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Fibrosis

Defined here as abnormal presence or deposition of ECM-proteins around parenchymal tissues. This mainly serves four purposes, to reinforce tissue-biomechanics, provide a scaffold for injured tissues, guide movements of immune-cells in the extracellular matrix and to provide an anti-microbial barrier. The local histological characteristics of the fibrotic tissue provides clues as to what is going on. For example: peri-cellular accumulation of type-I collagen is associated with cell-migration in the ECM, collagen-V increases with active inflammation while type-VI seems to be associated with microbial defence and immune-functions. Altered presence of non-collagenous proteins, like fibronectin and laminin which is associated with wound-healing and cell-adhesion also ads to the picture. A relative state of ECM-abundance in relationship to parenchymal tissue might in some cases reflect a degenerative process rather than increased ECM-synthesis. Fibrosis changes the biomechanical behaviour and local hemodynamics of the tissue which may affect function and resilience to load.

Angiogenesis is tightly associated with fibrosis, but the nature of this association is unclear. My initial assumption was that fibrosis would cause an impairment i vascular exchange, driving angiogenesis, but contrary to this studies have consistently shown that inhibition of angiogenesis cause regression of fibrosis. Fibrosis and hypoxia seems to be strongly correlated, and it could be that they co-occur because ECM synthesis provides the necessary scaffold for the new vessels to form. This would mean that the association between angiogenesis and fibrosis is mediated by a third variable, like hypoxia and/or inflammation. My suspicion is that fibrosis is the main reason behind pathological stiffening of musculoskeletal tissues, and that it is primarily caused by a metabolic disturbance rather than physical inactivity. The effects of fibrosis may be hard to distinguish from that of non-enzymatic glycation, which also cause increased thickness and rigidity of connective-tissue, but there seems to be a pathophysiological overlap between these two processes that might account for this.

Supporting Evidence

  • The inflammatory response mainly takes place in the ECM.1) ...continue
  • The structure of the ECM seems to affect mode of migration used by macrophages2)https://www.jimmunol.org/content/184/2/1049
  • Fibrillar collagen has a role in directing cell-movement in the ECM3)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021709/
  • The amount of type-V collagen is increased two to nine-fold in response to inflammation4)https://www.ncbi.nlm.nih.gov/pubmed/6413124
  • Collagen around injured muscles increase by 18% after 12 weeks5)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397750/
  • Perivascular fibrosis impairs oxygen diffusion and seems to precede tissue-fibrosis6)https://www.nature.com/articles/hr200560.pdf?origin=ppub
  • Provides attachment for antimicrobial peptides as a peri-cellular defence-mechanism7)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081658/
  • Collagen VI seems to posses anti-microbial properties8)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127292/
  • Collagen VI is one of the major components of muscle ECM, forming the basal membrane9)https://jcs.biologists.org/content/128/19/3525
  • Collagen VI  is abundant in other connective tissue-barriers, such as in the brain and intestine10)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031366/11)https://www.ncbi.nlm.nih.gov/pubmed/21406227
  • Collagen VI facilitates macrophage adhesion, mediating tissue regeneration12)https://www.ncbi.nlm.nih.gov/pubmed/25421425/
  • Bacteria can use ECM-components such as collagen for adhesion and invasion of host cells13)https://academic.oup.com/femsre/article/36/6/1122/729706
  • Reduced lung-expansion in PF might reflect the biomechanical compromise with the fibrotic response14)https://err.ersjournals.com/content/27/147/170062
  • Sub-cellular fibrosis in PF. A prognostic marker, maybe related to oxygenation 15)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624898/16)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624898/
  • Mutation in genes expressing VEGF or TGF-B cause embryonic lethality, both through vascular defects17)https://www.ncbi.nlm.nih.gov/pubmed/860224218)https://www.ncbi.nlm.nih.gov/pubmed/9020852
  • Increased levels of fibronectin is correlated with thickening of the basement-membrane in DM.19)http://iovs.arvojournals.org/article.aspx?articleid=2185222
  • Certain bacteria uses host fibronectin and laminin to adhere to cell-surfaces.20)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143885/
  • Pain and perceived stiffness in MPS is unrelated to levels of muscle contraction.21)https://www.ncbi.nlm.nih.gov/pubmed/8650509
  • 48h of immobilisation decreases rather than increases the amount of ECM-proteins in muscle tissues.22)https://www.ncbi.nlm.nih.gov/pubmed/16763108
  • Accumulation of AGEs might produce a similar tissue phenotype as fibrosis.23)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6413015/

Conflicting Evidence

  • Anti-angiogenic drugs seem to reduce fibrosis24)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223242/
  • Mice over-expressing VEGF seem to be protected from experimental PF25)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621899/
  • Increased thickness of the capillary basement-membrane is related to DM vascular complications.26)http://iovs.arvojournals.org/article.aspx?articleid=2185222

Association with Disease

  • Synovial fibrosis is seen with OA27)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372675/28)https://www.ncbi.nlm.nih.gov/pubmed/26175472
  • Increased stiffness in perimysial fascia of patients with NSLBP.29)https://www.ncbi.nlm.nih.gov/pubmed/21929806
  • Increased tissue-stiffness in MPS.30)https://www.ncbi.nlm.nih.gov/pubmed/2974598331)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508225/
  • Fibrosis of epimysial fascia can cause elevated intramuscular pressure and potentially pain.32)https://www.ncbi.nlm.nih.gov/pubmed/2371824
  • Increased sub-fascial accumulation of loose connective tissue in muscles of patients with neck-pain.33)https://www.ncbi.nlm.nih.gov/pubmed/23975091
  • Fibrosis and increased levels of collagen VI is involved in Duchennes muscular dystrophy34)https://www.ncbi.nlm.nih.gov/pubmed/17662584
  • Altered expression of pro-fibrotic mediators and increased fibroblast-activation in TP.35)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116130/36)https://pubmed.ncbi.nlm.nih.gov/28122639
  • Increased in ECM-proteins around tendons affected by TP.37)https://pubmed.ncbi.nlm.nih.gov/25792859
  • Fibrotic changes in DDD.38)https://www.ncbi.nlm.nih.gov/pubmed/2646345139)https://austinpublishinggroup.com/orthopedics-rheumatology/fulltext/ajor-v1-id1001.php
  • Histological evidence of fibrosis and increased levels of TGF-B in synovium from RA-patients.40)https://onlinelibrary.wiley.com/doi/abs/10.1002/art.178031080341)https://onlinelibrary.wiley.com/doi/epdf/10.1002/art.178034020542)https://www.ncbi.nlm.nih.gov/pubmed/2201470/43)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828828/
  • Arterial stiffening in AT is caused by fibrosis.44)https://www.sciencedirect.com/science/article/abs/pii/S1054880713000069
  • Perivascular fibrosis co-occurring with atherosclerosis development in mice.45)https://www.sciencedirect.com/science/article/abs/pii/S0021915015300459
  • Increased adventitial thickness in subjects with common cardiovascular risk-factors.46)https://www.sciencedirect.com/science/article/pii/S1936878X08004622?via%3Dihub
  • Decreased flexibility in trunk forward-flexion is associated with arterial stiffening.47)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967435/?platform=hootsuite
  • Severity of OA is associated with arterial stiffness, implying that fibrosis might be a common denominator.48)http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967435/?platform=hootsuite

References   [ + ]

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