Fibrosis, also known as fibrotic scarring, is a pathological
wound healing in which
connective tissue replaces normal
parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of permanent
scar tissue.[1][2]
Repeated injuries,
chronic inflammation and repair are susceptible to fibrosis, where an accidental excessive accumulation of extracellular matrix components, such as the collagen, is produced by fibroblasts, leading to the formation of a permanent fibrotic scar.[1]
In response to injury, this is called
scarring, and if fibrosis arises from a single cell line, this is called a
fibroma. Physiologically, fibrosis acts to deposit connective tissue, which can interfere with or totally inhibit the normal architecture and function of the underlying organ or tissue. Fibrosis can be used to describe the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing.[3] Defined by the pathological accumulation of
extracellular matrix (ECM) proteins, fibrosis results in scarring and thickening of the affected tissue — it is in essence an exaggerated wound healing response which interferes with normal organ function.[4]
Physiology
Fibrosis is similar to the process of scarring, in that both involve stimulated
fibroblasts laying down
connective tissue, including
collagen and
glycosaminoglycans. The process is initiated when immune cells such as
macrophages release soluble factors that stimulate fibroblasts. The most well characterized pro-fibrotic mediator is
TGF beta, which is released by macrophages as well as any damaged tissue between surfaces called
interstitium. Other soluble mediators of fibrosis include
CTGF,
platelet-derived growth factor (PDGF), and
interleukin 10 (IL-10). These initiate signal transduction pathways such as the AKT/mTOR[5] and SMAD[6] pathways that ultimately lead to the proliferation and activation of fibroblasts, which deposit extracellular matrix into the surrounding connective tissue. This process of tissue repair is a complex one, with tight regulation of
extracellular matrix (ECM) synthesis and degradation ensuring maintenance of normal tissue architecture. However, the entire process, although necessary, can lead to a progressive irreversible fibrotic response if tissue injury is severe or repetitive, or if the wound healing response itself becomes deregulated.[4][7]
Anatomical location
Fibrosis can occur in many tissues within the body, typically as a result of inflammation or damage. Common sites of fibrosis include the lungs, liver, kidneys, brain, and heart:
Bridging fibrosis – an advanced stage of liver fibrosis, seen in the progressive form of chronic liver diseases. The term bridging refers to the formation of a "bridge" by a band of mature and thick fibrous tissue from the portal area to the central vein. This form of fibrosis leads to the formation of pseudolobules. Long-term exposure to
hepatotoxins, such as
thioacetamide,
carbon tetrachloride, and
diethylnitrosamine, has been shown to cause bridging fibrosis in experimental animal models.[8]
Senescence of
hepatic stellate cells could prevent progression of liver fibrosis, although has not yet been implemented as a therapy due to risks assosciated with hepatic dysfunction.[9]
Historically, fibrosis was considered an irreversible process. However, several recent studies have demonstrated reversal in liver and lung tissue,[14][15][16] and in cases of renal,[17] myocardial,[18] and oral-submucosal fibrosis.[19]
^Nelson FR, Blauvelt CT (January 2015). "Chapter 2 - Musculoskeletal Diseases and Related Terms". A Manual of Orthopaedic Terminology (Eighth ed.). Philadelphia: W.B. Saunders. pp. 43–104.
doi:
10.1016/B978-0-323-22158-0.00002-0.
ISBN978-0-323-22158-0.
^Ismail MH, Pinzani M. Reversal of liver fibrosis. Saudi J Gastroenterol. 2009 Jan;15(1):72-9. doi: 10.4103/1319-3767.45072. PMID 19568569; PMCID: PMC2702953.
^Zoubek ME, Trautwein C, Strnad P. Reversal of liver fibrosis: From fiction to reality. Best Pract Res Clin Gastroenterol. 2017 Apr;31(2):129-141. doi: 10.1016/j.bpg.2017.04.005. Epub 2017 Apr 24. PMID 28624101.
^C -H Chang, Y -H Juan, H -C Hu, K -C Kao, C -S Lee, Reversal of lung fibrosis: an unexpected finding in survivor of acute respiratory distress syndrome, QJM: An International Journal of Medicine, Volume 111, Issue 1, January 2018, Pages 47–48,
https://doi.org/10.1093/qjmed/hcx190
^Frangogiannis NG. Can Myocardial Fibrosis Be Reversed? J Am Coll Cardiol. 2019 May 14;73(18):2283-2285. doi: 10.1016/j.jacc.2018.10.094. PMID 31072571.
^Shetty SS, Sharma M, Kabekkodu SP, Kumar NA, Satyamoorthy K, Radhakrishnan R. Understanding the molecular mechanism associated with reversal of oral submucous fibrosis targeting hydroxylysine aldehyde-derived collagen cross-links. J Carcinog. 2021 Aug 13;20:9. doi: 10.4103/jcar.JCar_24_20. PMID 34526855; PMCID: PMC8411980.