Crohn's Strictures-Moving Away from the Knife

Abstract

Crohn's disease (CD) is a lifelong inflammatory bowel disease with a rapidly rising incidence in the pediatric population. A common complication of CD is the development of fibrotic strictures, which may be present at initial diagnosis or develop many years later. Clinical presentation depends on stricture location and degree of obstruction, and strictures frequently contain a mixture of inflammatory and fibrotic tissue. Histological examination of Crohn's strictures shows thickening of the muscular layers and the submucosa, where increased collagen deposition by activated myofibroblasts is concentrated around islands of smooth muscle cells and at the superficial margin of the muscularis propria. No antifibrotic therapies for Crohn's strictures exist. Profibrotic transforming growth factor-β (TGFβ)/bone morphogenetic protein signaling stimulates myofibroblast differentiation and extracellular matrix deposition. Understanding and targeting TGFβ1 downstream signaling is the main focus of current research, raising the possibility of specific antifibrotic therapy in CD becoming available in the future.

Keywords: Crohn’s disease; NADPH oxidase; fibrosis; inflammatory bowel disease; intestine; reactive oxygen species.

Figure 1

In intestinal fibrosis, hypertrophy and hyperplasia of smooth muscle cells cause thickening of the muscularis mucosa and muscularis propria; smooth muscle cells proliferate in the thickened submucosa, where activated myofibroblasts secrete extracellular matrix proteins.

Figure 2

TGFβ1 signaling induces SMAD2 and SMAD3 phosphorylation and activation of non-canonical mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, which upregulate the expression of profibrotic genes including NADPH oxidase 4 (NOX4). Reactive oxygen species (ROS) generated by NOX4 and/or mitochondria promote further release of active TGFβ1.