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.
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.
|Zemski Berry, Karin A; Murphy, Robert C; Kosmider, Beata et al. (2017) Lipidomic characterization and localization of phospholipids in the human lung. J Lipid Res 58:926-933|
|Mould, Kara J; Barthel, Lea; Mohning, Michael P et al. (2017) Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury. Am J Respir Cell Mol Biol 57:294-306|
|Gibbings, Sophie L; Thomas, Stacey M; Atif, Shaikh M et al. (2017) Three Unique Interstitial Macrophages in the Murine Lung at Steady State. Am J Respir Cell Mol Biol 57:66-76|
|Yun, Bogeon; Lee, HeeJung; Jayaraja, Sabarirajan et al. (2016) Prostaglandins from Cytosolic Phospholipase A2?/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages. J Biol Chem 291:7070-86|
|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|
|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|
|Kandasamy, Pitchaimani; Numata, Mari; Berry, Karin Zemski et al. (2016) Structural analogs of pulmonary surfactant phosphatidylglycerol inhibit toll-like receptor 2 and 4 signaling. J Lipid Res 57:993-1005|
|Zemski Berry, Karin A; Murphy, Robert C (2016) Phospholipid Ozonation Products Activate the 5-Lipoxygenase Pathway in Macrophages. Chem Res Toxicol 29:1355-64|
|Frasch, S Courtney; McNamee, Eóin N; Kominsky, Douglas et al. (2016) G2A Signaling Dampens Colitic Inflammation via Production of IFN-?. J Immunol 197:1425-34|
|Janssen, William J; Bratton, Donna L; Jakubzick, Claudia V et al. (2016) Myeloid Cell Turnover and Clearance. Microbiol Spectr 4:|
Showing the most recent 10 out of 268 publications