Subarachnoid hemorrhage is the third leading cause of stroke in the United States but accounts for fifty percent of the mortality and morbidity in cerebral vascular events. The syndrome of delayed cerebral ischemia (vasospasm) is a common, dangerous and poorly understood complication of subarachnoid hemorrhage. Neutrophil infiltration is the predominant early inflammatory response in subarachnoid hemorrhage;however, the role of neutrophils and their products in mediating vasospasm has not been elucidated. Neutrophils make reactive oxidant species (ROS). ROS are implicated in the pathogenesis of vasospasm and are believed to contribute to oxidative injury and nitric oxide (NO) depletion. These are believed to contribute to the blood vessel dysfunction in vasospasm. We proposal to test the hypothesisthat neutrophil accumulation in the subarachnoid space and selective increase in neutrophil-derived molecular markers of oxidative pathways will correlate with the occurrence of vasospasm after subarachnoid hemorrhage. We plan to investigate this by developing two specific aims: 1) We will establish the relationship between neutrophil enrichment in the subarachnoid space, stable molecular markers of distinct oxidative pathways and vasospasm;and 2) We will determine the implications of neutrophil depletion, activation, the inactivation of two neutrophil enzymes, NADPH oxidase and MPO, and the inactivation of the chemokines CXCR2 on the development of vasospasm in a murine model. There is no effective treatment of vasospasm. This proposal will lead to a better understanding of the pathways by which neutrophil infiltration and action may lead to vasospasm. This is relevant because neutrophils and neutrophil chemokines are potential targets for pharmacologic therapy to prevent or treat vasospasm. This proposal and the educational components included form the basis for Dr. Provencio to develop into an independent physician-scientist.
