Inflammation-Independent Mechanisms of Intestinal Fibrosis: The Role of the Extracellular Matrix

Abstract

Current therapies controlling inflammation in patients with Crohn’s disease do not modify natural disease progression to stenosis, suggesting that the molecular mechanisms contributing to intestinal fibrosis occur partly independent from inflammation. This may be explained by auto-propagation of fibrosis, accomplished by components of the interstitial, non-cellular environment referred to as the extracellular matrix (ECM). Aside from its function in maintaining tissue integrity, the ECM is a highly dynamic structure that closely communicates with cells, including with those that produce ECM components. Interaction of fibroblasts with the ECM through multi-protein focal adhesions orchestrates a variety of processes including proliferation, migration and activation. In particular, the mechanical properties of the ECM, determined by the degree of ‘stiffness’ which is typically increased in the stenotic bowel, induces a variety of pro-fibrotic signaling cascades in fibroblasts. Although the mechanical cues translating into the activation of these cells have only begun to be unraveled, mechanotransduction in fibroblasts should be considered as an important inflammation-independent contributor to intestinal fibrosis. In addition, the ECM is a reservoir of growth factors and a source of ‘danger signals’ that can trigger pro-fibrotic responses in the rigid ECM. This chapter provides an overview of the components of the intestinal ECM, the interaction with fibroblasts, and the inflammation-independent mechanisms contributing to fibrosis including mechanotransduction of fibroblasts and mechanical activation of the ECM. Finally, the potential therapeutic targets in these pathways to tackle fibrogenesis in the intestine are discussed.