Intestinal Inflammation Induced by Pathogens

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DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBDs) including Crohn's disease (CD) and ulcerative colitis (UC) are chronic diseases characterized by a pronounced infiltration of neutrophils (PMNs) into colonic mucosal lesions, accompanied by epithelial cell necrosis and ulceration. Disease activity and patient symptoms also correlate with the histologic finding of PMN infiltrates within the mucosa and surface epithelium. This same histological event of massive transepithelial migration of PMNs occurs in the acute phase of gastroenteritis induced by Salmonella enterica serovar Typhimurium (salmonellosis). Thus, insight into pathogen elicited active inflammation of the intestine will serve as an important model to provide valuable information relating to active inflammation in IBD. Using the enteric pathogen S. typhimurium as a tool to investigate mechanisms underlying PMN recruitment across the intestinal epithelia, we have demonstrated a novel and central role for the eicosanoid hepoxilin A3 (HXA3). HXA3 is a derivative of arachidonic acid formed from the enzymatic action of the 12-lipoxygenase (12-LO) pathway. This observation has unlocked a previous unexplored phenomenon that mechanistically explains a primary histopathologic feature of active states of intestinal inflammation. Moreover, we have recently shown that HXA3 is secreted through an efflux transport system located at the apical surface of the intestinal epithelia that involves the ABC transporter MRP2. We also revealed that induction of intestinal inflammation corresponds to a profound up-regulation of the apical expression of MRP2. Such up-regulation of MRP2 was further demonstrated in vivo in chronic murine models of IBD and human intestinal biopsy tissues from patients with active CD or UC. Thus, the primary objectives of this project are to understand the molecular mechanisms underlying HXA3 synthesis (Specific Aim 1), as well as to determine how HXA3 production is regulated (Specific Aim 2). To accomplish these aims we plan to use a combination of complementary in vitro and in vivo models coupled with state of the art cellular, molecular, and biochemical techniques. We hypothesize that understanding HXA3/MRP2 based signaling, which directs the movement of PMNs across the intestinal epithelium, will lead to the development of important therapeutics designed to help control this inflammatory event in patients with infectious, allergic, and idiopathic (IBD) colitis.