Dynamic Calcium Regulation in Airway Smooth Muscle

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DESCRIPTION (provided by applicant): Asthma is an inflammatory disease in which TH2 (such as IL-13) and proinflammatory (such as TNFa) cytokines induce abnormalities of airway smooth muscle (ASM) function that causes airway hyperresponsiveness (AHR), a hallmark of this disease. Inflammatory cytokines alter calcium signaling and contractility of ASM which results in hyperreactivity to agonists. Investigations from our laboratory have provided evidence that the CD38/Cyclic ADP-ribose signaling has a central role in calcium regulation in ASM and this signaling pathway is regulated by TH2 and proinflammatory cytokines through transcriptional mechanisms involving NF-?B and AP-1 and transcript stability. The signaling mechanisms involved in this regulation are mediated by activation of PI3 kinases and Mitogen-activated Protein Kinases (MAPK). Mice deficient in CD38 exhibit an airway phenotype characterized by attenuated methacholine responsiveness. ASM cells from these mice also have reduced calcium responses to agonists. While these observations implicate CD38 in normal airway function, its potential role in the pathophysiology of asthma remains to be determined. In ASM cells, CD38 expression is augmented by cytokines, and glucocorticoids, a mainstay of asthma therapy, decrease this expression. Preliminary results reveal that CD38 deficient mice exhibit attenuated AHR following IL-13 or allergen sensitization and challenge. Reconstitution of CD38+/+ inflammatory cells by bone marrow transfer into CD38 deficient mice restores AHR to allergen challenge. These studies are the first to implicate the CD38/Cyclic ADP-ribose signaling pathway in asthma and bring a physiological significance of the mechanisms of regulation of CD38 expression in cells/tissues outlined in the proposal. The goal of the proposed studies is to delineate the signaling mechanisms involved in the regulation of CD38 expression and to define the role of CD38 in airway smooth muscle cells and inflammatory cells in AHR. The overall hypothesis is that cytokines regulate CD38 expression in ASM through PI3 kinase activation, down-stream MAPK signaling and activation of NF-?B and AP-1, and that the CD38/Cyclic ADP-ribose signaling in airway resident cells is sufficient to cause AHR resulting from the inflammatory response. Glucocorticoid effects are mediated through inhibition of MAPK and transcription factor activation, and transcript stability. In the proposed studies, we will determine specific mechanisms of CD38 regulation by inflammatory and TH2 cytokines in ASM and the in vivo significance of these mechanisms in mouse models of experimental asthma. This new information may identify CD38 as a potential pharmacological target in the prevention and control of asthma. We propose that modulators of the CD38/Cyclic ADP-ribose signaling pathway in the airways should afford protection from airway hyperresponsiveness in diseases such as asthma. PUBLIC HEALTH RELEVANCE. Asthma is an inflammatory disease in which patients have exaggerated airway smooth muscle response to stimuli. Cytokines such as IL-13 and TNFa have a central role in the pathogenesis of asthma. Mice deficient in a protein, CD38, do not develop an asthmatic response to challenges with cytokines. We are proposing to study how the expression of CD38 in the airways is regulated by cytokines and establish its role in different mouse models of asthma. This new information may identify CD38 as a potential pharmacological target in the prevention and control of asthma.