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Mast cell-dependent mechanism of action of estradiol in the intestinal epithelial barrier dysfunction induced by systemic inflammation

Grant number: 16/01053-9
Support type:Regular Research Grants
Duration: October 01, 2016 - September 30, 2018
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal researcher:Celso Rodrigues Franci
Grantee:Celso Rodrigues Franci
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers:Aline Barbosa Ribeiro

Abstract

The initial phase of sepsis is characterized by excessive systemic production of inflammatory mediators. The "dysregulation" of the inflammatory response is directly related to tissue injury, increased intestinal permeability and bacterial translocation. Inflammatory mediators compromise the structure of the intestinal tight junctions by modifying the expression of its constituent proteins. The estradiol appears to have a protective function in experimental models of sepsis, possibly by modulating the immune cells function and the synthesis of inflammatory mediators. The two subtypes of estradiol receptors (ERs) are normally expressed in the intestinal mucosa, but its participation in maintaining the integrity of the intestinal epithelial barrier during systemic inflammation is unknown, as well as its mechanisms of action. Mast cells also appear to be important for maintaining the integrity of the intestinal epithelial barrier, and their degranulation proteases (chymases and tryptases) and histamine are directly correlated with the increase of colonic permeability in rats. Several studies demonstrate the ERs expression in mast cells and have highlighted the inhibitory character of estradiol on the activity of these cells, including the secretion of cytokines and proteases. The aim of the present study is to evaluate the role of estradiol in the intestinal epithelial barrier dysfunction induced by systemic inflammation in rats and its relation to the activation of mucosal mast cells. Our hypothesis is that estradiol treatment modulates the inflammatory response, intestinal permeability and activation of mast cells. The study of the pathogenesis of sepsis and the development of new therapeutic strategies are important steps towards increasing survival of septic patients. (AU)

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