BRADYKININ IN ENTERIC NEUROIMMUNE COMMUNICATION

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This project will use methods of electrophysiological recording and molecular biological techniques for study of gene expression to test the hypothesis that bradykinin is an important inflammatory mediator in the enteric nervous system (ENS). Pilot/feasibility studies found that bradykinin excites neurons and produces presynaptic inhibition in the ENS. These effects are mediated in part by increased release of endogenous prostaglandins (PGs) following activation of cyclooxygenases including constitutive cyclooxygenase-1 (COX- 1) and inducible cyclooxygenase-2 (COX-2). This proposal focuses on electrophysiological responses to bradykinin and functional expression of the bradykinin BZ receptor, COX- 1 and COX-2 proteins and their genes in the ENS. The studies are designed to test the hypothesis that bradykinin activates Bz type receptors together with activation of COX- 1 and induced expression of COX-2 which in turn catalyze the biosynthesis of the PGs from arachidonic acid. PGs release appears to be partly responsible for presynaptic inhibition of neurotransmitters release and postsynaptic excitation of enteric neurons. Integrated output of these effects is a stereotypical pattern of intestinal behavior consisting of copious secretion of water and electrolytes across the mucosa in coordination with a powerful propulsive motility pattern that propagates over extensive lengths of bowel. This is especially important under pathophysiological circumstances such as inflammatory bowel disease where bradykinin is increased. Aim 1 will identify the actions of bradykinin and mechanisms of signal transduction in electrophysiologically and morphologically identified enteric neurons in the myenteric and submucous plexuses of the small intestine. Aim 2 will test the hypothesis that B2 receptor protein and mRNA are functionally expressed in the myenteric and submucous plexuses. Aim 3 will test the hypothesis that B2 receptors are expressed by specific enteric neurons and/or glia. Aim 4 will identify the PGs postulated to be involved in bradykinin actions. Aim 5 will identify the ENS cell types expressing COX-2 protein and mRNA after bradykinin exposure. The overall goal of the study is to better understand the role of bradykinin in motility disturbances, diarrhea, abdominal pain and inflammation.