Fibrosis

Fibrosis is a pathological process in which tissue becomes scarred and stiffened because of excessive deposition of extracellular matrix proteins, mainly collagen, produced by activated cells called myofibroblasts. Fibrosis is a normal part of wound healing, but when the triggering injury or chronic inflammation persists, the repair program does not switch off. The result is structural damage and loss of function in the affected organ. Because the same basic process can occur in almost any tissue, fibrosis links many diseases of the lung, liver, kidney, heart and skin, and it is a major cause of chronic organ failure worldwide.

This entry first defines fibrosis and separates it from normal tissue repair, then describes the cellular and molecular machinery behind it, including the origins of myofibroblasts, the signalling pathways that drive them, and the role of immune cells in sustaining the response. It next surveys the causes and types of fibrosis and how it manifests in major organs. The final sections cover how fibrosis is diagnosed and measured, current therapeutic strategies, the history of its scientific study, and its relationship to cancer and to unresolved questions about reversibility and mechanism.

定义与基本特征

Fibrosis is the excessive deposition of extracellular matrix (ECM) in a tissue, which causes scarring and hardening of the affected organ. The ECM is a network of proteins and polysaccharides that gives tissues structure and provides signals to the cells within them. Its main structural component is collagen, especially types I and III. In a healthy organ, matrix production and degradation are kept in balance, and the matrix turns over slowly. Normal wound repair is different: it produces a temporary matrix that is remodelled and then withdrawn once the injury has closed. Fibrosis is a failure of that self-limiting process. Matrix production continues after the initiating stimulus has passed, or matrix builds up faster than it can be cleared, so the tissue becomes stiff and its normal architecture is lost.

Four histological features are usually considered the core hallmarks of fibrosis. The first is proliferation of fibroblasts and their activated descendants, the myofibroblasts. The second is accumulation of matrix, mainly collagen and other fibrillar proteins. The third is a change in matrix composition: the proportion of fibrillar collagen rises, while more elastic, basement-membrane and other tissue-specific components are lost, and enzymatic cross-linking, for example by lysyl oxidase, makes the deposited matrix more rigid and more resistant to breakdown. The fourth is reduced matrix degradation. This reflects a shift in the balance between enzymes that break down matrix, such as matrix metalloproteinases, and their inhibitors, such as tissue inhibitors of metalloproteinases (TIMPs). Together these changes sustain the fibrotic state even when the original trigger is gone.

Persistent fibrosis is harmful because the scar tissue replaces functional parenchyma. Specialised cells such as hepatocytes, alveolar epithelial cells and nephron cells are lost or isolated from their blood supply, and the stiff matrix distorts the tissue architecture that normal function depends on. As the proportion of functional tissue falls, organ capacity declines progressively. In the late stages, this can result in organ failure, as seen in the liver in cirrhosis and in the kidney in chronic-kidney-disease. Fibrosis is therefore often described less as a single lesion than as a process that reduces functional reserve over time.

Several related terms are used in pathology, and their meanings overlap. Fibrosis refers to the process of excess fibrous connective tissue formation and, in the broad sense, to the resulting tissue. Scarring is a clinical and descriptive term for the visible or structural result of healing after injury, and it may be normal or pathological. Sclerosis describes hardening of tissue and is often used as a synonym for fibrosis in disease names, such as systemic sclerosis, although it has other meanings in other fields; multiple sclerosis, for example, involves demyelination rather than matrix deposition as its defining feature. Desmoplasia is a term used mainly in oncology for a dense fibrous stromal reaction around tumours. It is a specific form of fibrotic change within the tumour context rather than a separate process.

研究与语境说明

细胞来源与成纤维细胞–肌成纤维细胞转化

Resident fibroblasts and the myofibroblast switch

Under normal conditions, the extracellular matrix is maintained by quiescent resident fibroblasts that synthesise and remodel matrix at a low rate. When tissue is injured, these cells can be pushed into an activated state. Profibrotic cytokines are known to drive this shift both in animals and in cultured cells, which is why resident fibroblasts have long been treated as the reference population for myofibroblast formation. Until the mid-1990s, the prevailing assumption was that myofibroblasts came almost entirely from these resident cells. Until the mid-1990s, it was generally assumed that myofibroblasts were derived from resident fibroblasts. Later work added several other possible precursors, and the field has since been divided over how large each contribution is.

Defining features of the myofibroblast

The myofibroblast is distinguished by the expression of α-smooth muscle actin (α-SMA), a name that reflects its resemblance to smooth muscle cells. These cells are called myofibroblasts, because of alpha smooth muscle actin (αSMA) expression and the similarities of their characteristics to those of fibroblasts. In culture, α-SMA is incorporated into stress fibres, and this change is linked to the maturation of focal adhesions. One study found that myofibroblasts incorporate α-SMA in stress fibers, develop mature FAs and their adhesion capacity is significantly increased.

Contractility is the second defining property. Myofibroblasts use an actin–myosin machinery that allows them to pull on the matrix, which is useful in wound closure. Myofibroblasts can contract by using smooth muscle type actin-myosin complex, rich in a form of actin called alpha-smooth muscle actin. These cells are then capable of speeding wound repair by contracting the edges of the wound. The role of α-SMA itself is less clear-cut. Experiments with cardiac fibroblasts showed that siRNA knockdown and overexpression experiments demonstrated that α-SMA is involved in collagen pad contraction, but is not sufficient to induce contraction of the matrix. A knockout study also found that SMαA-null fibroblasts can acquire the myofibroblast phenotype in response to TGF-β1, which suggests that α-SMA is a marker and effector rather than a prerequisite. Its reliability as a marker has also been questioned. One study concluded that αSMA is an inconsistent marker of both contractile fibroblasts and collagen-producing fibroblast in murine models of tissue fibrosis.

