Evaluation of the immunomodulatory activity of annexin A1 protein in the regulation of inflammatory disorders of the gastrointestinal system: studies in vivo and in vitro experimental models

Abstract

. The protein annexin A1 (AnxA1) acts on the resolution of inflammation and has beenassociated to gastrointestinal mucosa protection. Several surveys have shown the protective effect ofAnxA1 in acute inflammation, regulating the influx of neutrophils, monocytes and mast celldegranulation and, in chronic inflammatory processes acting in response to infections and neoplasias. Forthese reasons, our investigation seeks to evaluate the involvement of this protein in the break of intestinalimune tolerance, resulting in ulcerative colitis (UK), and in the microenvironmental response tocarcinogenic damage. Initially, in the chemically induced colitis model, the objective is to investigateAnxA1 expression and the cytokines production in wild mice (WT) treated with anti-TNF-a neutralizer,while the AnxA1 deficient (AnxA1-/-) ones will be used to test this protein in mediating TNF-a blockageduring acute intestinal inflammation. In colorectal cancer (CRC), the AnxA1 expression is unregulatedand affects the growth and malignant transformation of colonic tumors. Thus, mast cells, because of theirheterogeneity and importance in this setting, will be evaluated as to the production of post tumormediators in WT and AnxA1-/- mice exposed to chemical carcinogenesis. Finally, using an in vitromodel, human mast cell and colon tumor cell lines will be co-cultured in hypoxia with the addition of theAc2-26 peptide of the AnxA1 to evaluate the effect on the synthesis of protumoral mediators. In theproposed investigations, the clinical, histopatholocial and molecular parameters evaluated will allow for abetter understanding of the role of AnxA1 in regulating the inflamatory intestinal microenvironment, and,possibly, to result in an effective contribution to preventive and therapeutic applications. (AU)