Pathophysiology of fibrosis in systemic sclerosis

Fibrogenesis is a multistage pathological process leading to scarring of virtually any organ. Fibrosis is characterized by disruption of normal tissue architecture and its replacement with stiff collagen-rich connective tissue. The process results in progressive functional impairment, culminating in organ failure. Fibrosis is the hallmark of scleroderma, as well as a large and heterogeneous collection of human diseases. In these conditions, fibrosis represents the end result of a complex series of vascular and immune-mediated responses to chronic or recurrent injury in a genetically predisposed individual. As illustrated in Fig. 18.1, injured activated vascular, epithelial, and immune cells generate soluble mediators, functional autoantibodies, and reactive oxygen species (ROS) that serve as cues for mesenchymal cells to induce their sustained activation, differentiation, and survival, leading to excessive matrix deposition, tissue stiffness, and, ultimately, fibrosis. While fibrosis is potentially reversible, effective therapies to prevent or repair fibrosis are not yet available.