The third feature is high matrix output. Myofibroblasts produce large amounts of collagen and other structural proteins. Isolated cardiac fibroblasts that express high levels of α-SMA in stress fibres are also described as synthesising large amounts of extracellular matrix proteins. The balance between useful and harmful contraction is clinically important: contractile force is physiological during repair, but it has negative implications for tissue function when produced excessively, such as in hypertrophic scar cases.

Alternative origins

Several other cell types have been proposed as sources of myofibroblasts. Circulating bone marrow–derived fibrocytes were among the first alternatives proposed. Epithelial and endothelial cells may also transition into the mesenchymal state through EMT (transition from either epithelial or endothelial cells (EMT or EndoMT), and pericytes, vascular smooth muscle cells and adipocytes have been named as additional precursors in various organs. In most tissues, myofibroblasts are thought to originate from resident fibroblasts, but they may also be derived from other cell types, mostly of mesenchymal origin, such as vascular smooth muscle cells, pericytes and adipocytes.

Endothelial-to-mesenchymal transition (EndMT) has attracted particular attention in the heart. A 2007 study reported that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells. Later work has been contradictory. Some studies have refuted these claims, suggesting that de novo EndMT plays little role in cardiac fibrosis in the adult. A distinction has to be made between cardiac fibroblasts that arise from endothelium during embryonic development, where there is broad agreement, and de novo EndMT in adult cells, where the disagreement lies. In the kidney, EndMT has been linked to capillary loss and hypoxia, but despite the evidence on endMT in human renal biopsies and renal fibrosis animal models, controversy remains over to what extent endMT truly contributes to the emerging myofibroblast pool in CKD.

Organ-specific patterns and the unresolved debate

The relative importance of each source depends strongly on the organ and the type of injury. In the lung, lineage-tracing studies have failed to provide experimental evidence for epithelial and fibrocyte origins of lung myofibroblasts. Instead, the strongest evidence points to resident mesenchymal cells, which appear to be important sources of myofibroblasts in murine models of lung injury and fibrosis. A 2025 kidney study using combined genetic tracing found that renal myofibroblasts primarily arise from resident fibroblasts, with no significant contribution from other cell lineages via mesenchymal transition. Earlier kidney reviews, by contrast, gave bone marrow–derived fibrocytes a major role. One of them suggested that resident fibroblasts and bone marrow–derived fibrocytes are the two major sources of myofibroblasts in kidney fibrosis.

The quantitative estimates from different studies vary widely, partly because of differences in models and lineage-tracing tools. For example, in one table of kidney studies, the share of myofibroblasts attributed to bone marrow-derived fibrocytes ranged from 8.6% Of myofibroblasts in UUO to 32% Of myofibroblasts in rat IRI, while resident fibroblasts or pericytes were credited with much larger shares in other reports. Such figures should be read as model-dependent rather than as settled proportions.

Taken together, the current consensus is that resident mesenchymal cells, mainly fibroblasts and pericytes, supply most myofibroblasts in many tissues. Other cell types may nonetheless matter through paracrine signalling even when their direct contribution is small. Although lineage-tracing experiments have failed to show significant contribution from epithelial cells or fibrocytes, they may play important functional roles in myofibroblast activation through paracrine signaling. The open questions concern how these sources overlap, how much each one contributes in human disease, and whether such contributions can be separated experimentally from one another.

信号通路：TGF-β、Wnt 与其他调控因子

TGF-β and myofibroblast differentiation

Of the signals that drive scarring, the growth factor TGF-β1 has the strongest reputation. It is the main growth factor inducing myofibroblast differentiation from a variety of different precursor cells. Its canonical route starts when ligand binding brings together type II and type I serine/threonine receptor kinases. The activated type I receptor then phosphorylates SMAD2 and SMAD3. These proteins pair with SMAD4, enter the nucleus and change the transcription of fibrosis-related genes, including those linked to myofibroblast markers such as α-smooth muscle actin.

Signalling through TGF-β also runs along routes that do not require SMAD proteins. These include MAPK family members (ERK, JNK, p38), Rho-like GTPases and the PI3K/AKT pathway. The weight of each route depends on cell type and context. In primary human lung fibroblasts, myofibroblast differentiation induced by TGF-β required the phosphatidylinositol 3-kinase pathway. PPARγ ligands, by contrast, were reported to block this differentiation largely through a SMAD-independent mechanism (PPAR-γ ligands inhibit TGFβ-mediated differentiation of human lung fibroblasts via a Smad-independent pathway). In a study of fibroblast apoptosis, the anti-death effect of TGF-β1 depended on SMAD2/3 and ERK1/2 acting together, and the Akt pathway was not involved.

The routes also interact. ERK strengthens the transcriptional activity of SMAD, which helps drive TGF-β/SMAD-dependent epithelial–mesenchymal transition. Mechanical inputs can feed into this network as well. In mesenchymal stromal cells, collagen matrices and the Rho/ROCK pathway influence the TGF-β3/Smad2/3 pathway by regulating different phosphorylation sites of the Smad linker region. This study used tenogenic rather than fibrotic cells, so its relevance to fibrosis is indirect.

Latent TGF-β stored in the matrix and its mechanical activation

Much of the TGF-β in tissue is deposited as an inactive complex. TGF-β is stored in the extracellular matrix as a latent complex with its prodomain. Latent TGF-β1 is tethered to latent TGF-β1-binding protein-1 (LTBP-1), which is part of the extracellular matrix. LTBP1 anchors the latent complex into the extracellular matrix by binding to fibrillin or fibronectin.

