Ozone is a reactive oxygen species that reacts with lipids in the pulmonary airways and initiates a complex inflammatory response even when breathed at low concentrations. Ozone is also one of the important environmental pollutants that is present in urban population (less than 300 ppb) known to execerbate lung inflammation in susceptible individuals. A major hypothesis to be tested is that low concentrations of ozone are particularly damaging to individuals with existing lung disease due to an applification of the inflammatory response caused by ozone generated bioactive lipids, which could have a synergistic effect on ongoing pulmonary cell activation. The specific model to be examined will be the effect of ozone derived lipids on the response of macrophages to apoptotic cells and to cells that have phagocytized Candida albicans. The structural analysis and quantitation of lipid mediators derived from reaction of ozone with endogenous lipids requires the development of sophisticated yet nonspecific analytical techniques capable of providing specific data for lipids even though they are present in complex mixtures of closely related compounds. Mass spectrometry is such a tool. The major objective of this grant is to further understand the mechanism by which ozone can alter the inflammatory response in the lung through generation of bioactive lipid products. Specific responses of cells relevant to the lung (alveolar macrophage) will be studied when lung surfactant is exposed to low concentrations of ozone. These responses will be used to guide isolation and purification of lipid products that will be structurally characterized using mass spectrometry. The potential for mass spectrometry as a tool used for imaging lipids in tissues will also be investigated with the Intent of applying mass spectrometric imaging to determine the precise localization of ozone generated novel lipid products in pulmonary airways following exposure of mice to environmentally relevant concentrations of ozone. The specific goal is to understand the molecular basis underline the toxicity of ozone in lung. The oxidation of cholesterol by ozone and the formation of active oxysterols will be further examined. The reaction of ozone with plasmalogen glycerophospholipids will also be investigated in studies to test the hypothesis that vinyl ether phospholipids serve as an important precursor of bioactive lysophospholipids.
Certain individuals, specifically individuals with pulmonary diseases are uniquely susceptible to low concentrations of ozone in the environment, since ozone can react with endogenous lipids to form many different unique products. The hypothesis will be tested that these ozonized lipid products can amplify the inflammatory response. Understanding the biochemical events and the mechanism by which these previously uncharacterized oxidized lipid products can have in the lung could be used to mitigate the inflammatory response of susceptible individuals to ozone present in the environment.
|Yun, Bogeon; Lee, HeeJung; Ghosh, Moumita et al. (2014) Serine hydrolase inhibitors block necrotic cell death by preventing calcium overload of the mitochondria and permeability transition pore formation. J Biol Chem 289:1491-504|
|Zemski Berry, Karin A; Gordon, William C; Murphy, Robert C et al. (2014) Spatial organization of lipids in the human retina and optic nerve by MALDI imaging mass spectrometry. J Lipid Res 55:504-15|
|Redente, Elizabeth F; Keith, Rebecca C; Janssen, William et al. (2014) Tumor necrosis factor-* accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages. Am J Respir Cell Mol Biol 50:825-37|
|Caceres, Silvia M; Malcolm, Kenneth C; Taylor-Cousar, Jennifer L et al. (2014) Enhanced in vitro formation and antibiotic resistance of nonattached Pseudomonas aeruginosa aggregates through incorporation of neutrophil products. Antimicrob Agents Chemother 58:6851-60|
|Henson, Peter M; Bratton, Donna L (2013) Antiinflammatory effects of apoptotic cells. J Clin Invest 123:2773-4|
|Aldrovandi, Maceler; Hammond, Victoria J; Podmore, Helen et al. (2013) Human platelets generate phospholipid-esterified prostaglandins via cyclooxygenase-1 that are inhibited by low dose aspirin supplementation. J Lipid Res 54:3085-97|
|Suram, Saritha; Silveira, Lori J; Mahaffey, Spencer et al. (2013) Cytosolic phospholipase A(2)? and eicosanoids regulate expression of genes in macrophages involved in host defense and inflammation. PLoS One 8:e69002|
|Fernandez-Boyanapalli, Ruby; Goleva, Elena; Kolakowski, Christena et al. (2013) Obesity impairs apoptotic cell clearance in asthma. J Allergy Clin Immunol 131:1041-7, 1047.e1-3|
|Talahalli, Ramaprasad; Zarini, Simona; Tang, Jie et al. (2013) Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienes. J Leukoc Biol 93:135-43|
|Frasch, S Courtney; Fernandez-Boyanapalli, Ruby F; Berry, Karin A Zemski et al. (2013) Neutrophils regulate tissue Neutrophilia in inflammation via the oxidant-modified lipid lysophosphatidylserine. J Biol Chem 288:4583-93|
Showing the most recent 10 out of 247 publications