Mechanisms That Mediate the Development of Fibrosis in Patients With Crohnʼs Disease

Abstract

Crohn’s disease is complicated by the development of fibrosis and stricture in ~30–50% of patients over time. The pathogenesis of fibrostenotic disease is multifactorial involving the activation of mesenchymal cells by cytokines, growth factors and other mediators released by immune cells, epithelial cells and mesenchymal cells themselves. Transforming growth factor-β (TGF-β), a key activator of mesenchymal cells, is central to the process of fibrosis and regulates numerous genes involved in the disordered wound healing including collagens, and other extracellular matrix proteins, connective tissue growth factor (CTGF), and insulin-like growth factors (IGFs). The activated mesenchymal compartment is expanded by recruitment of new mesenchymal cells via epithelial to mesenchymal transition, endothelial to mesenchymal transition and invasion of circulating fibrocytes. Cellular hyperplasia and increased extracellular matrix (ECM) production, particularly collagens, from fibroblasts, myofibroblasts and smooth muscle cells add to the disturbed architecture and scarring on the intestine. ECM homeostasis is further disrupted by alterations in the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) in the gut. Among the 163 susceptibility genes identified that contribute to susceptibility in IBD mutations in NOD2/CARD15, innate immune system components, and autophagy jointly contribute to the activation of mesenchymal cells and pathogenesis of fibrosis in this polygenic disorder. Numerous growth factorscytokinesand other mediators. The review focuses on the molecular mechanism that regulate mesenchymal cell function, particularly smooth muscle cells, the largest compartment of mesenchyme in the intestine, that lead to fibrosis in Crohn’s disease.

Pathogenic aspects and therapeutic avenues of intestinal fibrosis in Crohn's disease

“…Proliferation of myofibroblasts and smooth muscle cells and production of collagen by these cell types are also stimulated by IGF-1 (insulin-like growth factor 1) [69][70][71][72][73][74][75], CTGF (connective tissue growth factor), PDGF (platelet-derived growth factor) and multiple inflammatory cytokines produced in excess in Crohn's disease [27,49,76].…”

Pathological study of chronic pulmonary toxicity induced by intratracheally instilled Asian sand dust (Kosa): possible association of fibrosis with the development of granulomatous lesions

“…MMPs play a central role in the regulation of multiple cellular functions such as cell proliferation, adhesion, migration, differentiation, angiogenesis, and apoptosis [33] and are capable of digesting extracellular matrix such as collagen and basement membrane components [34] and also acting as cell mediators. Because of its strong destructive ability, the activity of MMPs is strictly regulated by TIMPs [35]. TIMPs are also able to promote the proliferation of a variety of cells including fibroblasts [36].…”

Noncanonical STAT3 Activation Regulates Excess TGF-β1 and Collagen I Expression in Muscle of Stricturing Crohn’s Disease

“…Once activated autocrine TGF-β1 production increases and elicits excess extracellular matrix production including collagen I. Activation of intestinal mesenchymal cells also increases their autocrine production of a number cytokines including IL-6, IL-10, IL-12, IL-13, and IL-17a and TNF-α (15). Synthesis of IL-6 increases also in response to IL-1β and TNF-α (16, 17).…”