Release depends on force. Integrins, specifically αvβ1, αvβ3, αvβ5, and αvβ6, bind an RGD motif in the prodomain and transmit cell traction to it. This integrin-mediated force activation requires latent TGFβ to be cross-linked to LTBP1, to provide mechanical resistance against the cell traction forces and induce a conformational change in LAP that leads to liberation of active TGFβ. Single-molecule measurements indicated that tension of roughly 40 piconewtons, the scale a single integrin can transmit, is sufficient to open the "straitjacket" that keeps the factor latent (integrin-transmitted forces of >40 pN activate TGF-β1 from the large latent complex). The mechanical input can also come earlier: ECM remodeling, preceding the activation step, mechanically primes latent TGF-β1 akin to loading a mechanical spring. In this way, matrix mechanics is directly coupled to the strength of the TGF-β signal. Based on these findings, researchers have suggested that interfering with mechanical activation by reducing integrin affinity, cell contractility, and binding of latent TGF-β1 to the ECM could offer a way to modulate TGF-β action therapeutically.

Wnt/β-catenin signalling and PPARγ antagonism

TGF-β1 sits within a regulatory system in which TGF-β1 acts on a dual antagonism system comprising the canonical WNT/β-catenin and peroxisome proliferator activated receptor gamma (PPARγ). The two arms oppose each other: when PPARγ expression rises, WNT/β-catenin signalling falls, and when WNT/β-catenin signalling rises, PPARγ expression falls. A TGF-β1 stimulus therefore tends to push cells toward WNT activity while suppressing PPARγ, and PPARγ in turn restrains this combined loop (TGF-β1 can activate canonical WNT signaling, and can decrease PPARγ expression. In contrast, PPARγ decreases the TGF-β1/WNT/β-catenin pathway.).

At the level of the destruction complex, inflammation stimulates WNT ligand release. When these ligands engage Frizzled and LRP5/6 receptors, the destruction complex AXIN/APC/GSK-3β is inactivated, and β-catenin phosphorylation stops, preventing its degradation in the proteasome. Pharmacological activation of PPARγ works against this by raising the levels of Smad7, GSK-3β and DKK1, which lower β-catenin (PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1).). In hepatic stellate cells, Dkk-1 enhances PPARγ-driven PPRE promoter activity, a key adipogenic transcriptional parameter, abrogates agonist-stimulated contraction, and restores HSC quiescence in culture. In mice, blocking Wnt signaling suppresses liver fibrosis. WNT signalling also operates beyond the TGF-β axis: in addition to the TGF-β signaling pathway, which is a key mediator of fibroblast activation, the Wnt/β-catenin signaling pathway plays an important role in fibrotic reactions.

YAP/TAZ mechanotransduction and matrix stiffness

YAP and TAZ are transcriptional co-activators that shuttle between the cytoplasm and the nucleus in response to the mechanical state of the cell, a process regulated in part through the Hippo pathway and actomyosin tension. On a stiff matrix, with high contractile tension, they accumulate in the nucleus, partner with TEAD transcription factors, and drive genes for matrix proteins and α-smooth muscle actin. This creates a positive feedback loop: a stiffer matrix supports more myofibroblasts, which deposit more collagen and stiffen the tissue further. YAP and TAZ also connect to WNT signalling; the destruction complex is inhibited because YAP and TAZ dissociate from the complex. The relative contribution of YAP/TAZ compared with SMAD and WNT inputs in living fibrotic tissue remains an active area of investigation.

炎症与免疫系统的作用

Fibrosis is usually understood as the result of a repair response that fails to switch off once the injury has been dealt with. In many organs, damaged tissue recruits macrophages, T cells, neutrophils and other leukocytes. When this recruitment persists, the immune infiltrate keeps the wound in an active state and prevents resolution. Macrophages are central to this process. They can initiate, sustain and amplify the inflammatory reaction. In the liver, Kupffer cells and monocyte-derived macrophages both shape how fibrosis progresses and whether it regresses. The composition of the infiltrate also changes over time. Early lesions are dominated by neutrophils and monocyte-derived macrophages, whereas chronic lesions contain a larger share of lymphocytes. The balance between pathogenic and pro-resolving T and B cell programmes can therefore decide whether injured tissue heals or scars.

Immune cells act mainly through cytokines and chemokines, which reach the fibroblasts and epithelial cells in the surrounding tissue. The most prominent of these signals is TGF-β, which pushes fibroblasts toward a contractile myofibroblast phenotype and increases collagen output. Type 2 cytokines add to this effect. IL-4 and IL-13 activate fibroblasts through STAT6 signalling. IL-13 also raises levels of tissue inhibitors of metalloproteinases, suppresses matrix-degrading enzymes, and activates TGF-β itself, which creates an autocrine loop of inflammation and matrix accumulation. IL-5 expands eosinophils and suppresses IFN-γ, a cytokine with antifibrotic activity. Th17 cells and M2-polarised macrophages release IL-17A, platelet-derived growth factor and SPP1, which further drive fibroblast activation and collagen deposition. In pulmonary fibrosis, activation of the NLRP3 inflammasome leads to maturation of caspase-1 and release of IL-1β and IL-18, which promote the fibrotic programme.

