Cytokine mediated tissue fibrosis

Abstract

Acute inflammation is a recognised part of normal wound healing. However, when inflammation fails to resolve and a chronic inflammatory response is established this process can become dysregulated resulting in pathological wound repair, accumulation of permanent fibrotic scar tissue at the site of injury and the failure to return the tissue to normal function. Fibrosis can affect any organ including the lung, skin, heart, kidney and liver and it is estimated that 45% of deaths in the western world can now be attributed to diseases where fibrosis plays a major aetiological role. In this review we examine the evidence that cytokines play a vital role in the acute and chronic inflammatory responses that drive fibrosis in injured tissues. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

Fig. 1

Pathological vs. physiological wound healing. Infection or exposure to harmful molecules can lead to epithelial damage and loss of epithelial integrity. Following injury fibroblasts, endothelial cells, and neighbouring epithelial cells release a range of soluble factors that trigger clotting and initiate the development of a provisional ECM. The aggregation and subsequent degranulation of platelets triggers increased blood flow, vasculature dilation and vasculature permeability allowing the effective recruitment of inflammatory cells to the site of tissue injury. The first responders are the neutrophils, eosinophils and basophils that are responsible for neutralising any invading pathogens via an oxidative burst response and eliminating cell debris/dying cells by phagocytosis. The granulocyte number in the site of epithelial injury peaks rapidly, within minutes, but is followed by a rapid decline. Once in the wound micro-environment the recruited monocytes mature to increase the number of macrophages in the wound and perform similar functions to those described for granulocytes. In addition they produce cytokines and chemokines that amplify the wound response by promoting the formation and stabilisation of a provisional ECM and promoting angiogenesis. Myofibroblast numbers are increased at the wound site from several sources (see Fig. 2). Once recruited to the wound area the myofibroblasts become activated and traverse the provisional ECM until they reach the edge of the wound and initiate contraction of the wound. Finally epithelial cells at the edge of the wound loosen adherence junctions and migrate over the ECM to restore a continuous epithelium and tissue homeostasis. At this point the myofibroblasts in the wound area undergo apoptosis and the macrophage numbers are significantly reduced via egress into the lymphatic system. Fibrosis occurs when the initial wound is severe, the wound repair process becomes dysregulated or the source of epithelial damage persists resulting in repeated injury and chronic inflammation.

Fig. 2

Proposed origins of myofibroblasts in fibrosis. It was originally thought that the activation or proliferation of local resident stromal cells and their differentiation in to myofibroblasts was the only source of myofibroblasts during fibrosis. However it is also now widely believed that myofibroblasts are derived from at least four other sources; through the recruitment and differentiation of fibrocytes, through the activation and proliferation of pericytes, via epithelial to mesenchymal transition (EMT) or via endothelial to mesenchymal transition (EnMT).