Ambient ozone is associated with increased respiratory illness, hospitalizations,and cardiovascular mortality. Because the lung is commonly exposed to low level inhaledozone, understanding how ozone modifies innate immune mechanisms is of considerableimportance to human health. Previously, we have identified that ozone enhances pulmonaryinnate immune response to lipopolysaccharide (LPS) including; cellular inflammation, cytokineproduction, lung injury, cellular apoptosis, and airway hyper-responsiveness. We discoveredthat ozone-priming of innate pulmonary immunity, in part, involved enhanced surface expressionof tlr4 on alveolar macrophages, which amplifies the biological response to inhaled LPS.Oxidant-dependent release of extracellular matrix hyaluronan fragments induces trafficking oftlr4 to the cell surface in a manner dependent on activation of NF-kB. However, the intracellularsignaling pathways required for ozone-induced alterations in tlr4-signaling remain unknown. Wenow identify that inhalation of ozone results in robust increased levels of NAD+ and NADP+ inalveolar macrophages. The focus of this competitive renewal is understanding the role ofspecific NAD(P)H-dependent enzymes in ozone-induced alterations in innate immunity.Mechanistic understanding of the pathways that regulate macrophage-derived toll-like receptor4 signaling after exposure to this common air pollutant is of considerable interest in thepathogenesis of airways disease. Our overall hypothesis is that macrophage-derived innateimmune response after inhalation of ambient ozone is dependent on NAD(P)H-dependentenzymes including both PKC-dependent activation of NOX2 resulting in enhanced intracellularROS and NQO1-dependent alterations in global chromatin structure in both mice and humans.We will address this hypothesis through the following Specific Aims.
Specific Aim 1. Determine the role of NOX2 (gp91phox/p47phox) in the biological response toinhaled ozone and tlr4-dependent signaling.
Specific Aim 2. Determine the role of NQO1 in ozone regulation of innate immunity throughmodifications in SIRT1-dependent alterations in chromatin structure.
Specific Aim 3. Determine whether inhaled ozone modifies NAD(P)+/NAD(P)H and the functionof NOX2 and NQO1 in primary alveolar macrophages from healthy human subjects.
Intensity of pulmonary innate immunity can contribute to many human diseases includingasthma; COPD/emphysema; ARDS; and pneumonia. Inhalation of ambientenvironmental ozone contributes to both respiratory morbidity and mortality in humanpopulations. Understanding the biological mechanisms; which inhaled ozone regulatesintensity of innate immunity; provides insight broadly into novel therapeutic targets forlung disease. This new proposal is the natural extension of our novel observations. Weanticipate that the proposed work will lead to the development of new therapeutic targetsfor the many patients suffering from airways disease.
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