fibrosis

{{Infobox medical condition (new)

| name = Fibrosis

| image = Cardiac amyloidosis very high mag movat.jpg

| caption = Micrograph of a heart showing fibrosis (yellow – left of image) and amyloid deposition (brown – right of image). Stained using Movat's stain.

| field = Pathology, rheumatology

| pronounce =

| synonyms =

| symptoms =

| complications = Cirrhosis

| onset =

| duration =

| types =

| causes =

| risks = Repeated injuries, chronic inflammation.

| diagnosis =

| differential =

| prevention =

| treatment =

| medication =

| prognosis =

| frequency =

| deaths =

}}

Fibrosis, also known as fibrotic scarring, is the development of fibrous connective tissue in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease.{{cite book |title=Dictionary of Toxicology |chapter=Fibrosis |publisher=Springer Nature Singapore |publication-place=Singapore |date=2024 |isbn=978-981-99-9282-9 |doi=10.1007/978-981-99-9283-6_957 |page=375–376}}

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.{{cite journal | vauthors = Wynn TA | title = Fibrotic disease and the T(H)1/T(H)2 paradigm | journal = Nature Reviews. Immunology | volume = 4 | issue = 8 | pages = 583–594 | date = August 2004 | pmid = 15286725 | pmc = 2702150 | doi = 10.1038/nri1412 }}{{cite journal | vauthors = Birbrair A, Zhang T, Files DC, Mannava S, Smith T, Wang ZM, Messi ML, Mintz A, Delbono O | display-authors = 6 | title = Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner | journal = Stem Cell Research & Therapy | volume = 5 | issue = 6 | pages = 122 | date = November 2014 | pmid = 25376879 | pmc = 4445991 | doi = 10.1186/scrt512 | doi-access = free }}

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.{{cite web | url = http://dermnetnz.org/pathology/pathology-glossary.html | title = Glossary of dermatopathological terms. | work = DermNet NZ}} Defined by the pathological accumulation of extracellular matrix (ECM) proteins, fibrosis results in scarring and thickening of the affected {{nowrap|tissue{{hsp}}{{mdash}}}}{{hsp}}it is in essence a natural wound healing response which interferes with normal organ function.{{cite journal | vauthors = Neary R, Watson CJ, Baugh JA | title = Epigenetics and the overhealing wound: the role of DNA methylation in fibrosis | journal = Fibrogenesis & Tissue Repair | volume = 8 | pages = 18 | date = 2015 | pmid = 26435749 | pmc = 4591063 | doi = 10.1186/s13069-015-0035-8 | doi-access = free }}

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{{cite journal | vauthors = Mitra A, Luna JI, Marusina AI, Merleev A, Kundu-Raychaudhuri S, Fiorentino D, Raychaudhuri SP, Maverakis E | display-authors = 6 | title = Dual mTOR Inhibition Is Required to Prevent TGF-β-Mediated Fibrosis: Implications for Scleroderma | journal = The Journal of Investigative Dermatology | volume = 135 | issue = 11 | pages = 2873–6 | date = November 2015 | pmid = 26134944 | pmc = 4640976 | doi = 10.1038/jid.2015.252 }} and SMAD{{cite journal | vauthors = Leask A, Abraham DJ | title = TGF-beta signaling and the fibrotic response | journal = FASEB Journal | volume = 18 | issue = 7 | pages = 816–827 | date = May 2004 | pmid = 15117886 | doi = 10.1096/fj.03-1273rev | doi-access = free | s2cid = 2027993 | citeseerx = 10.1.1.314.4027 }} 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.{{cite journal | vauthors = Meyer KC | title = Pulmonary fibrosis, part I: epidemiology, pathogenesis, and diagnosis | journal = Expert Review of Respiratory Medicine | volume = 11 | issue = 5 | pages = 343–359 | date = May 2017 | pmid = 28345383 | doi = 10.1080/17476348.2017.1312346 | s2cid = 42073964 }}

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:

Image:Cirrhosis high mag.jpg

= Lungs =

Fibrothorax
Pulmonary fibrosis
Cystic fibrosis
Idiopathic pulmonary fibrosis (idiopathic meaning 'of unknown cause')
Radiation-induced lung injury (following radiation therapies commonly used to treat cancer)

= Liver =

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.{{cite journal | vauthors = Dwivedi DK, Jena GB | title = Glibenclamide protects against thioacetamide-induced hepatic damage in Wistar rat: investigation on NLRP3, MMP-2, and stellate cell activation | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 391 | issue = 11 | pages = 1257–74 | date = November 2018 | pmid = 30066023 | doi = 10.1007/s00210-018-1540-2 | s2cid = 51890984 }}
Senescence of hepatic stellate cells could prevent progression of liver fibrosis, although has not yet been implemented as a therapy due to risks associated with hepatic dysfunction.{{cite journal | vauthors = Zhang M, Serna-Salas S, Damba T, Borghesan M, Demaria M, Moshage H | title = Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives | journal = Mechanisms of Ageing and Development | volume = 199 | pages = 111572 | date = October 2021 | pmid = 34536446 | doi = 10.1016/j.mad.2021.111572 | s2cid = 237524296 | doi-access = free | url = https://pure.rug.nl/ws/files/183050805/Hepatic_stellate_cell_senescence_in_liver_fibrosis_Characteristics_mechanisms_and_perspectives.pdf }}

File:Bridging fibrosis in rat liver exposed to thioacetamide.jpg following a six-week course of thioacetamide. Sirius Red stain]]

