acute inflammatory response signals a stronger anabolic response than could be achieved with higher levels of chronic inflammation.

11-5. 신호 대 잡음 이론

국소 급성 염증이 근육의 생장에 필요한 요소라는 점, 그리고 저수준의 만성염증이 근육의 생장을 개시하는 동화작용 신호의 파괴와 관련이 있다는 점을 고려하면, 신호 대 잡음 모델이 염증과 근육생장의 관련성을 가장 잘 설명할 수 있다고 이론적으로 설명된 바 있다. 국소 급성 염증반응은 만성 염증이라는 "잡음"을 최소 수준으로 유지함으로써 만성염증의 수준이 높을 때보다 더 강한 동화반응( anabolic response ) 신호를 보낸다.