Ambient ozone is associated with increased hospitalizations, respiratory illness, and increased cardiovascular mortality. Given the continuous exposure of the lung to a variety of airborne toxins, understanding the biologic mechanisms that regulate the patho-physiologic responses to common ambient air pollutants is of considerable interest to human health. In previous work, we have demonstrated a critical role for the innate immune gene, toll-like receptor 4, in the development of airway hyperresponsiveness after exposure to ozone. We now recognize that degradation products of the extracellular matrix glycosaminoglycan hyaluronan (HA) accumulate following ozone exposure. Fragments of this glycosaminoglycan can function as an endogenous ligand of tlr4 activating of innate immune responses. Our data support that HA fragments regulate the airway physiological response to ozone. The instillation of HA fragments into the lungs of mice leads to tlr4-dependent airway hyperresponsiveness. In addition, we now provide data that the development of HA-dependent airway hyperresponsiveness requires the downstream adaptor molecule MyD88. However, the cell-types and specific mechanisms, which regulate the physiologic response to matrix fragments in the lung, remain unexplored. We provide novel evidence that osteopontin contributes to the biological response to ozone and our data suggest that osteopontin can function as an adaptor molecule during innate immune response to oxidant lung injury. Clear understanding of the mechanisms, which regulate the development of airway hyperresponsiveness after exposure to ambient ozone, could provide a novel therapeutic approach to many forms of airways disease including asthma. Furthermore, we provide evidence that NF-?B is activated in lung macrophages and airway epithelia following either ozone exposure or HA challenge. Collectively, our data suggest that matrix fragments accumulate in the context of non-infectious air pollutant exposure and that macrophage-derived innate immunity play a central role in mediating airway hyperreactivity. These data have led us to test the hypothesis that exposure to ambient ozone generates hyaluronan degradation products which mediate airway hyperresponsiveness through activation of macrophage-derived NF-?B in a manner dependent on the adaptor proteins MyD88 and OPN. We will address this hypothesis through the following specific aims.
Specific Aim 1 : Define the roles of MyD88 and NF-?B activation in macrophages and airway epithelia for the complete biologic response to ozone, and to hyaluronan fragments.
Specific Aim 2 : Define the role of intracellular OPN in response to ozone inhalation and recruitment of MyD88 to the cell surface of macrophages.
Specific Aim 3 : Utilizing human BALF define the role of soluble hyaluronan in MyD88, and OPN- dependent airway hyperresponsiveness to methacholine and NF-?B activation.
Asthma is a common disease affecting approximately 8% of the population in the US. Inhalation of ambient environmental ozone contributes to both respiratory morbidity and mortality in human populations. Understanding the biological mechanisms, which regulate the response to inhaled ozone, provides insight broadly into novel therapeutic targets for reactive airways disease. Using the ozone inhalation as a model of reactive airways disease, we have newly discovered the role of extracellular matrix hyaluronan in many forms of asthma. This new proposal is the natural extension of our novel observation. We anticipate that the proposed work will lead to the development of new therapeutic targets for the many patients suffering from reactive airways disease.
|Frush, Benjamin W; Li, Zhuowei; Stiles, Jane V et al. (2016) Ozone primes alveolar macrophage-derived innate immunity in healthy human subjects. J Allergy Clin Immunol 138:1213-1215.e1
|Yu, Yen-Rei A; Hotten, Danielle F; Malakhau, Yuryi et al. (2016) Flow Cytometric Analysis of Myeloid Cells in Human Blood, Bronchoalveolar Lavage, and Lung Tissues. Am J Respir Cell Mol Biol 54:13-24
|Pinilla-Vera, Miguel; Xiong, Zeyu; Zhao, Yutong et al. (2016) Full Spectrum of LPS Activation in Alveolar Macrophages of Healthy Volunteers by Whole Transcriptomic Profiling. PLoS One 11:e0159329
|Ogawa, Hirohisa; Ledford, Julie G; Mukherjee, Sambuddho et al. (2014) Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-?. Respir Res 15:143
|Stober, Vandy P; Szczesniak, Christopher; Childress, Quiana et al. (2014) Bronchial epithelial injury in the context of alloimmunity promotes lymphocytic bronchiolitis through hyaluronan expression. Am J Physiol Lung Cell Mol Physiol 306:L1045-55
|Horr, Samuel; Roberson, Russell; Hollingsworth, John W (2013) Pseudohypoxemia in a patient with chronic lymphocytic leukemia. Respir Care 58:e31-3
|Murphy, Susan K; Hollingsworth, John W (2013) Stress: a possible link between genetics, epigenetics, and childhood asthma. Am J Respir Crit Care Med 187:563-4
|Li, Zhuowei; Tighe, Robert M; Feng, Feifei et al. (2013) Genes of innate immunity and the biological response to inhaled ozone. J Biochem Mol Toxicol 27:3-16
|Feng, Feifei; Li, Zhuowei; Potts-Kant, Erin N et al. (2012) Hyaluronan activation of the Nlrp3 inflammasome contributes to the development of airway hyperresponsiveness. Environ Health Perspect 120:1692-8