Cellular and molecular mechanisms of intestinal fibrosis

Abstract

Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.

Keywords: Endothelial cells; Epithelial cells; Extracellular matrix; Inflammatory bowel disease; Inflammatory cells; Intestinal fibrosis; Mesenchymal cells; Molecular mediators; Myofibroblasts.

Figure 1

Mechanisms of fibrogenesis. Inflammatory response to tissue damage promotes the release of fibrogenic molecules. These molecules increase activation and proliferation of ECM-producing cells. ECM: Extracellular matrix.

Figure 2

Transforming growth factor-α signaling and induction of gene transcription. Smad: Small mother against decapentaplegic; SARA: Smad anchor for receptor activation; TGF-β: Transforming growth factor β.

Figure 3

Components and effects of the renin-angiotensin system. ACE: Angiotensin-converting enzyme; AT1: Angiotensin II type 1 receptor; AT2: Angiotensin II type 2 receptor; AT4: Angiotensin II type 4 receptor; MAS: Mas receptor; RAS: Renin-angiotensin system.

Figure 4

Activation of the peroxisome proliferator activator receptor-γ pathway. Regulation of several genes involved in fibrogenesis. PPAR-γ: Peroxisome proliferator activator receptor-γ; PPRE: PPAR response elements; RXR: Retinoid X receptors; L: Ligand; FA: Fatty acids.

Figure 5

Features of mammalian target of rapamycin. mTORC1: Mammalian target of rapamycin complex1; mTORC2: Mammalian target of rapamycin complex 2; 4EBP1: 4E binding protein; S6K: S6 kinase; PKB/Akt: Protein kinase B; SGK: Serum- and glucocorticoid-inducible kinase; PKC: Protein kinase C.