The concept underlying this project is that a variety of lipid mediators, many of them previously thought to be involved in the induction of inflammatory responses, have an opposing, anti-inflammatory effect by virtue of their ability to suppress the production of pro-inflammatory mediators from macrophages. PAR and oxidized phospholipids are candidates for such an effect and may exemplify the mechanisms by which uptake of apoptotic cells into macrophages also induce an anti- inflammatory """"""""phenotype"""""""". The active suppressive species generated by oxidizing phospholipids in vitro or isolated from apoptotic cells will be identified and characterized structurally in collaboration with Project 2 and their mode of action determined. A direct effect of intact phospholipid or intracellular signaling proteins, in particular members of the PPAR family of nuclear receptors, is hypothesized and will be tested. In order to function in this way the phospholipid would have to be taken up into the macrophage, a process suggested to involve the phospholipid scramblases studied in Project 4. A second set of anti-inflammatory lipids are prostanoids deriving from the action of macrophage COX2. Expression of COX2 in these cells is suggested to result in part from activation of cPLA2, subsequent stimulation of PPARs by oxidized arachidonate products and effects at a PPRE site on the COX2 promoter. This process, as well as mechanisms for transcriptional regulation of cPLA2 and 5-lipoxygenase activating protein (FLAP) in resident pulmonary macrophages, will be examined with a focus on adhesive- driven events in collaboration with Project 3. A common point of action in macrophage mediator suppression induced by PAF and the oxidized phospholipids appears to be inhibition of p38 MAPkinase activation. The potential mechanisms by which this occurs and results in blockade of NfkappaB transactivation will be explored with Project 5. Both the oxidized phospholipids acting through p38 blockade and the suppressive prostanoids (with no effect on p38) are suggested to by inhibiting (in part) the transactivating activity of NfkappaB due to their binding the co- activator proteins, CBP and p300. Mediators more dependent on transcriptional regulation by AP-1 seem not be blocked by these anti- inflammatory mediators. The net effect is suppression of pro- inflammatory mediators but not of anti-inflammatory mediators but not of anti-inflammatory mediators. The net effect is suppression of pro- inflammatory mediators but not of anti-inflammatory TGFbeta or the monocyte chemoattractant, MCP-1. Finally, the processes and agents will be examined in vivo to show their presence and effect in resolution of pulmonary inflammation.
| 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 |
| 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: |
| 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 |
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