Mechanisms of initiation and progression of intestinal fibrosis in IBD

Abstract

Intestinal fibrosis is a common complication of the inflammatory bowel diseases (IBDs). It becomes clinically apparent in >30% of patients with Crohn's disease (CD) and in about 5% with ulcerative colitis (UC). Fibrosis is a consequence of local chronic inflammation and is characterized by excessive extracellular matrix (ECM) protein deposition. ECM is produced by activated myofibroblasts, which are modulated by both, profibrotic and antifibrotic factors. Fibrosis depends on the balance between the production and degradation of ECM proteins. This equilibrium can be impacted by a complex and dynamic interaction between profibrotic and antifibrotic mediators. Despite the major therapeutic advances in the treatment of active inflammation in IBD over the past two decades, the incidence of intestinal strictures in CD has not significantly changed as the current anti-inflammatory therapies neither prevent nor reverse the established fibrosis and strictures. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is also gradually changing in light of an improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis is thus vital and may pave the way for the developments of antifibrotic agents and new therapeutic approaches in IBD.

Calycosin Inhibits Intestinal Fibrosis on CCD-18Co Cells via Modulating Transforming Growth Factor-β/Smad Signaling Pathway

“…Due to the sustained action of chronic inflammation in the intestine, proinflammatory cytokines and profibrotic factors are secreted in large quantities and induce the migration, proliferation, activation, and differentiation of fibroblasts, epithelial cells, endothelial cells, and stellate cells into myofibroblasts cells. ECM is produced by activated myofibroblasts that are regulated by profibrotic and antifibrotic factors [9]. The main components of ECM are collagen and fibronectin [27].…”

“…Surgery is the only choice for symptoms/ complex stenosis. However, 70-90% of patients relapse within 1 year after surgery, and more than half of patients may require further bowel resection [4,5,9].…”

Mechanisms, Management, and Treatment of Fibrosis in Patients With Inflammatory Bowel Diseases

“…Tissue repair mechanisms, which restore integrity to tissues with inflammatory damage, involve a controlled response mediated by mesenchymal cells and the ECM 4-6 . In contrast, fibrosis is an exaggerated response characterized by accumulation of collagen-rich ECM, produced by a permanent or transient numerical expansion of mesenchymal cells, including fibroblasts, myofibroblasts and smooth muscle cells 7 .…”

“…These abnormalities are not unique to CD, because increases in collagen I and III and fibronectin have also been observed in intestinal tissues from patients with UC 75 . In this form of IBD the muscularis mucosa can be greatly thickened 76 , but fibrosis extends to the submucosa, at a maximum, with the thickness of the submucosa remaining unchanged 4, 77, 78 .…”

Concise Commentary: Is Nrf2 a Master Regulator of Intestinal Fibrosis?

“…Although the transforming growth factor β1 (TGF-β1)/ small mothers against decapentaplegic (Smad) pathway is the main driving force for fibrosis, several pro-and antifibrogenic molecules may also directly interact with this pathway [1,2]. Emerging evidence indicates that reactive oxygen species/reactive nitrogen species (ROS/RNS) and nuclear factor erythroid-2-related factor 2 (Nrf2) are connected with TGF during fibrosis development in numerous organs, including the intestine [3][4][5][6].…”