The gaseous molecule CO is a predominant component of cigarette smoke and a major industrial pollutant in the environment. Although CO has many detrimental effects on aerobic life, it has been well documented that CO from cigarette smoke has paradoxically protective effects in the human inflammatory bowel disease (IBD) ulcerative colitis (UC). CO has been demonstrated by various groups to have important antiinflammatory effects in mouse models of acute inflammation. Data from our groups suggests CO can inhibit innate immune responses in macrophages. Despite these important observations, molecular mechanisms underlying this phenomenon are essentially unknown. In this application, we propose studies to demonstrate that CO has immunomodulatory effects in intestinal epithelial cells (lECs), macrophages, and in vivo mouse models of IBD. We will determine how CO alters innate immune signaling in lECs. We will test the ability of chronic low dose CO exposure to prevent Th1 and Th2 mediated murine models of colitis. These studies will provide important proof of concept for further investigations pursuing molecular mechanisms of the effects of CO in human cells. The overall objectives of this proposal are to begin to understand the role of carbon monoxide in mucosal innate immunity and IBD. Understanding the molecular mechanisms of action of CO may explain the protective effect of cigarette smoking in UC, and may give new insights into therapeutic targets in IBD. ? ?
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