The contribution of neutrophil COX-2 expression to inflammatory bowel disease

• Grant number: 14/14634-4
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 31, 2015
• End date: January 30, 2016
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Carlos Amilcar Parada
• Grantee: Felipe Meira de Faria
• Supervisor: Harvey Roy Herschman
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of California, Los Angeles (UCLA), United States
• Associated to the scholarship: 14/05649-8 - Investigation upon a role of neutrophils and their COX-2 expression on hyperalgesy development during experimental colitis, BP.PD

Abstract

There is substantial evidence to suggest that COX-2-derived prostaglandins exert anti-inflammatory and mucosal protective effects in human and experimental colitis. Nevertheless, COXIBS (COX-2 selective inhibitors) are effective in reducing inflammation and pain while causing significantly less gastrointestinal damage than standard NSAIDS. Recent findings using targeted Cox-2 gene deletion, showed a protective effect of COX-2 expression in endothelial and myeloid cells (macrophages) in chemically-induced colitis in a mouse model. COX-2 is also known to play a role in additional pathologies, e.g. inflammation, neurodegenerative diseases, cancer and pain. Stipulating the involvement of prostanoids in inflammation and pain, it is attractive to consider the hypothesis that prostanoids derived from specific cell types modulate cytoprotection/recovery in the gastrointestinal tract while promoting hyperalgesia in neural tissue. During intestinal inflammation, resident monocytes contribute to the recruitment of neutrophils through production of macrophage-derived chemokines. As part of the normal gut inflammatory response, neutrophils are recruited to sites of infection or inflammatory stimuli within minutes. Despite the beneficial effects of neutrophils for mucosal homeostasis, it is clear that neutrophils also directly contribute to disease pathology; their excessive recruitment and activation leads to release of toxic products and massive trans-epithelial migration, resulting in crypt abscesses and extensive mucosal injury. Neutrophils are also implicated in the development of inflammatory and neuropathic pain, however such mechanisms have not been completely elucidated. Based on these observations, I propose that neutrophil-derived, COX-2 dependent prostanoids may have a causal role both in intestinal inflammation and in the hyperalgesia associated with inflammatory bowel disease (IBD). Consequently, I plan to evaluate the consequences of targeted neutrophil Cox-2 gene deletion on colitis development, to determine whether neutrophil-derived, COX-2 dependent prostanoids contribute to chemically-induced colitis inflammation in a mouse model. (AU)