Role of cholecystokinin in intestinal epithelial barrier dysfunction induced by systemic inflammation

• Grant number: 13/15214-6
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2014
• End date: April 30, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Rafael Simone Saia
• Grantee: Rafael Simone Saia
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Aline Barbosa Ribeiro

Abstract

The intestinal mucosa plays a critical role in the organism, acting as a barrier for separation between the lamina propria and the external environment existing in the intestinal lumen. The systemic inflammation is a primary injury to this epithelium, promoting change in intestinal permeability and bacterial translocation. The proinflammatory mediators synthesized during endotoxemia, such as interferon-g, interleukin (IL)-1b, IL-6, tumor necrosis factor-a and nitric oxide, contribute to the intestinal barrier disruption by reducing the expression of tight junctions (TJs) proteins. The cholecystokinin (CCK) is a peptide synthesized in enteroendocrine cells, which immunoregulatory role has been reported in several models of systemic and local inflammation. Thus, this study aims to determine the role of CCK in restoring the integrity of the intestinal barrier during systemic inflammation induced by lipopolysaccharide (LPS) in rats. It will be also evaluated intestinal permeability, expression of protein members of TJs (ZO-1, ocludin, claudin-1 e claudin-2) by Western blot and cytokines production in the ileal and colonic mucosal in control, endotoxemic, CCK and antagonist receptor-treated rats. Our hypothesis is that CCK reduces bacterial translocation to the mesenteric lymph nodes, since it preserves the expression of TJs protein constituents, as a result of negative modulation of the inflammatory response induced by LPS. The elucidation of the mechanisms of CCK action in preserving the integrity of the intestinal mucosa may provide a scientific basis for the development of new hormonal therapeutic strategies to septic shock patients. (AU)