The body’s wound healing response is a highly coordinated biological process designed to restore tissue integrity following injury. While this process typically results in functional repair or a minimal, stable scar, it can sometimes become dysregulated. Fibrosis is a pathological form of healing characterized by the excessive and persistent accumulation of dense, non-functional connective tissue. This condition is an overzealous repair mechanism that fails to turn itself off, leading to rigid tissue that impairs normal organ function.
The Stages of Normal Tissue Repair
Healthy tissue repair proceeds through a series of overlapping and tightly controlled phases. The initial phase is inflammation, which begins immediately upon injury and involves the recruitment of immune cells like neutrophils and macrophages. These cells clear debris, fight infection, and release chemical signals that guide subsequent repair processes.
The next phase is proliferation, where the body begins to rebuild the damaged area by forming granulation tissue. Specialized cells called fibroblasts migrate into the wound bed and deposit a temporary extracellular matrix (ECM) rich in new blood vessels and collagen fibers. This temporary matrix provides a scaffold for new cell growth and begins wound contraction.
The final phase, maturation or remodeling, can last for months or even years as temporary granulation tissue is replaced by a more organized, permanent scar. During this stage, the newly deposited collagen is reorganized, strengthened, and cross-linked, improving the tissue’s tensile strength. In normal healing, the cells responsible for laying down the matrix eventually undergo programmed cell death, signaling the end of the repair process and resulting in a functional, non-progressive scar.
The Cellular Mechanism of Fibrotic Scarring
Fibrosis begins when the normal repair program becomes stuck in perpetual wound healing, revolving around the persistent activation of myofibroblasts. These cells are the main drivers of pathological scarring and excessive matrix deposition.
Myofibroblasts are derived primarily from resident fibroblasts, but they can also originate from other cell types through transdifferentiation. Unlike normal fibroblasts, myofibroblasts express alpha-smooth muscle actin (\(\alpha\)-SMA), which gives them contractile properties. While this contractility helps pull wound edges together during normal healing, its persistence in fibrosis leads to tissue stiffening and contraction.
The major function of the myofibroblast is the excessive production and secretion of Extracellular Matrix components, particularly Type I collagen. This process is driven by potent signaling molecules, most notably Transforming Growth Factor-beta (TGF-\(\beta\)). The overabundance of collagen creates a dense, rigid fibrotic scar that lacks the specific cellular architecture of the original tissue.
In healthy remodeling, myofibroblasts are cleared from the site by apoptosis after the wound is closed. In fibrosis, however, they resist this programmed cell death. Their continued survival and activity result in a progressive buildup of stiff, disorganized matrix material. This failure to turn off the pro-fibrotic program is the difference between a temporary, functional scar and a permanent, disease-causing fibrotic lesion.
Conditions That Promote Excessive Fibrosis
The transition from controlled repair to pathological fibrosis is triggered by conditions that prevent the natural resolution of healing. Chronic, unresolved inflammation is a major driver, as the sustained presence of inflammatory cells continuously releases profibrotic cytokines like TGF-\(\beta\). This prolonged signaling keeps myofibroblasts active long after the initial injury should have been resolved.
Repeated or persistent injury, such as chronic viral infection in the liver or constant toxin exposure in the lungs, prevents adequate time for proper remodeling. This cycle of damage and incomplete repair continually reactivates the inflammatory and proliferative phases. Systemic conditions, including diabetes and genetic predispositions, also increase susceptibility to fibrosis by impairing the body’s ability to regulate the inflammatory response.
Mechanical stress on the wound site is another influential factor that can exacerbate scar formation. Physical tension is sensed by cells through mechanotransduction, which activates fibroblasts and promotes their differentiation into contractile myofibroblasts. This external force prevents the “off switch” for healing from being activated, leading to exaggerated scarring like hypertrophic scars.
How Fibrotic Tissue Impairs Organ Function
The consequence of fibrosis is the disruption of normal tissue architecture, which directly leads to organ dysfunction. Fibrotic tissue is structurally rigid and non-elastic, replacing the flexible, specialized cells required for proper organ mechanics.
In the lungs, pulmonary fibrosis replaces the delicate, gas-exchanging air sacs with stiff, thick connective tissue, severely reducing the organ’s ability to transfer oxygen into the bloodstream. Hepatic fibrosis, or cirrhosis, distorts the normal lobular structure of the liver with bands of scar tissue, impeding blood flow and preventing liver cells from carrying out their metabolic and detoxification roles.
Cardiac fibrosis involves the deposition of excessive matrix within the heart muscle, increasing myocardial stiffness and interfering with the electrical signaling necessary for coordinated contraction. This results in reduced pumping efficiency and can lead to heart failure. The replacement of functional tissue with this non-functional, dense collagen matrix can cause organ failure, contributing to a significant percentage of mortality worldwide.