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Basic IBD Research at Rush  
Basic IBD Research at Rush 

Inflammatory bowel disease (IBD) affects more than 1 million Americans with more than 30,000 new cases diagnosed each year. IBD increases patient morbidity and susceptibility to colorectal cancer, yet its etiology remains unknown.

Current models identify two key determinants of IBD pathogenesis: 1) hyperpermeability of the gut epithelial barrier to bacterial products; and 2) an abnormal immune response to bacterial products.

Two factors seem critical for hyperpermeability: oxidant-induced stress and proinflammatory cytokines (e.g., tumor necrosis factor-alpha). The aim of our research was to investigate the role of oxidant stress-mediated transactivation of the epidermal growth factor receptor (EGFR) in intestinal hyperpermeability. This study used the Caco-2 human colonic epithelial cell in vitro model of intestinal epithelium. Cells were grown on inserts forpermeability and signaling studies and glass coverslips for microscopy studies. We show that oxidant-induced intestinal hyperpermeability can be blocked by specific inhibitors of the EGFR, tumor necrosis factor convertase (TACE) metalloprotease, transforming growth factor (TGF)-alpha, and mitogen-activated protein kinases, especially extracellular signal-regulated kinase 1/2.

We also show that oxidant initiates these signaling events, in part by causing translocation of TACE to cell-cell contact zones. In this study, our data identify a novel mechanism for oxidant-induced intestinal hyperpermeability relevant to IBD. We propose a newintestinal permeability model in which oxidant transactivates EGFR signaling by activation of TACE and cleavage of precursor TGF-alpha. These data could have a significant effect on our view of IBD pathogenesis and provide new therapeutic targets for IBD treatment. 

Forsyth, CB, Banan, A, Farhadi, A, Fields, Tang, Y,  JZ, Shaikh, M, Zhang, LJ, Engen, PA, Keshavarzian A. Regulation of Oxidant-induced Intestinal Permeability by Metalloprotease-Dependent EGFR Signaling. J Pharmacol Exp Ther. 2007. 321:84-97.

Christopher B. Forsyth, PhD

Christopher Forsyth, PhD, is an assistant professor in the departments of internal medicine (primary appointment, Section of Gastroenterology) and biochemistry. Forsyth is a new investigator who has still managed to establish a strong track record of innovation in different fields of inflammation related research.

His doctoral work in immunology focused on the host response to fungal pathogens and he identified the adhesion molecule on CD8+ lymphocytes used during killing of opportunistic fungi. His first postdoctoral study at the Cleveland Clinic focused on the molecular biology of vascular inflammation and the leukocyte CD11b integrin. He identified new fibrinogen peptides mediating cell migration and mapped binding of fibrinogen and Candida albicans fungi to CD11b. His second postdoctoral study at Rush University Medical Center in Chicago focused on the role of integrins in regulating matrix metalloproteases (MMPs) in osteoarthritis, especially the role of intracellular signaling pathways regulating MMPs. He identified novel signaling pathways regulating MMP-13 expression in human chondrocytes and also showed these pathways changed in aged chondrocytes, identifying a possible contributing mechanism in osteoarthritis.

His interest in inflammation and MMPs led him to join the Section of Gastroenterology at Rush where he has focused on the role of MMPs and the tumor necrosis factor alpha converting enzyme (TACE) in inflammation signaling in inflammatory bowel disease (IBD) and cancer. He has recently identified a novel mechanism regulating intestinal permeability during inflammation involving TACE transactivation of epidermal growth factor receptor (EGFR) signaling. He has also shown that this pathway of EGFR activation may be involved alcohol stimulation of intestinal permeability and in promotion of breast and colon cancer by alcohol. Current experiments are also examining how so called “good bacteria” (probiotics) in the intestine can inhibit these oxidant and alcohol inflammation and cancer promoting pathways.

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