The helper T cell profile is also critical. Effective healing is usually associated with a dominant Th1 response, and a shift toward Th2 responses is linked to chronic inflammation that can end in fibrosis. Regulatory T cells and IL-10 normally restrain this process, so impaired regulation favours scarring. In systemic sclerosis, T cell subsets are skewed toward Th2 and Th17 phenotypes, regulatory T cell function is reduced, and the associated cytokines correlate with disease activity. Non-conventional lymphocytes are also involved. In patients with alcohol-related or fatty liver disease, mucosal-associated invariant T cells accumulate in fibrotic septa, and in mouse models, animals enriched for these cells develop more liver fibrosis. Similarly, activation of invariant natural killer T cells has been linked to neutrophil recruitment, inflammasome activation and macrophage and fibroblast activation.

Once established, fibrotic tissue sustains its own inflammatory environment. Fibroblasts and macrophages engage in bidirectional paracrine crosstalk that is normally required for tissue maintenance. Under chronic stress, injury or ageing, this exchange becomes skewed, and stable pathological cell states emerge that are resistant to resolution. Activated fibroblasts secrete chemokines and cytokines that attract further immune cells, while the immune cells in turn reinforce fibroblast activation. This cycle explains why scarring can continue after the original trigger has been reduced. Immune dysregulation also explains why the same tissue can develop fibrosis after an injury that another person's immune system resolves without lasting damage.

Autoimmune disease and persistent antigen provide two major routes into this cycle. In autoimmune disorders, fibrosis is viewed as a failure to resolve wound healing, in which ongoing immune-mediated injury drives a transition to chronic inflammation. The process is often described as sequential: early damage sensing, followed by innate amplification and then adaptive immune polarisation. Fibrotic changes are prominent in rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, Sjögren's syndrome, inflammatory bowel disease and autoimmune hepatitis. Infections that the immune system cannot fully clear have similar effects. Viral injury to alveolar epithelium can trigger chronic low-grade inflammation in the lung, and chronic viral hepatitis is a well-established cause of liver fibrosis. Granulomatous infections such as tuberculosis are a classic example, because persistent antigen keeps immune cells activated. In many cases, the precise immune trigger remains uncertain, and the role of innate and adaptive responses varies between organs and diseases.

病因与类型

Principal triggers

Fibrosis is a response that many kinds of injury can provoke rather than a single disease. Its triggers fall into several broad groups. Toxins include inhaled mineral dusts such as silica and asbestos, certain drugs such as the chemotherapy agent bleomycin and the antiarrhythmic amiodarone, and alcohol, which injures the liver. Infectious agents, including hepatitis B and C viruses, Mycobacterium tuberculosis and Schistosoma species, cause persistent inflammation and granulomas, and the resulting repair can leave fibrotic tissue behind. Autoimmune reactions, as in autoimmune disease such as systemic sclerosis, combine immune activation with injury to small blood vessels and promote fibroblast activation in the skin and internal organs. Mechanical stress, such as chronic pressure overload from hypertension or aortic stenosis, drives interstitial fibrosis in the heart. Metabolic injury, including lipid accumulation in fatty liver disease and sustained hyperglycaemia in diabetic kidney disease, provides a steady stimulus for matrix deposition. Radiation damages both parenchymal and stromal cells and can produce late fibrosis months or years after treatment. Several triggers often coexist in the same patient, and their combined effect is generally greater than that of any one alone.

Classification by cause and by tissue

Fibrosis is commonly sorted according to the nature of the injury and the pattern of tissue involvement. The distinction between reparative and reactive fibrosis is the clearest example. Replacement (reparative) fibrosis forms when cells die and a collagen-rich scar fills the gap. In the heart, this follows myocardial infarction, where the scar maintains the structural integrity of the ventricle, although an excessive scar can impair function. Reactive fibrosis, by contrast, develops without substantial loss of parenchymal cells. It involves diffuse deposition of extracellular matrix in the interstitium or around vessels, and it is typically driven by sustained haemodynamic or inflammatory signals. Perivascular fibrosis often precedes interstitial fibrosis and can restrict oxygen and nutrient supply to the tissue. Infiltrative fibrosis, in which abnormal substances such as amyloid or glycosphingolipids accumulate, forms a further category. These patterns are not mutually exclusive; after myocardial infarction, for example, replacement fibrosis at the infarct can coexist with reactive interstitial fibrosis in the surrounding myocardium.

Classification by cause also distinguishes fibrosis with an identifiable trigger from fibrosis of unknown origin. Idiopathic pulmonary fibrosis is the best-known example of the latter, while fibrosis secondary to infection, toxin exposure or autoimmunity is classed by its precipitating event. Such schemes are useful clinically but are imperfect, because the same organ can display several forms at once and because a single trigger may act through different mechanisms in different people.

Well-characterised conditions and their precipitating injuries

Several conditions illustrate how a specific injury leads to a recognisable fibrotic disease. In idiopathic pulmonary fibrosis, repeated injury to the alveolar epithelium is thought to lead to abnormal repair, although the initiating events remain uncertain. Chronic hepatitis B or C, alcohol misuse and metabolic dysfunction-associated steatohepatitis are the most frequent precursors of cirrhosis, in which progressive scarring reorganises the liver into regenerative nodules. In the kidney, long-standing diabetes and hypertension, as well as glomerular injury, are the common routes into chronic kidney disease and the interstitial fibrosis that accompanies it. Systemic sclerosis is an autoimmune condition in which vascular injury is followed by progressive thickening of the skin and, in some patients, of internal organs. Schistosomal infection can cause periportal fibrosis in the liver, and radiation can cause late fibrosis in the lung, bowel and skin.