Cirrhosis

= Kidney =

CYR61 induction of cellular senescence in the kidney has shown potential to limit renal fibrosis.{{cite journal | vauthors = Valentijn FA, Falke LL, Nguyen TQ, Goldschmeding R | title = Cellular senescence in the aging and diseased kidney | journal = Journal of Cell Communication and Signaling | volume = 12 | issue = 1 | pages = 69–82 | date = March 2018 | pmid = 29260442 | pmc = 5842195 | doi = 10.1007/s12079-017-0434-2 }}

= Brain =

Glial scar

=Heart=

Myocardial fibrosis has two forms:

Interstitial fibrosis, described in cases of congestive heart failure and hypertension, and as part of normal cellular aging.{{cite journal | vauthors = Chute M, Aujla P, Jana S, Kassiri Z | title = The Non-Fibrillar Side of Fibrosis: Contribution of the Basement Membrane, Proteoglycans, and Glycoproteins to Myocardial Fibrosis | journal = Journal of Cardiovascular Development and Disease | volume = 6 | issue = 4 | pages = 35 | date = September 2019 | pmid = 31547598 | pmc = 6956278 | doi = 10.3390/jcdd6040035 | doi-access = free }}
Replacement fibrosis, indicating tissue damage from previous myocardial infarction.

File:Histopathology of interstitial fibrosis in dilated cardiomyopathy.jpg|Healthy myocardium versus interstitial fibrosis in dilated cardiomyopathy. Alcian blue stain.

File:Histopathology of dense fibrous scar replacing myocyte loss in myocardial infarction.jpg|Replacement fibrosis in myocardial infarction, being boundless and dense.

= Other =

Arterial stiffness
Arthrofibrosis (knee, shoulder, other joints)
Chronic kidney disease{{cite journal | vauthors = Duffield JS | title = Cellular and molecular mechanisms in kidney fibrosis | journal = The Journal of Clinical Investigation | volume = 124 | issue = 6 | pages = 2299–2306 | date = June 2014 | pmid = 24892703 | pmc = 4038570 | doi = 10.1172/JCI72267 }}
Crohn's disease (intestine)
Dupuytren's contracture (hands, fingers)
Keloid (skin)
Lipedema (fat cells, typically in lower limbs)
Mediastinal fibrosis (soft tissue of the mediastinum)
Myelofibrosis (bone marrow)
Myofibrosis (skeletal muscle){{cite book | vauthors = Nelson FR, Blauvelt CT | chapter = Chapter 2 - Musculoskeletal Diseases and Related Terms |date= January 2015 | doi = 10.1016/B978-0-323-22158-0.00002-0 | title = A Manual of Orthopaedic Terminology |pages=43–104 |publisher=W.B. Saunders |isbn=978-0-323-22158-0 | edition = 8th }}
Peyronie's disease (penis)
Nephrogenic systemic fibrosis (skin)
Progressive massive fibrosis (lungs); a complication of pneumoconiosis
Retroperitoneal fibrosis (soft tissue of the retroperitoneum)
Scleroderma/systemic sclerosis (skin, lungs)
Some forms of adhesive capsulitis (shoulder)

Fibrosis reversal

Historically, fibrosis was considered an irreversible process. However, several recent studies have demonstrated reversal in liver and lung tissue,{{cite journal |vauthors=Ismail MH, Pinzani M |title=Reversal of liver fibrosis |journal=Saudi J Gastroenterol |volume=15 |issue=1 |pages=72–9 |date=January 2009 |pmid=19568569 |pmc=2702953 |doi=10.4103/1319-3767.45072 |doi-access=free }}{{cite journal |vauthors=Zoubek ME, Trautwein C, Strnad P |title=Reversal of liver fibrosis: From fiction to reality |journal=Best Pract Res Clin Gastroenterol |volume=31 |issue=2 |pages=129–141 |date=April 2017 |pmid=28624101 |doi=10.1016/j.bpg.2017.04.005 }}{{cite journal |vauthors=Chang CH, Juan YH, Hu HC, Kao KC, Lee CS |title=Reversal of lung fibrosis: an unexpected finding in survivor of acute respiratory distress syndrome |journal=QJM |volume=111 |issue=1 |pages=47–48 |date=January 2018 |pmid=29036729 |doi=10.1093/qjmed/hcx190 }} and in cases of renal,{{cite journal |vauthors=Eddy AA |title=Can renal fibrosis be reversed? |journal=Pediatr Nephrol |volume=20 |issue=10 |pages=1369–75 |date=October 2005 |pmid=15947978 |doi=10.1007/s00467-005-1995-5 }} myocardial,{{cite journal |vauthors=Frangogiannis NG |title=Can Myocardial Fibrosis Be Reversed? |journal=J Am Coll Cardiol |volume=73 |issue=18 |pages=2283–85 |date=May 2019 |pmid=31072571 |doi=10.1016/j.jacc.2018.10.094 }} and oral-submucosal fibrosis.{{cite journal |vauthors=Shetty SS, Sharma M, Kabekkodu SP, Kumar NA, Satyamoorthy K, Radhakrishnan R |title=Understanding the molecular mechanism associated with reversal of oral submucous fibrosis targeting hydroxylysine aldehyde-derived collagen cross-links |journal=J Carcinog |volume=20 |issue= |pages=9 |date=2021 |pmid=34526855 |pmc=8411980 |doi=10.4103/jcar.JCar_24_20 |doi-access=free }}