Research interest
We determine how cells respond to external stimuli and transduce these signals into functional responses. We explore the biology of the vascular system, particularly the rapid trafficking of inflammatory cells that underlie nearly all of the events leading to cardiovascular disease. The phospholipid PAF is a potent inflammatory mediator that activates all inflammatory cells, and many of the cardiovascular and renal systems. We discovered a new class of phospholipids derived from the uncontrolled oxidation of phospholipids – as happens during organ transplant injury, inflammation, chronic alcohol ingestion,and atherosclerosis— that activate the PAF receptor. Other oxidized phospholipids induce the process of regulated cell death, apoptosis, through a potent disruption of mitochondrial function. We find mitochondria are particularly sensitive to certain oxidized phospholipids, even when presented outside the cell. We identified a mammalian phospholipid importer, and investigate how mitochondrial function is compromised by phospholipid oxidation products. At least one unexpected outcome of this work is that platelets are directly affected by oxidized phospholipids in ways that change their phenotype in ways that affect thrombosis and vascular disease. We also find that renal cells and kidney function are compromised by circulating PAF and oxidized phospholipids in animals and humans during the chronic oxidative stress of alcohol ingestion. The regulated inflammatory mediator PAF and unregulated oxidized phospholipids signal in diverse pathologies.
In other words ...
We are interested in the molecular details of inflammation, the process that controls invading organims, and sometimes interacts with and responds to the molecules of normal cells. We focus on lipid mediatators, that is signaling molecules derived from insoluble fatty acids and phospholipids, that drive and control the innate immune or inflammatoyr system. We establish assays, purify enzymes, molecularly manipulate exression of enzmes, adhesion molecules and transcription factors and other elements that control the amount of the enzymes and receptors that make, metabolize or respond to lipid signaling molecules. This approach now leads to understanding acute kidney disease because chronic inflammatory and oxidative stresses damage kidney homeostasis, in part, through abnormal circulating lipid mediators. Lipid mediators are also essential, we find, in stimulated mitochondrial damage and cell death.
Highlighted Publications
Bioactive oxidatively truncated phospholipids in inflammation and apoptosis: Formation, targets, and inactivation. McIntyre TM. Biochim Biophys Acta. 2012
Oxidatively truncated phospholipids are required agents of TNFα induced apoptosis. Latchoumycandane et al J Biol Chem. 2012
Intracellular erythrocyte platelet-activating factor acetylhydrolase I inactivates aspirin in blood. Zhou et al J Biol Chem. 2011 286:34820
Lipopolysaccharide signaling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1β-rich microparticles. Brown GT, McIntyre TM. J Immunol. 2011 186:5489
Human TMEM30a promotes uptake of antitumor and bioactive choline phospholipids into mammalian cells. Chen et al. J Immunol 186:3215
Circulating platelet-activating factor is primarily cleared by transport, not intravascular hydrolysis by lipoprotein-associated phospholipase A2/ PAF acetylhydrolase. Liu et al Circ Res. 2011 108:469
Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis Feldstein et al J Lipid Res. 2010 51:3046
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