Genetic and environmental susceptibility

Exposure alone does not explain who develops fibrosis. Most adult-onset cases are sporadic, and genetic risk in these patients is generally attributed to many weak alleles rather than a single strong one. Familial clustering is more uncommon but informative: strong familial aggregation is seen in a minority of pulmonary fibrosis cases, and estimates of familial cases in idiopathic pulmonary fibrosis typically range from about 5% to 20%. The best-characterised variant is a promoter polymorphism in MUC5B (rs35705950), which is associated with a several-fold increase in risk among heterozygotes and a larger increase among homozygotes, yet many carriers never develop disease, so the variant is not fully penetrant. Its frequency differs markedly between populations, being far more common among people of European ancestry than among East Asian or African populations. Rare mutations in telomerase genes such as TERT and TERC are also implicated, and shortened telomeres in affected families are linked to earlier onset in successive generations. Environmental factors, including cigarette smoking, occupational dusts, viral infection, air pollution and gastro-oesophageal reflux, act on these genetic backgrounds, and the interactions between genes, exposures and ageing appear to shape the final phenotype. This model explains why two people with similar exposures may follow very different courses, and why fibrosis in one organ can be more strongly linked to inherited factors than fibrosis in another. Much of this variability remains only partly understood.

主要器官中的纤维化

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. It is characterized by irreversible scarring of the lung parenchyma and progressive decline in lung function. Onset is most often between about 50 and 70 years of age, and survival after diagnosis is commonly 3 to 5 years. The leading model holds that sustained alveolar epithelial micro-injury in genetically susceptible older adults starts a chain of disordered repair. Activated epithelial cells release TGF-β, which drives fibroblast migration, proliferation, and differentiation into myofibroblasts. Fibroblastic foci, small clusters of active fibroblasts near the air–tissue interface, are regarded as sites of new fibrosis. Ageing, smoking, and telomerase-related genetic variants are among the recognized risk factors. Diagnosis usually depends on high-resolution CT.

Fibrosis following lung injury, infection, or connective-tissue disease shares the same endpoint of stiff, poorly ventilated tissue but has identifiable triggers. Examples include scarring after severe acute respiratory distress, sequelae of tuberculosis and COVID-19 pneumonia, and interstitial lung disease associated with rheumatoid arthritis and systemic lupus erythematosus. Autoantibodies arising in collagen vascular diseases have been proposed as one route to alveolar injury.

Liver fibrosis is a wound-healing response to acute or chronic damage that is dynamic and, in principle, reversible. Activated hepatic stellate cells multiply and deposit matrix, producing fibrous bands that distort the architecture of the liver. The METAVIR system grades the process from F0 (no fibrosis) to F4. At F1 and F2 the scar extends around the portal tracts; at F3, fibrous bridges link portal tracts with central veins. A liver with stage 4 fibrosis is equivalent to a cirrhotic liver. Cirrhosis is defined by the formation of regenerative nodules within a web of cross-linked collagen, which in turn distorts the architecture and normal vascular anatomy. Alcohol-related and fatty liver disease account for roughly 40 to 60% of cases in Europe and North America, and chronic viral hepatitis for a further 25 to 30%. Distorted vessels raise portal pressure, which leads to varices, ascites, and hepatic encephalopathy, and the synthetic capacity of the liver declines as parenchyma is lost.

Regression is possible in earlier stages. Early-stage fibrosis can potentially be reversed if the underlying cause is successfully treated. Patients who achieve sustained viral clearance with hepatitis C treatment often show regression of liver scarring over time. In a cohort of patients with hereditary hemochromatosis, among 23 patients with cirrhosis (F4) on their initial biopsy, fibrosis decreased in 10 (43.5%) on repeat biopsy after phlebotomy. Regression of established cirrhosis is far less consistent, because the nodular and vascular remodelling tends to persist even when the scar thins.

Renal fibrosis is the shared endpoint of most chronic kidney disease (CKD), regardless of the initial insult. The final common pathway in the pathophysiology of CKD involves glomerular sclerosis, tubular atrophy and interstitial fibrosis. Interstitial matrix expansion compresses the surrounding tubules and capillaries, so that the nephrons that remain must handle a growing filtration load, and each loss of nephrons accelerates the decline in glomerular filtration. TGF-β is generally regarded as the dominant driver. Its effects include increased production of collagens, proteoglycans, and glycoproteins, together with reduced matrix degradation. In animal models of obstructive, remnant-kidney, and diabetic nephropathy, blocking the Smad2/3 branch of signalling reduced collagen accumulation and fibrosis. Because CKD has a global prevalence estimated at roughly 11 to 13% of adults, the renal scarring pathway has broad clinical significance. For patients with end-stage kidney failure, transplantation or dialysis remains the principal treatment.

Cardiac fibrosis develops in two principal patterns. Replacement fibrosis forms a non-contractile scar after myocardial infarction, while reactive interstitial and perivascular fibrosis accumulates in pressure-overloaded or ageing myocardium, as seen in long-standing hypertension or aortic stenosis. Excess collagen stiffens the ventricle, impairing diastolic filling and contributing to heart failure with preserved ejection fraction. Scar tissue also separates and disorganizes cardiomyocytes, slowing and fragmenting electrical conduction; this creates a substrate for re-entrant arrhythmias such as ventricular tachycardia. Cardiac fibrosis is therefore a major link between tissue remodelling and cardiovascular disease.

In skin, fibrosis is most clearly represented by systemic sclerosis, an autoimmune disease in which dermal thickening and hardening progress, typically assessed by a clinical skin score. The same fibrotic process can involve the lungs, with interstitial lung disease, the kidneys, with scleroderma renal crisis, the heart, and the gastrointestinal tract. Organ involvement, rather than skin changes alone, usually determines prognosis.

