Fibrosis, also known as fibrotic scarring, is the development of fibrous

connective tissue Connective tissue is one of the four primary types of animal tissue, a group of cells that are similar in structure, along with epithelial tissue, muscle tissue, and nervous tissue. It develops mostly from the mesenchyme, derived from the mesod ...

in response to an injury. Fibrosis can be a normal connective tissue deposition or excessive tissue deposition caused by a disease. Repeated injuries,

chronic inflammation Chronic systemic inflammation is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions such ...

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. In response to injury, this is called

scar A scar (or scar tissue) is an area of fibrosis, 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 Organ (anatomy), organs, and biological tissue, t ...

ring, and if fibrosis arises from a single cell line, this is called a

fibroma Fibromas are benign tumors that are composed of fibrous or connective tissue. They can grow in all organs, arising from mesenchyme tissue. The term "fibroblastic" or "fibromatous" is used to describe tumors of the fibrous connective tissue. Wh ...

. 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. Defined by the pathological accumulation of

extracellular matrix 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 bio ...

(ECM) proteins, fibrosis results in scarring and thickening of the affected it is in essence a natural wound healing response which interferes with normal organ function.

Physiology

Fibrosis is similar to the process of scarring, in that both involve stimulated

fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...

s laying down

, including

collagen Collagen () is the main structural protein in the extracellular matrix of the connective tissues of many animals. It is the most abundant protein in mammals, making up 25% to 35% of protein content. Amino acids are bound together to form a trip ...

and

glycosaminoglycan Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case o ...

s. The process is initiated when immune cells such as

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

s release soluble factors that stimulate fibroblasts. The most well characterized pro-fibrotic mediator is

TGF beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the Transforming growth factor beta family, transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HUGO Gene Nomen ...

, which is released by macrophages as well as any damaged tissue between surfaces called

interstitium In anatomy, 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 s ...

. Other soluble mediators of fibrosis include

CTGF 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 (see also CCN intercellular signaling protein). CTGF has important roles in man ...

platelet-derived growth factor Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing bloo ...

(PDGF), and

interleukin 10 Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti- inflammatory cytokine. In humans, interleukin 10 is encoded by the ''IL10'' gene. IL-10 signals through a receptor complex consisting of two IL- ...

(IL-10). These initiate signal transduction pathways such as the AKT/mTOR and SMAD 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

(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.

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:

Lungs

Fibrothorax Fibrothorax is a medical condition characterised by severe scarring ( fibrosis) and fusion of the layers of the pleural space surrounding the lungs resulting in decreased movement of the lung and ribcage. The main symptom of fibrothorax is shor ...

Pulmonary fibrosis 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 ...

Cystic fibrosis Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of Sputum, mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably ''Staphy ...

Idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis (IPF) synonymous with cryptogenic fibrosing alveolitis is a rare, progressive illness of the respiratory system, characterized by the thickening and stiffening of lung tissue, associated with the formation of scar ...

(''idiopathic'' meaning 'of unknown cause') *

Radiation-induced lung injury Radiation-induced lung injury (RILI) is a general term for damage to the lungs as a result of exposure to ionizing radiation. In general terms, such damage is divided into early inflammatory damage (''radiation pneumonitis'') and later complicati ...

(following radiation therapies commonly used to treat cancer)

Liver

Bridging fibrosis In histology (microscopic anatomy), the lobules of liver, or hepatic lobules, are small divisions of the liver defined at the microscopic scale. The hepatic lobule is a building block of the liver tissue, consisting of portal triads, hepatocytes ...

– 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 Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...

, such as

thioacetamide Thioacetamide is an organosulfur compound with the formula C2 H5 N S. This white crystalline solid is soluble in water and serves as a source of sulfide ions in the synthesis of organic and inorganic compounds. It is a prototypical thioamide. ...

carbon tetrachloride Carbon tetrachloride, also known by many other names (such as carbon tet for short and tetrachloromethane, also IUPAC nomenclature of inorganic chemistry, recognised by the IUPAC), is a chemical compound with the chemical formula CCl4. It is a n ...

, and

diethylnitrosamine ''N''-Nitrosodiethylamine (NDEA) is an organic compound with the formula Et2NNO (Et = C2H5). A member of the nitrosamines, it is a light-sensitive, volatile, clear yellow oil that is soluble in water, lipids, and other organic solvents. It has ...

