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Pathological fibrosis is excessive deposition of extracellular matrix (primarily collagen) that disrupts organ architecture and function. It results from aberrant wound healing where the proliferative phase does not resolve and myofibroblasts persist, continuously secreting collagen. Key drivers include chronic inflammation, TGF-β signaling, epithelial-mesenchymal transition (EMT), and impaired matrix degradation. Fibrosis is irreversible and leads to organ dysfunction in liver, lung, kidney, and heart.
Compare normal wound healing with pathological fibrosis. Study fibrosis in different organs (liver cirrhosis from chronic hepatitis, lung fibrosis from idiopathic pulmonary fibrosis, cardiac fibrosis from MI). Understand anti-fibrotic therapeutics targeting myofibroblasts.
Fibrosis is not scar tissue—it is active, ongoing collagen deposition. Not all collagen deposition is fibrosis; some is necessary for healing. Once established, fibrosis is largely irreversible with current treatments.
Normal wound healing, which you've studied in depth, proceeds in three phases that must occur in sequence and then *stop*: inflammation, proliferation, and remodeling. In the proliferative phase, myofibroblasts — fibroblasts that have acquired contractile properties under stimulation by TGF-β — synthesize collagen and other extracellular matrix components to scaffold the wound. In the remodeling phase, matrix metalloproteinases degrade excess collagen, apoptosis removes myofibroblasts, and the scar matures. Pathological fibrosis occurs when this final resolution step fails. The myofibroblasts don't die, TGF-β continues to signal, collagen accumulates beyond what repair requires, and the architecture of the organ is progressively replaced by dense, functionless scar tissue.
The central villain is TGF-β1, a pleiotropic cytokine that drives virtually every component of the fibrotic program. It induces myofibroblast differentiation from resident fibroblasts, suppresses matrix metalloproteinase production (blocking collagen breakdown), and stimulates more TGF-β secretion in a self-amplifying loop. Chronic inflammation, your second prerequisite, is what keeps TGF-β elevated. When an injurious stimulus — a virus, a toxin, repeated mechanical stress, ischemia — persists or recurs, macrophages and other immune cells continuously release TGF-β and other profibrotic cytokines. The wound never reaches the resolution phase because the wound-healing signal never turns off.
Myofibroblasts have multiple cellular origins, which is one reason fibrosis is so difficult to interrupt. They arise from local fibroblasts, from epithelial-mesenchymal transition (EMT) in which epithelial cells shed their identity and acquire a mesenchymal, collagen-secreting phenotype, and from circulating bone marrow-derived fibrocytes. Each source responds to TGF-β and contributes to collagen deposition. Once a myofibroblast population is established, it is self-sustaining — the matrix stiffness it creates mechanically activates more TGF-β via integrin signaling, creating a biomechanical feedback loop independent of the original injurious stimulus.
The organ-specific consequences depend on which tissue is affected. In the liver, chronic hepatitis or alcohol toxicity drives hepatic stellate cells (the liver's myofibroblasts) to replace hepatocyte parenchyma with collagen, ultimately producing cirrhosis — loss of lobular architecture, portal hypertension, and liver failure. In the lung, idiopathic pulmonary fibrosis (IPF) replaces alveolar tissue with fibrotic scar, creating a restrictive ventilatory defect and impaired gas exchange. In the heart, following myocardial infarction, fibrotic replacement of cardiomyocytes creates non-contractile scar tissue, reducing ejection fraction and increasing arrhythmia risk. In every case the pathological endpoint is the same: functional cells replaced by non-functional matrix, organ capacity irreversibly reduced.