诊断、分期与测量

组织学评估与活检的局限

Liver biopsy has long been the benchmark for judging hepatic scarring. Liver biopsy, first introduced in 1923, has been widely used in diagnosing liver disease and remains the reference standard for assessing liver fibrosis in chronic liver disease. Under the microscope, collagen deposition is revealed by specific stains. Masson's trichrome colours fibres so that septa and bridging collagen stand out from hepatocytes, while picrosirius red, viewed under polarised light, distinguishes thick and thin collagen fibres. Pathologists then assign a stage using semi-quantitative schemes. Ishak's modified Histology Activity Index, METAVIR and Batts-Ludwig systems are used to grade histology samples. These systems are not uniform, and the staging systems of hepatic fibrosis are not consistent, which might increase heterogeneity and reduce the reliability of diagnostic performance across studies.

The weaknesses of biopsy arise mainly from the size of the sample and the way fibrosis is distributed. Typical core biopsies measure 10–30 mm by 1–2 mm, representing only about 0.002% of the total liver mass. Because fibrosis severity is often regionally heterogeneous within the liver, a single core may misrepresent the whole organ. In paired-sample studies, the histologic fibrosis stage may differ in approximately one-third of specimen pairs taken from different regions. Reader disagreement adds a second source of error, with estimates of sampling error (up to 35%) and inter- and intra-observer variability (up to 20%). Procedural risk is also relevant: the risk of bleeding from liver biopsy in F3/F4 disease is 0.6%, and it is greatest when the platelet count is below 50,000 to 60,000 per microlitre. These factors make repeated biopsy impractical for monitoring. Repeated biopsies are infeasible in clinical settings for continuous monitoring of fibrosis grade.

弹性成像（Elastography）

Because scarred tissue is stiffer, non-invasive methods estimate hardness by measuring how mechanical waves move through it. In normal liver, the tissue is softer, resulting in shear waves with higher attenuation and slower propagation. As fibrosis develops, liver stiffness increases and wave propagation becomes faster. Transient elastography (FibroScan) applies low-frequency compressional impulses through the intercostal spaces. Magnetic resonance elastography generates shear waves with a driver device, images them with a modified phase-contrast MR sequence, and processes the images to produce a quantitative map of shear stiffness. The output is expressed in kilopascals (kPa), and MRE is used to evaluate tissue stiffness in diverse organs such as liver, breast, muscle, kidney, and spleen.

Accuracy is high in liver but depends on thresholds and conditions. In a meta-analysis of five trials, MRE showed a sensitivity of 94% and specificity of 95% in differentiating F0 to F1 from F2 to F4. Optimal cut-offs differ between studies: among 12 studies, the reported optimum stiffness threshold for diagnosing advanced fibrosis (≥ F3) ranged from 2.9 to 4.8 kPa. Stiffness is also not specific to fibrosis. Elastography may overestimate fibrosis in active inflammation, cholestasis, or hepatic congestion, or after food intake, and may be technically limited in obesity, ascites, or narrow intercostal spaces. Results from ultrasound-based techniques show a similar pattern: standardization remains challenging in obese patients and in cases of acute inflammation.

血清生物标志物与评分系统

Serum tests fall into two groups. Indirect markers combine routine laboratory values. FIB-4 is an index based on age, AST, ALT serum activities and platelet concentration. It is probably the most widely used serum index for screening hepatic fibrosis as a first step. Direct markers reflect matrix turnover itself. The ELF test measures three elements involved in matrix turnover: hyaluronic acid, tissue inhibitor of metalloproteinase-1, and N-terminal procollagen III peptide. Many services combine these in a stepwise pathway. In one primary-care cohort, when the FIB-4 was ≥ 1.3 it was defined as positive and the ELF Test was performed, and FIB-4 positivity was confirmed when ELF was ≥ 9.8, indicating advanced fibrosis.

Biomarkers have limits of their own. Cut-offs are not settled, and the absence of established cutoff values for diagnosing advanced fibrosis and cirrhosis is a recognised limitation. Their readings also shift with inflammation: in hepatitis C, all four biomarkers of liver fibrosis were influenced by histopathological activity grading, which is why biopsy is still cited as the reference in that setting.

测量的局限与分级困难

No single method performs well across all stages. Most non-invasive tests perform better for excluding advanced fibrosis or identifying cirrhosis than for distinguishing intermediate stages, which creates a diagnostic grey zone where combined testing or liver biopsy may still be required. Because biopsy is itself imperfect, it sets a ceiling on measured accuracy: uncertainty from observer variation and sampling effects imposes a ceiling on the diagnostic performance that can be shown with a comparative test, no matter how accurate.

Detecting early or reversible fibrosis is especially difficult. Regression is documented in some settings; fibrosis regression can be achieved after long-term antiviral therapy, yet routine surveillance by liver biopsy is hindered by its invasive nature, sampling error and observer variability. Repeated non-invasive measurements can help track such change, but their precision at small changes remains limited. Applying these methods outside the liver is also less extensively validated, and the staging thresholds used for liver fibrosis cannot be transferred directly to other organs.

治疗策略与干预

Antifibrotic therapy is most developed in the lung. Pirfenidone and nintedanib are the only two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF), and both received approval from the US Food and Drug Administration in October 2014 following the first pharmacological treatments for IPF. Neither drug restores lost tissue. Their main benefit is a slower rate of decline in lung function, and they slow, but do not reverse, the progression of fibrosis. Their mechanisms are only partly understood. Pirfenidone is usually linked to anti-inflammatory activity and suppression of TGF-β and tumour necrosis factor signalling. Nintedanib is an intracellular tyrosine kinase inhibitor that acts on vascular endothelial, fibroblast and platelet-derived growth factor receptors, and it interferes with fibroblast proliferation, differentiation and migration as well as extracellular matrix secretion. Electron microscopy of IPF fibroblast cultures has also shown that both drugs reduce collagen fibril formation, a finding that points to effects on matrix assembly as well as on cell behaviour. Side effects, including gastrointestinal symptoms, skin reactions and liver toxicity, are common enough to require ongoing monitoring. Trials in other interstitial lung diseases with a progressive fibrosing phenotype have extended this approach, and recent well-designed randomised controlled trials have confirmed the hypothesis that these agents can benefit some non-IPF patients.

