Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases (original) (raw)
Fibrosis is often defined as a wound-healing response that has gone out of control. Repair of damaged tissues is a fundamental biological process that allows the ordered replacement of dead or damaged cells after injury, a mechanism that is critically important for survival. Damage to tissues can result from various acute or chronic stimuli, including infections, autoimmune reactions, and mechanical injury. The repair process typically involves two distinct stages: a regenerative phase, where injured cells are replaced by cells of the same type, leaving no lasting evidence of damage; and a phase known as fibroplasia, or fibrosis, where connective tissue replaces normal parenchymal tissue. Although initially beneficial, the healing process becomes pathogenic if it continues unchecked, resulting in substantial remodeling of the ECM and formation of permanent scar tissue (Figure 1). In some cases, it might ultimately lead to organ failure and death.
Outcomes of wound healing: tissue regeneration or fibrosis. Following tissue injury, epithelial and/or endothelial cells release inflammatory mediators that initiate an antifibrinolytic-coagulation cascade, which triggers blood clot formation. This is followed by an inflammatory and proliferative phase, when leukocytes are recruited and then activated and induced to proliferate by chemokines and growth factors. The activated leukocytes secrete profibrotic cytokines such as IL-13 and TGF-β. Stimulated epithelial cells, endothelial cells, and myofibroblasts also produce MMPs, which disrupt the basement membrane, and additional cytokines and chemokines that recruit and activate neutrophils, macrophages, T cells, B cells, and eosinophils, important components of reparative tissue. The activated macrophages and neutrophils clean up tissue debris, dead cells, and invading organisms. Shortly after the initial inflammatory phase, myofibroblasts produce ECM components, and endothelial cells form new blood vessels. The myofibroblasts can be derived from local mesenchymal cells, recruited from the bone marrow (where they are known as fibrocytes), or derived by EMT. In the subsequent remodeling and maturation phase, the activated myofibroblasts stimulate wound contraction. Collagen fibers also become more organized, blood vessels are restored to normal, scar tissue is eliminated, and epithelial and/or endothelial cells divide and migrate over the basal layers to regenerate the epithelium or endothelium, respectively, restoring the damaged tissue to its normal appearance. However, in the case of chronic wounds, the normal healing process is disrupted. Persistent inflammation, tissue necrosis, and infection lead to chronic myofibroblast activation and excessive accumulation of ECM components, which promotes the formation of a permanent fibrotic scar.
In contrast to acute inflammatory reactions, which are characterized by rapidly resolving vascular changes, edema, and neutrophilic infiltration, pathogenic fibrosis typically results from chronic inflammatory reactions — defined as responses that persist for several weeks or months and in which inflammation, tissue destruction, and repair processes occur simultaneously. Despite having obvious etiological and clinical distinctions, most chronic fibrotic disorders have in common a persistent irritant that sustains the production of growth factors, proteolytic enzymes, angiogenic factors, and fibrogenic cytokines, which together stimulate the deposition of connective tissue elements that progressively remodel and destroy normal tissue architecture (1, 2).
When injuries occur, damaged epithelial and/or endothelial cells release inflammatory mediators that initiate an antifibrinolytic-coagulation cascade (3), which triggers formation of both blood clots and a provisional ECM (Figure 1). Platelets are exposed to ECM components, triggering aggregation, clot formation, and hemostasis. Next, platelet degranulation promotes vasodilation and increased blood vessel permeability, while stimulated myofibroblasts (collagen-secreting α-SMA+ fibroblasts) and epithelial and/or endothelial cells produce MMPs, which disrupt the basement membrane, allowing the efficient recruitment of inflammatory cells to the site of injury. Epithelial and endothelial cells also secrete growth factors, cytokines, and chemokines, which stimulate the proliferation and recruitment of leukocytes across the provisional ECM. Neutrophils are the most abundant inflammatory cell at the early stages of wound healing. When they degranulate and die, macrophages are recruited. During this initial leukocyte migration phase, the activated macrophages and neutrophils eliminate tissue debris, dead cells, and any invading organisms. They also produce cytokines and chemokines, which amplify the wound-healing response. These factors are also mitogenic and chemotactic for endothelial cells, which surround the injury and form new blood vessels as they migrate toward its center. Subsequently, T cells become activated and secrete profibrotic cytokines such as IL-13 and TGF-β (4, 5), which in turn further activate the macrophages and fibroblasts. Activated fibroblasts transform into α-SMA–expressing myofibroblasts as they migrate along the fibrin lattice into the wound. Myofibroblasts are derived from local mesenchymal cells or recruited from the bone marrow (where they are known as fibrocytes) (Figure 1). Epithelial cells can also undergo epithelial-mesenchymal transition (EMT), providing a rich renewable source of myofibroblasts (6). Following activation, myofibroblasts promote wound contraction, the process in which the edges of the wound migrate toward the center. Finally, epithelial and/or endothelial cells divide and migrate over the basal layers to regenerate the damaged tissue, which completes the normal healing process. However, when repeated injury occurs, chronic inflammation and repair cause an excessive accumulation of ECM components (such as hyaluronic acid, fibronectin, proteoglycans, and interstitial collagens), which contribute to the formation of a permanent fibrotic scar.
The net amount of collagen deposited by fibroblasts is regulated continuously by collagen synthesis and collagen catabolism. The turnover of collagen and other ECM proteins is controlled by various MMPs and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]), which are produced by granulocytes, macrophages, epidermal cells, and myofibroblasts. Shifts in these opposing mechanisms (synthesis versus catabolism) regulate the net increase or decrease of collagen within a wound (7). The expanding pool of mesenchymal cells further exacerbates the response. In the remodeling phase, the synthesis of new collagen by fibroblasts exceeds the rate at which it is degraded such that the total amount of collagen continues to increase. Although inflammation typically precedes fibrosis, results from experimental models of this process have demonstrated that fibrosis is not necessarily driven by inflammation at all times, suggesting that the mechanisms that regulate fibrogenesis are, to a certain extent, distinct from those regulating inflammation (8). This might explain the general lack of efficacy of antiinflammatory mediators in the treatment of fibrotic disease and the need to identify targeted antifibrotic therapies.
The spectrum of diseases that result from chronic tissue damage or out-of-control wound-healing responses are too numerous to list. However, the goal of this Review series on fibrotic diseases is to highlight some of the major fibrotic diseases and to identify common and unique mechanisms of fibrogenesis in the various organ systems affected by these diseases.