Assistant Professor of Surgery and Pediatrics
Our laboratory has concentrated on an understanding of the cellular and molecular mechanisms involved in hepatic matrix metabolism. This work is important given that chronic cholestatic liver disease is a common primary or secondary injury that predisposes children to the development of end-stage liver disease.
Research DescriptionOur focus has been on Matrix metalloproteinase-8 (MMP-8), an interstitial collagenase, highly expressed by neutrophils (PMNs), and recently described in fibroblasts. We have previously demonstrated the sustained neutrophil chemotaxis and novel hepatic gene expression of MMP-8 during liver injury and repair, and described active MMP-8 as the collagenase associated with matrix resorption. Moreover, our neutrophil depletion studies revealed a lack of collagenase activity despite increased gene expression. The primary goal of this research is to delineate the molecular mechanisms by which MMP-8 modulates hepatic fibrosis. The translational aspiration is to develop innovative therapies to improve recovery from fibrosis.
This work is significant given that chronic cholestatic liver disease is a common primary or secondary injury that predisposes children to the development of end-stage liver disease. Moreover, biliary obstruction and the majority of liver injuries share common inflammatory cascades with cumulative hepatic fibrogenesis that predispose to carcinogenesis and cirrhosis. The mechanisms of hepatic stellate cell activation that lead to type I collagen deposition are well described compared to our poor understanding of recovery from cholestasis during liver repair; a process many consider a more important investigation with organ preservation and lifesaving potential. Our studies have broad and important clinical implications for the treatment of cholestatic or chronic liver injury as seen in infants with biliary atresia, intestinal failure from short bowel syndrome and parenteral nutrition-induced injury where there is no biologic assurance of adequate hepatic repair despite surgical decompression.