Thomas M. McIntyre, PhD

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.