There is immense potential to generate a variety of bioactive lipids in the lung in response to injury and infection. The central theme of this proposal is that lipid mediators have diverse functions in controlling the amplitude of the inflammatory response and its resolution. Our goals are to define the role of specific lipid mediators in protecting the lung during inflammatory injury and infection, and to determine how the environmental toxicant ozone induces production of novel lipid metabolites that interfere with these processes leading to pathological consequences. The objectives are to: Elucidate mechanisms of Group IVA cytosolic phospholipase A2 activation and eicosanoid production in resident peritoneal and alveolar macrophages by Cantjida albicans and Aspergillus fumigatus, and determine the role of this pathway in regulating immune responses to fungal infection in the lung. Define the mechanisms of production of the novel lipid mediator lysophosphatidylserine by neutrophils and macrophages, and determine how it mediates the removal of apoptotic cells and suppresses pro-inflammatory cytokine production to promote the resoiution of lung inflammation. Structurally characterize by mass spectrometry novel lipid mediators produced following exposure of lung surfactant to low levels of ozone, and to determine their impact on the ability of the lung to control inflammation and infection. Novel mass spectrometry approaches will be developed to image these lipid mediators in ozonized lung tissues. This program brings together investigators with diverse expertise in cell biology, biochemistry and structural biology. By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses.

Public Health Relevance

The studies in this PPG will enhance our understanding of how specific lipid mediators contribute to the unique ability ofthe lung to protect itself from excess inflammation during injury and infection. Importantly, our ability to identify novel lipid mediators produced as a result of exposure to ozone will provide insight for developing strategies to protect from this deleterious environmental lung toxicant.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL034303-26
Application #
8017850
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Moore, Timothy M
Project Start
1997-09-01
Project End
2016-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
26
Fiscal Year
2011
Total Cost
$1,761,473
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Yun, Bogeon; Lee, HeeJung; Jayaraja, Sabarirajan et al. (2016) Prostaglandins from Cytosolic Phospholipase A2α/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages. J Biol Chem 291:7070-86
Zemski Berry, Karin A; Murphy, Robert C (2016) Phospholipid Ozonation Products Activate the 5-Lipoxygenase Pathway in Macrophages. Chem Res Toxicol 29:1355-64
Janssen, William J; Bratton, Donna L; Jakubzick, Claudia V et al. (2016) Myeloid Cell Turnover and Clearance. Microbiol Spectr 4:
Jayaraja, Sabarirajan; Dakhama, Azzeddine; Yun, Bogeon et al. (2016) Cytosolic phospholipase A2 contributes to innate immune defense against Candida albicans lung infection. BMC Immunol 17:27
Frasch, S Courtney; McNamee, Eóin N; Kominsky, Douglas et al. (2016) G2A Signaling Dampens Colitic Inflammation via Production of IFN-γ. J Immunol 197:1425-34
Desch, A Nicole; Gibbings, Sophie L; Goyal, Rajni et al. (2016) Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes. Am J Respir Crit Care Med 193:614-26
Fernandez-Boyanapalli, Ruby F; Falcone, Emilia Liana; Zerbe, Christa S et al. (2015) Impaired efferocytosis in human chronic granulomatous disease is reversed by pioglitazone treatment. J Allergy Clin Immunol 136:1399-401.e1-3
Ito, Yoko; Correll, Kelly; Zemans, Rachel L et al. (2015) Influenza induces IL-8 and GM-CSF secretion by human alveolar epithelial cells through HGF/c-Met and TGF-α/EGFR signaling. Am J Physiol Lung Cell Mol Physiol 308:L1178-88
Almstrand, Ann-Charlotte; Johnson, Christopher; Murphy, Robert C (2015) Evidence for an N-methyl transfer reaction in phosphatidylcholines with a terminal aldehyde during negative electrospray ionization tandem mass spectrometry. Anal Bioanal Chem 407:5045-52
Leslie, Christina C (2015) Cytosolic phospholipase Aâ‚‚: physiological function and role in disease. J Lipid Res 56:1386-402

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