Fibrosis

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Fibrosis
Cardiac amyloidosis very high mag movat.jpg
Micrograph of a heart showing fibrosis (yellow – left of image) and amyloid deposition (brown – right of image). Stained using Movat's stain.
Specialty Pathology, rheumatology
Complications Cirrhosis
Risk factors Repeated injuries, chronic inflammation. [1]

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]

Contents

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 tissueit 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:

Micrograph showing cirrhosis of the liver. The tissue in this example is stained with a trichrome stain, in which fibrosis is colored blue. The red areas are the nodular liver tissue Cirrhosis high mag.jpg
Micrograph showing cirrhosis of the liver. The tissue in this example is stained with a trichrome stain, in which fibrosis is colored blue. The red areas are the nodular liver tissue

Lungs

Liver

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

Kidney

Brain

Heart

Myocardial fibrosis has two forms:

Other

Fibrosis reversal

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]

Related Research Articles

<span class="mw-page-title-main">Extracellular matrix</span> Network of proteins and molecules outside cells that provides structural support for cells

In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and biochemical support to surrounding cells. Because multicellularity evolved independently in different multicellular lineages, the composition of ECM varies between multicellular structures; however, cell adhesion, cell-to-cell communication and differentiation are common functions of the ECM.

Haptotaxis is the directional motility or outgrowth of cells, e.g. in the case of axonal outgrowth, usually up a gradient of cellular adhesion sites or substrate-bound chemoattractants. These gradients are naturally present in the extracellular matrix (ECM) of the body during processes such as angiogenesis or artificially present in biomaterials where gradients are established by altering the concentration of adhesion sites on a polymer substrate.

Durotaxis is a form of cell migration in which cells are guided by rigidity gradients, which arise from differential structural properties of the extracellular matrix (ECM). Most normal cells migrate up rigidity gradients.

<span class="mw-page-title-main">Pulmonary fibrosis</span> Disease that causes scarring of the lungs

Pulmonary fibrosis is a condition in which the lungs become scarred over time. Symptoms include shortness of breath, a dry cough, feeling tired, weight loss, and nail clubbing. Complications may include pulmonary hypertension, respiratory failure, pneumothorax, and lung cancer.

<span class="mw-page-title-main">Myofibroblast</span>

A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.

<span class="mw-page-title-main">Liver sinusoid</span> Hepatic sinusoidal blood vessel

A liver sinusoid is a type of capillary known as a sinusoidal capillary, discontinuous capillary or sinusoid, that is similar to a fenestrated capillary, having discontinuous endothelium that serves as a location for mixing of the oxygen-rich blood from the hepatic artery and the nutrient-rich blood from the portal vein.

<span class="mw-page-title-main">CTGF</span> Protein found in humans

CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins. CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.

<span class="mw-page-title-main">Heat shock protein 47</span> Protein-coding gene in the species Homo sapiens

Heat shock protein 47, also known as SERPINH1 is a serpin which serves as a human chaperone protein for collagen.

Type V collagen is a form of fibrillar collagen associated with classical Ehlers-Danlos syndrome. It is found within the dermal/epidermal junction, placental tissues, as well as in association with tissues containing type I collagen.

<span class="mw-page-title-main">Hepatic stellate cell</span>

Hepatic stellate cells (HSC), also known as perisinusoidal cells or Ito cells, are pericytes found in the perisinusoidal space of the liver, also known as the space of Disse. The stellate cell is the major cell type involved in liver fibrosis, which is the formation of scar tissue in response to liver damage, in addition these cells store and concentrate vitamin A.

<span class="mw-page-title-main">CYR61</span> Protein-coding gene in the species Homo sapiens

Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.

<span class="mw-page-title-main">Dermatopontin</span> Protein-coding gene in the species Homo sapiens

Dermatopontin also known as tyrosine-rich acidic matrix protein (TRAMP) is a protein that in humans is encoded by the DPT gene. Dermatopontin is a 22-kDa protein of the noncollagenous extracellular matrix (ECM) estimated to comprise 12 mg/kg of wet dermis weight. To date, homologues have been identified in five different mammals and 12 different invertebrates with multiple functions. In vertebrates, the primary function of dermatopontin is a structural component of the ECM, cell adhesion, modulation of TGF-β activity and cellular quiescence). It also has pathological involvement in heart attacks and decreased expression in leiomyoma and fibrosis. In invertebrate, dermatopontin homologue plays a role in hemagglutination, cell-cell aggregation, and expression during parasite infection.

<span class="mw-page-title-main">Integrin alpha 11</span> Protein-coding gene in the species Homo sapiens

Integrin alpha-11 is a protein that, in humans, is encoded by the ITGA11 gene.

<span class="mw-page-title-main">Desmoplasia</span> Growth of fibrous or connective tissue

In medicine, desmoplasia is the growth of fibrous connective tissue. It is also called a desmoplastic reaction to emphasize that it is secondary to an insult. Desmoplasia may occur around a neoplasm, causing dense fibrosis around the tumor, or scar tissue (adhesions) within the abdomen after abdominal surgery.

Pancreatic stellate cells (PaSCs) are classified as myofibroblast-like cells that are located in exocrine regions of the pancreas. PaSCs are mediated by paracrine and autocrine stimuli and share similarities with the hepatic stellate cell. Pancreatic stellate cell activation and expression of matrix molecules constitute the complex process that induces pancreatic fibrosis. Synthesis, deposition, maturation and remodelling of the fibrous connective tissue can be protective, however when persistent it impedes regular pancreatic function.

