Faculty Bibliography

Stricture formation is a common complication of Crohn's disease, occurring in approximately one third of all patients with this condition. While the traditional management of such strictures has been largely surgical, there have been case series going back three decades highlighting the potential role of endoscopic balloon dilation in this clinical setting. This review article summarizes the stricture pathogenesis, focusing on known clinical and genetic risk factors. It then highlights the endoscopic balloon dilation research to date, with particular emphasis on three large recent case series. It concludes by describing the literature consensus regarding specific methodology and presenting avenues for future investigations.

BACKGROUND AND AIMS/OBJECTIVE:Matrix metalloproteinase-2 (MMP-2), a type IV collagenase secreted by activated hepatic stellate cells (HSCs), is upregulated in chronic liver disease and is considered a profibrotic mediator due to its proliferative effect on cultured HSCs and ability to degrade normal liver matrix. Although associative studies and cell culture findings suggest that MMP-2 promotes hepatic fibrogenesis, no in vivo model has definitively established a pathologic role for MMP-2 in the development and progression of liver fibrosis. We therefore examined the impact of MMP-2 deficiency on liver fibrosis development during chronic CCl(4) liver injury and explored the effect of MMP-2 deficiency and overexpression on collagen I expression. METHODS:Following chronic CCl(4) administration, liver fibrosis was analyzed using Sirius Red staining with quantitative morphometry and real-time polymerase chain reaction (PCR) in MMP-2-/- mice and age-matched MMP-2+/+ controls. These studies were complemented by analyses of cultured human stellate cells. RESULTS:MMP-2-/- mice demonstrated an almost twofold increase in fibrosis which was not secondary to significant differences in hepatocellular injury, HSC activation or type I collagenase activity; however, type I collagen messenger RNA (mRNA) expression was increased threefold in the MMP-2-/- group by real-time PCR. Furthermore, targeted reduction of MMP-2 in cultured HSCs using RNA interference significantly increased collagen I mRNA and protein, while overexpression of MMP-2 resulted in decreased collagen I mRNA. CONCLUSIONS:These findings suggest that increased MMP-2 during the progression of liver fibrosis may be an important mechanism for inhibiting type I collagen synthesis by activated HSCs, thereby providing a protective rather than pathologic role.