, has been shown to cause bridging fibrosis in experimental animal models. * Senescence of

hepatic stellate cell Hepatic stellate cells (HSC), also known as perisinusoidal cells or Ito cells (earlier ''lipocytes'' or ''fat-storing cells''), are pericytes found in the perisinusoidal space of the liver, also known as the space of Disse (a small area between ...

s could prevent progression of liver fibrosis, although has not yet been implemented as a therapy due to risks associated with hepatic dysfunction. Bridging fibrosis in rat liver exposed to thioacetamide

Bridging fibrosis in rat liver exposed to thioacetamide

Cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

Kidney

CYR61 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. CYR61 is a secreted, extracellular matrix (ECM)-associated signaling protein of the CCN family ...

induction of

cellular senescence Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of appro ...

in the kidney has shown potential to limit renal fibrosis.

Brain

Glial scar A glial scar formation (gliosis) is a reactive cellular process involving astrogliosis that occurs after injury to the central nervous system. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and beg ...

Heart

Myocardial fibrosis Cardiac fibrosis commonly refers to the excess deposition of extracellular matrix in the cardiac muscle, but the term may also refer to an abnormal thickening of the heart valves due to inappropriate proliferation of cardiac fibroblasts. Fibrotic c ...

has two forms: * Interstitial fibrosis, described in cases of congestive heart failure and hypertension, and as part of normal cellular aging. * Replacement fibrosis, indicating tissue damage from previous

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

. 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 Arterial stiffness occurs as a consequence of biological aging, arteriosclerosis and genetic disorders, such as Marfan, Williams, and Ehlers-Danlos syndromes. Inflammation plays a major role in arteriosclerosis and arterial stiffness. Incre ...

Arthrofibrosis Arthrofibrosis (from Greek: ''arthro-'' joint, ''fibrosis'' – scar tissue formation) has been described in most joints like knee, hip, ankle, foot joints, shoulder ( frozen shoulder, adhesive capsulitis), elbow (stiff elbow), wrist, hand joints ...

(knee, shoulder, other joints) *

Chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...

(intestine) * Dupuytren's contracture (hands, fingers) *

Keloid Keloid, also known as keloid disorder and keloidal scar, is the formation of a type of scar which, depending on its maturity, is composed mainly of either type III (early) or type I (late) collagen. It is a result of an overgrowth of granulation t ...

(skin) *

Lipedema Lipedema is a condition that is almost exclusively found in women and results in enlargement of both legs due to deposits of fat under the skin. Women of any weight may be affected and the fat is resistant to traditional weight-loss methods. The ...

(fat cells, typically in lower limbs) * Mediastinal fibrosis (soft tissue of the mediastinum) *

Myelofibrosis Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in ...

(bone marrow) * Myofibrosis (skeletal muscle) *

Peyronie's disease Peyronie's disease (PD) is a benign, acquired penile connective tissue disease characterized by the occurrence of fibrotic plaques within the Tunica albuginea (penis), tunica albuginea — the dense elastic covering of the Corpora cavernosa of pe ...

(penis) *

Nephrogenic systemic fibrosis Nephrogenic systemic fibrosis is a rare syndrome that involves fibrosis of the skin, joints, eyes, and internal organs. NSF is caused by exposure to gadolinium in gadolinium-based MRI contrast agents (GBCAs) in patients with impaired kidney funct ...

(skin) * Progressive massive fibrosis (lungs); a complication of

pneumoconiosis Pneumoconiosis is the general term for a class of interstitial lung disease where inhalation of dust (for example, ash dust, lead particles, pollen grains etc) has caused interstitial fibrosis. The three most common types are asbestosis, silico ...

Retroperitoneal fibrosis Retroperitoneal fibrosis or Ormond's disease is a disease featuring the proliferation of fibrous tissue (fibrosis) in the retroperitoneum, the compartment of the body containing the kidneys, aorta, renal tract, and various other structures. It m ...

(soft tissue of the retroperitoneum) *

Scleroderma Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...

systemic sclerosis Systemic scleroderma, or systemic sclerosis, is an autoimmune rheumatic disease characterised by excessive production and accumulation of collagen, called fibrosis, in the skin and internal organs and by injuries to small arteries. There are tw ...

(skin, lungs) * Some forms of

adhesive capsulitis Adhesive capsulitis, also known as frozen shoulder, is a condition associated with shoulder pain and stiffness. It is a common shoulder ailment that is marked by pain and a loss of range of motion, particularly in external rotation. There is ...

(shoulder) Fibrosis reversal Historically, fibrosis was considered an irreversible process. However, several recent studies have demonstrated reversal in liver and lung tissue, and in cases of renal, myocardial, and oral-submucosal fibrosis.

References

External links

* {{Connective tissue Symptoms and signs Medical terminology Rheumatology Scarring