靶向肝纤维化的药物

Liver fibrosis has a newer set of approved options. In March 2024, the US Food and Drug Administration granted accelerated approval to resmetirom for noncirrhotic MASH with moderate to advanced fibrosis. Resmetirom is a liver-directed thyroid hormone receptor-β agonist that lowers hepatic fat. In August 2025, the agency approved semaglutide 2.4 mg as the second treatment for MASH. Both approvals cover stages F2 and F3 but not established cirrhosis. The approval for resmetirom is still based on histological surrogate endpoints, which means that continued approval depends on confirmatory outcome trials. These drugs address the metabolic injury that drives fibrosis, and their effects on scarring have not yet been shown to change long-term clinical outcomes.

去除病因与纤维化逆转

Management of underlying causes remains the foundation of treatment across organs. The clearest example of regression comes from chronic hepatitis C. Effective, well-tolerated cures for hepatitis C have shown that fibrosis can regress once the virus is cleared. The degree of reversal depends on how far the scarring has progressed. The less extensive the fibrosis, the more likely complete reversal becomes. Regression is far less likely once patients already have portal hypertension and distortion of the hepatic architecture. In a 1990s-era Gastroenterology cohort, reversal was seen in 49% of patients with cirrhosis who had been treated. A 10-year prospective cohort reported a more modest picture: cirrhosis regressed in 24 of 43 patients, but 15 new cases occurred, a net reduction of only 5.3%. Mechanistically, regression reflects the breakdown of matrix by metalloproteinases, which is aided by reduced levels of their inhibitor TIMP-1, along with apoptosis of hepatic stellate cells. Advanced fibrosis stage and high baseline serum angiopoietin-2 levels were associated with failure of regression at 96 weeks, which suggests that these factors could help identify patients who need closer monitoring.

Regression is therefore uneven. Clinical trials remain the main route for testing new agents, but they must measure histological change, which is costly and sampling-dependent, or validated noninvasive markers. Transplantation is reserved for advanced organ failure, such as end-stage liver, kidney or lung disease, where replacing the damaged organ is the only option once scarring has passed the point of reversibility. Other approaches aim at TGF-β signalling and related pathways, but blocking these pathways broadly risks disrupting normal repair and immune regulation, so trials have had to balance efficacy against adverse effects, including unintended inflammation and skin lesions.

研究历史

Descriptions of scarring and tissue hardening date back to nineteenth- and early twentieth-century pathology, when fibrosis was recognised mainly by its gross and microscopic appearance. Pathologists could see dense connective tissue replacing functional parenchyma, but they had limited ways to identify which cells produced it. For much of that period, the word "fibroblast" was used loosely for any collagen-producing cell, so the source of scar tissue remained unresolved.

The myofibroblast

The modern history of fibrosis research begins with the myofibroblast. In 1971, Giulio Gabbiani and colleagues used electron microscopy to examine rat wound granulation tissue and found fibroblast-like cells containing bundles of microfilaments, a feature usually associated with smooth muscle. They proposed that these cells generated the contractile force behind wound contraction and named them myofibroblasts. A 1972 study extended this work by showing that isolated strips of granulation tissue could contract and relax in pharmacological baths, much as smooth muscle does. Early work therefore linked the cell to wound contraction rather than to disease. Its role in pathological scarring was developed later, and by the 2010s the myofibroblast was regarded as a central effector cell in fibrosis across many organs. A 1993 study by Desmoulière and colleagues then showed that TGF-β1 induces α-smooth muscle actin in granulation-tissue myofibroblasts and in cultured fibroblasts, which linked the cell type to a defined molecular trigger.

TGF-β

Transforming growth factor-β was first reported in 1978, when De Larco and Todaro described "sarcoma growth factors" secreted by fibroblasts transformed by a murine sarcoma virus. In 1981, the group led by Anita Roberts and Michael Sporn at the US National Cancer Institute isolated transforming growth factors from non-neoplastic tissues, showing that these molecules were not restricted to tumour cells. In the same year, Harold Moses's laboratory at the Mayo Clinic reported a parallel line of work. Subsequent research established that TGF-β belongs to a superfamily that now includes at least 33 members, among them bone morphogenetic proteins, activins and inhibins. Its role in stimulating matrix production became a central theme of fibrosis research, and this function is covered in more detail in the signalling section.

SMAD proteins

The intracellular pathway that carries TGF-β signals was clarified more slowly. Before the mid-1990s, the route from receptor to nucleus was poorly understood. Genetic screens in Drosophila identified the gene Mothers against decapentaplegic (Mad), and work in Caenorhabditis elegans identified the related sma genes. Vertebrate homologues were then found, and because the family combined elements of both names, it was designated SMAD in 1996. Subsequent biochemical work showed that receptor-activated SMADs, notably SMAD2 and SMAD3 for TGF-β and activin, are phosphorylated by type I receptors, form complexes with SMAD4, and move into the nucleus to regulate transcription. Genetic alterations in SMAD2 and SMAD4 were later found in specific tumour subsets, which established SMAD proteins as candidate tumour suppressors as well as signal transducers.

