My laboratory is interested in the rapid response of endothelial cells and blood cells to vascular injury. We have shown that endothelial cells store adhesion proteins, von Willebrand factor and P-selectin, in storage granules called Weibel-Palade bodies. Inflammatory stimuli (such as histamine) and injury stimuli (such as thrombin and fibrin) cause rapid exocytosis of the storage granules. To study the function of these molecules, we have prepared mice that are deficient in P-selectin or von Willebrand factor. The P-selectin-deficient mice have a pronounced defect in leukocyte interaction with the endothelium of the vessel wall and with activated platelets. von Willebrand factor-deficient mice have a prolonged bleeding time. We study these and other genetically engineered mice in experimental models of thrombosis, inflammation, cancer and wound healing. 

Endothelial cells treated with inflammatory cytokines synthesize another selectin: E-selectin, and similar to P-selectin, it also mediates binding to leukocytes. We prepared mice deficient in both P-and E-selectins. In contrast to the rather mild phenotypes observed in mice deficient in a single selectin gene, the doubly deficient mice exhibit extreme leukocytosis, elevated cytokine levels and alterations in hematopoiesis. Virtual lack of leukocyte rolling and low extravasation at sites of inflammation make these animals susceptible to opportunistic bacterial infections to which they succumb. The phenotype of these mice shows that the absence of endothelial selectins severely affects leukocyte homeostasis and indicates that these two selectins are as important for normal leukocyte function as the leukocyte ß2 integrins. 

Recently our lab is focusing on the role of neutrophil extracellular traps or NETs (decondensed chromatin ejected from neutrophil nuclei under stress) in pathological inflammation and thrombosis. We found that NETs are a critical component of deep vein thrombosis. Our observation that cancers induce NETs explains the link of cancer to thrombosis. NETs are injurious to tissues and likely exacerbate many common inflammatory diseases. They also form during the process of ischemia/reperfusion and contribute to brain or heart injury after stroke or myocardial infarction. The extent to which inhibition of NETosis improves outcome in different pathologies involving inflammation and thrombosis, such as diabetes is now the main topic of the lab’s investigations.