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.
Highlights
The incidence of Crohn’s disease (CD) is rapidly rising in the pediatric population [1]
Various growth factors and cytokines have been implicated in the development of fibrosis including IL-13, platelet-derived growth factor (PDGF), connective tissue growth factor, basic fibroblast growth factor, insulin-like growth factor, bone morphogenetic proteins (BMPs), and transforming growth factor-β (TGFβ) [23]
In a rat model of renal fibrosis and in cell-based assay systems, TGFβ1 stimulation was associated with increased NADPH oxidase 4 (NOX4) expression and H2O2 production, while reduced NOX4 expression by siRNA-mediated knockdown decreased Reactive oxygen species (ROS) production and expression of profibrotic proteins including collagen, α-SMA, and fibronectin [34]
Summary
The incidence of Crohn’s disease (CD) is rapidly rising in the pediatric population [1]. Fibrotic narrowing of the intestinal tract (stricturing disease) is present in approximately 10–17% of children at diagnosis [4], affecting up to 40% by 10 years after diagnosis [5,6,7]. The conventional conceptual framework of the pathobiology of fibrosis in CD is one of chronic inflammation leading to ongoing frustrated attempts at healing with formation of disorganized tissue. If this occurs circumferentially in a relatively narrow diameter organ such as the small intestine, the result is a fibrotic stricture. We will describe current knowledge and recent advances regarding the diagnosis and pathogenesis of intestinal fibrosis and will review potential future therapies
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