Translational research

From the 1980s onwards, research on fibrosis increasingly relied on experimental models in rodents, in which organ injury was induced chemically, surgically or immunologically to reproduce features of human scarring. These models allowed researchers to test the roles of individual cells and pathways in vivo, and they became the main platform for preclinical evaluation of candidate antifibrotic agents. The translation of mechanistic findings into targeted therapies, including attempts to interfere with TGF-β or SMAD signalling, is discussed in the treatment section.

与癌症及其他过程的关系；未解问题

Parallels with the tumour microenvironment

Tumours often contain a stroma that looks much like fibrotic tissue. Within a tumour, the balance that normally governs matrix synthesis and turnover is disrupted, producing abnormal vessels and collagen deposits of varying stiffness and organisation In tumors the homeostasis governing ECM synthesis and turnover is disturbed resulting in abnormal blood vessel formation and excessive fibrillar collagen accumulations of varying stiffness and organization.. The dense fibrous stroma that surrounds some carcinomas is termed desmoplasia, and it is the tumour counterpart of the fibrotic reaction described in other organs. In desmoplastic cancers, the activated fibroblasts known as cancer-associated fibroblasts (CAFs) are the dominant mesenchymal population, and their abundance has been linked to poor prognosis in several malignancies In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, where their presence and abundance signal a poor prognosis in multiple cancers..

The resemblance extends to the cells themselves. A subset of CAFs can be identified by contractile behaviour and expression of α-smooth muscle actin, which places them close to the myofibroblasts of fibrotic disease This is now known to be true for a subset of fibroblasts present in the tumour microenvironment, which can be identified based on their contractile characteristics and expression of certain proteins such as alpha smooth muscle actin (αSMA). Because these cells stay activated, they keep synthesising matrix and remodelling the stroma Fibroblasts at the site of a tumor, specifically referred to as CAFs, remain perpetually activated with a high capacity for ECM synthesis and microenvironmental remodeling, leading to stromal desmoplasia. Stromal fibrotic signatures also track with clinical behaviour: tumours with high fibrotic stroma are more often resistant to drugs and prone to relapse Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse..

Therapeutic work has followed this logic. In animal studies, CAF-directed approaches have been shown to deplete, eliminate or reprogramme these cells, but clinical translation remains incomplete Preclinical studies suggest that CAFs can be reduced, eliminated, or reprogrammed; however, clinical translation has not yet occurred.. Clinical trials of CAF-targeted agents have since begun, and their outcomes will test whether the fibrotic stroma is a valid target in cancer.

Overlap with wound healing and tissue repair

Fibroblasts sit at the centre of wound healing, tissue fibrosis and tumour fibrosis alike Fibroblasts are central in wound healing, tissue fibrosis and tumor fibrosis and studies of molecular mechanisms have demonstrated. The same cells, growth factors and matrix proteins participate in all three, so the distinction lies less in the molecular toolkit than in the timing and resolution of the response. Fibrosis is generally described as aberrant repair that follows chronic inflammatory injury, in which matrix accumulates and replaces normal parenchyma Fibrosis is a pathological change manifested as aberrant tissue repair after chronic inflammatory injury, resulting in excessive synthesis of extracellular matrix (ECM) and replacement of normal parenchyma by ECM such as collagen.. Repair that should end is instead sustained, and the signals that switch it off fail to operate.

The boundary is blurred in practice because the same signalling is used in both settings. Cells such as endothelial and epithelial derivatives, which are proposed as myofibroblast sources in fibrosis, may also play roles in normal repair. One review notes that EMT, EndMT and fibrocytes or other bone-marrow-derived precursors might have more important roles in normal repair than in fibrosis.. Thus, a single process may be physiological in one context and pathological in another, and the difference often depends on whether the injurious stimulus persists.

Open questions

Several questions remain unresolved. The first concerns the relative contribution of different myofibroblast origins. Results vary by organ and model. In the kidney, one 2025 lineage-tracing study concluded that myofibroblasts in kidney fibrosis mainly originate from resident fibroblasts, not full or partial EMT, EndoMT, or MMT, guiding research toward fibroblast-targeted therapies., whereas in pancreatic fibrosis, stellate cells were found to give rise to a large share of myofibroblasts stellate cells give rise to 65.7% of myofibroblasts in cerulein-induced pancreatic exocrine fibrosis.. In the heart, the origin of myofibroblasts is still considered unresolved, partly because there is a lack of an appropriate marker to uniformly identify resident fibroblasts and myofibroblasts within the heart..

The second question concerns reversibility. Early assumptions that fibrosis is permanent have been revised for some organs. Most information on fibrosis regression comes from studies in animal models, where resolution can occur in most cases if the underlying etiology is eliminated., but human disease is often harder to reverse because human fibrotic diseases are often multifactorial and eradication of the injurious stimuli may not be possible.. The liver offers the strongest human evidence, with regression described even after cirrhosis is established Reversal of established cirrhosis has also been documented.. In lung disease the picture is more mixed, as pulmonary fibrosis induced by drug or acute lung injury seems reversible after systematic treatment, whereas idiopathic pulmonary fibrosis is the most common fibrotic lung disease with progressive and irreversible development. The fate of the cells that drive regression is also unclear: the factors that determine the fate of myofibroblasts during liver fibrosis regression are still unknown.. Current staging systems compound the problem, since they were built to track progression and are limited by their categorical nature..

Ongoing research aims to address these gaps through improved biomarkers, better understanding of how mechanical forces shape fibrotic behaviour, and clarification of how ageing and metabolic states influence the balance between repair and scarring. Whether these approaches can be translated into validated interventions through clinical trials remains an open matter.

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