Mucosal inflammatory responses involve the early accumulation of neutrophils (PMN). Without efficient PMN clearance at sites of infiltration, PMN can accumulate and contribute to chronic inflammatory conditions, including ulcerative colitis (UC) and Crohn's disease (CD). Within these diseases, there is significant interest in defining components of the inflammatory microenvironment as a window to understanding molecular mechanisms of progression or resolution. Our ongoing studies for this renewal application have revealed that PMN transepithelial migration (TEM) results in significant extracellular acidosis, in part through generation of large amounts of lactate. Moreover, we demonstrate that PMN-derived adenosine (Ado) significantly promotes pH homeostasis within the mucosal microenvironment. Based on thes new studies, we hypothesize that PMN-derived Ado signaling elicits an adaptive tissue response by promoting pH homeostasis to inflammatory acidity.
Three specific aims are directed at testing this hypothesis:
In Specific Aim 1, we will elucidate the lactate release and signaling axis in intestinal epithelia.
In Specific Aim 2, we will extend preliminary data to determine the mechanism(s) of Ado-mediated pH homeostasis during PMN TEM.
Specific Aim 3 will utilize murine models to probe the role of pH homeostasis in protection afforded by Ado in vivo. The overall aim of this proposal is to identify novel metabolic signaling mediated by Ado within the mucosa during inflammatory acidosis.
The Inflammatory Bowel Diseases (IBD), which includes ulcerative colitis (UC) and Crohn's disease (CD), are diseases of the gastrointestinal tract that result from abnormal immune response to luminal antigens in genetically-susceptible individuals. IBD represents a disease of major interest, with nearly 3 million American afflicted with this chronic inflammatory disorder. The proposed studies are designed to identify and harness information from novel, inflammation-related metabolic pathways that promote tissue healing. Such studies should provide new avenues into our understanding of why inflammatory diseases develop, and in particular, how innate immune responses contribute to inflammatory resolution.
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