Fibrosis | |
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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]
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 a natural wound healing response which interferes with normal organ function. [4]
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]
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:
Myocardial fibrosis has two forms:
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]
A scar is an area of fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other organs, and tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound results in some degree of scarring. An exception to this are animals with complete regeneration, which regrow tissue without scar formation.
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.
Elastic fibers are an essential component of the extracellular matrix composed of bundles of proteins (elastin) which are produced by a number of different cell types including fibroblasts, endothelial, smooth muscle, and airway epithelial cells. These fibers are able to stretch many times their length, and snap back to their original length when relaxed without loss of energy. Elastic fibers include elastin, elaunin and oxytalan.
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.
The interstitium is a contiguous fluid-filled space existing between a structural barrier, such as a cell membrane or the skin, and internal structures, such as organs, including muscles and the circulatory system. The fluid in this space is called interstitial fluid, comprises water and solutes, and drains into the lymph system. The interstitial compartment is composed of connective and supporting tissues within the body – called the extracellular matrix – that are situated outside the blood and lymphatic vessels and the parenchyma of organs. The role of the interstitium in solute concentration, protein transport and hydrostatic pressure impacts human pathology and physiological responses such as edema, inflammation and shock.
A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.
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.
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.
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.
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.
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.
Integrin alpha-11 is a protein that, in humans, is encoded by the ITGA11 gene.
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.
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.
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.
Tissue remodeling is the reorganization or renovation of existing tissues. Tissue remodeling can be either physiological or pathological. The process can either change the characteristics of a tissue such as in blood vessel remodeling, or result in the dynamic equilibrium of a tissue such as in bone remodeling. Macrophages repair wounds and remodel tissue by producing extracellular matrix and proteases to modify that specific matrix.
Plasticosis is a form of fibrotic scarring that is caused by small pieces of plastic which inflame the digestive tract.