Cellular and Molecular Mediators of Intestinal Fibrosis

Abstract

Intestinal fibrosis is a major complication of the inflammatory bowel diseases (IBD) and although inflammation is necessary for its development, it would appear that it plays a minor role in its progression as anti-inflammatory treatments in IBD do not prevent fibrosis once it has started. The processes that regulate fibrosis would thus appear to be distinct from those regulating inflammation and, therefore, a detailed understanding of these pathways is vital to the development of anti-fibrogenic strategies. There have been several recent reviews exploring what is known, and what remains unknown, about the development of intestinal fibrosis. This review is designed to add to this literature but with a focus on the cellular components that are involved in the development of fibrogenesis and the major molecular mediators that impact on these cells. The aim is to heighten the understanding of the factors involved in intestinal fibrogenesis so that detailed research can be encouraged in order to advance the processes that could lead to effective treatments.

Keywords: chemokine; extracellular matrix; fibroblast; growth factor; inflammatory bowel disease; interleukin; intestinal fibrosis; myofibroblast.

Figure 1.

Process of tissue repair and fibrosis. Epithelial and endothelial damage promotes the release of chemotactic factors that promote the recruitment and activation of innate and adaptive inflammatory cells, as well as mesenchymal cell precursors. The activated myofibroblasts then secrete ECM proteins and promote an altered cytokine milieu that further supports the fibrotic process instead of normal healing.

Figure 2.

Intersection of immune response and fibrosis. Activated M1 pro-inflammatory macrophages activate myofibroblasts and fibrosis by both cytokine-dependent and independent mechanisms. M2a macrophages signal through STAT6 and produce crucial pro-fibrotic factors. M2c/reg (regulatory) phenotype macrophages are anti-fibrotic and inactivate myofibroblasts as well as inhibiting M1- and M2a-type macrophages. Th2-type T cells are potently fibrogenic as is the Th17-type immune response. By contrast, Th1-type immunity may have anti-fibrotic activity. Treg’s role in fibrogenesis is less clear, but may suppress Th17- and Th2-driven fibrosis.

Figure 3.

Progenitors of intestinal activated myofibroblasts. The activated mesenchymal cells are central to fibrogenesis. These cells are derived from resident mesenchymal fibroblasts and smooth muscle cells as well as from dedifferentiation of epithelial cells by epithelial–mesenchymal transition (EMT), and endothelial cells via epithelial/endothelial–mesenchymal transition, stellate cells, pericytes, and bone marrow stem cells.

Figure 4.

Promoting effects of multiple growth factors and cytokines on myofibroblasts. Numerous factors impact on fibrosis through their effect on the activated myofibroblast. The effect of numerous of these are demonstrated here with either their pro or anti-fibrogenic effect.

Figure 5.

Effects of the key pro-fibrogenic growth factors. The pro-fibrogenic effects that several key growth factors have on collagen, TIMP levels, cell proliferation, EMT, etc., are demonstrated.