<span class="mw-page-title-main">Myocardial scarring</span>

Myocardial scarring is the accumulation of fibrous tissue resulting after some form of trauma to the cardiac tissue. Fibrosis is the formation of excess tissue in replacement of necrotic or extensively damaged tissue. Fibrosis in the heart is often hard to detect because fibromas, scar tissue or small tumors formed in one cell line, are often formed. Because they are so small, they can be hard to detect by methods such as magnetic resonance imaging. A cell line is a path of fibrosis that follow only a line of cells.

<span class="mw-page-title-main">Pirfenidone</span> Chemical compound

Pirfenidone, sold under the brand name Pirespa among others, is a medication used for the treatment of idiopathic pulmonary fibrosis. It works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II.

Cenderitide is a natriuretic peptide developed by the Mayo Clinic as a potential treatment for heart failure. Cenderitide is created by the fusion of the 15 amino acid C-terminus of the snake venom dendroaspis natriuretic peptide (DNP) with the full C-type natriuretic peptide (CNP) structure. This peptide chimera is a dual activator of the natriuretic peptide receptors NPR-A and NPR-B and therefore exhibits the natriuretic and diuretic properties of DNP, as well as the antiproliferative and antifibrotic properties of CNP.

Scar free healing is the process by which significant injuries can heal without permanent damage to the tissue the injury has affected. In most healing, scars form due to the fibrosis and wound contraction, however in scar free healing, tissue is completely regenerated. During the 1990s, published research on the subject increased; it is a relatively recent term in the literature. Scar free healing occurs in foetal life but the ability progressively diminishes into adulthood. In other animals such as amphibians, however, tissue regeneration occurs, for example as skin regeneration in the adult axolotl.

<span class="mw-page-title-main">Plasticosis</span> Disease caused by small pieces of plastic

Plasticosis is a form of fibrotic scarring that is caused by small pieces of plastic which inflame the digestive tract.

References

  1. 1 2 3 Wynn TA (August 2004). "Fibrotic disease and the T(H)1/T(H)2 paradigm". Nature Reviews. Immunology. Springer Science and Business Media LLC. 4 (8): 583–594. doi:10.1038/nri1412. PMC   2702150 . PMID   15286725.
  2. Birbrair A, Zhang T, Files DC, Mannava S, Smith T, Wang ZM, et al. (November 2014). "Type-1 pericytes accumulate after tissue injury and produce collagen in an organ-dependent manner". Stem Cell Research & Therapy. 5 (6): 122. doi: 10.1186/scrt512 . PMC   4445991 . PMID   25376879.
  3. "Glossary of dermatopathological terms". DermNet NZ.
  4. 1 2 Neary R, Watson CJ, Baugh JA (2015). "Epigenetics and the overhealing wound: the role of DNA methylation in fibrosis". Fibrogenesis & Tissue Repair. 8: 18. doi: 10.1186/s13069-015-0035-8 . PMC   4591063 . PMID   26435749.
  5. Mitra A, Luna JI, Marusina AI, Merleev A, Kundu-Raychaudhuri S, Fiorentino D, et al. (November 2015). "Dual mTOR Inhibition Is Required to Prevent TGF-β-Mediated Fibrosis: Implications for Scleroderma". The Journal of Investigative Dermatology. 135 (11): 2873–2876. doi:10.1038/jid.2015.252. PMC   4640976 . PMID   26134944.
  6. Leask A, Abraham DJ (May 2004). "TGF-beta signaling and the fibrotic response". FASEB Journal. 18 (7): 816–827. CiteSeerX   10.1.1.314.4027 . doi:10.1096/fj.03-1273rev. PMID   15117886. S2CID   2027993.
  7. Meyer KC (May 2017). "Pulmonary fibrosis, part I: epidemiology, pathogenesis, and diagnosis". Expert Review of Respiratory Medicine. 11 (5): 343–359. doi:10.1080/17476348.2017.1312346. PMID   28345383. S2CID   42073964.
  8. Dwivedi DK, Jena GB (November 2018). "Glibenclamide protects against thioacetamide-induced hepatic damage in Wistar rat: investigation on NLRP3, MMP-2, and stellate cell activation". Naunyn-Schmiedeberg's Archives of Pharmacology. 391 (11): 1257–1274. doi:10.1007/s00210-018-1540-2. PMID   30066023. S2CID   51890984.
  9. Zhang M, Serna-Salas S, Damba T, Borghesan M, Demaria M, Moshage H (October 2021). "Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives" (PDF). Mechanisms of Ageing and Development. 199: 111572. doi: 10.1016/j.mad.2021.111572 . PMID   34536446. S2CID   237524296.
  10. Valentijn FA, Falke LL, Nguyen TQ, Goldschmeding R (March 2018). "Cellular senescence in the aging and diseased kidney". Journal of Cell Communication and Signaling. 12 (1): 69–82. doi:10.1007/s12079-017-0434-2. PMC   5842195 . PMID   29260442.
  11. 1 2 Chute M, Aujla P, Jana S, Kassiri Z (September 2019). "The Non-Fibrillar Side of Fibrosis: Contribution of the Basement Membrane, Proteoglycans, and Glycoproteins to Myocardial Fibrosis". Journal of Cardiovascular Development and Disease. 6 (4): 35. doi: 10.3390/jcdd6040035 . PMC   6956278 . PMID   31547598.
  12. Duffield JS (June 2014). "Cellular and molecular mechanisms in kidney fibrosis". The Journal of Clinical Investigation. 124 (6): 2299–2306. doi:10.1172/JCI72267. PMC   4038570 . PMID   24892703.
  13. 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. ISBN   978-0-323-22158-0.
  14. 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.
  15. 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.
  16. 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
  17. Eddy, A.A. Can renal fibrosis be reversed?. Pediatr Nephrol 20, 1369–1375 (2005). https://doi.org/10.1007/s00467-005-1995-
  18. 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.
  19. 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.