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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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NST-2 Subcommittee (NST)
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Bosetti, Francesca
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Cleveland Clinic Lerner
Internal Medicine/Medicine
Schools of Medicine
United States
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Elsharkawy, Hesham; Abd-Elsayed, Alaa; El-Hadi, Sherif et al. (2016) Fluctuating Electrocardiographic Changes Predict Poor Outcomes After Acute Subarachnoid Hemorrhage. Ochsner J 16:225-9
da Silva, Ivan Rocha Ferreira; Provencio, J Javier (2015) Intracerebral hemorrhage in patients receiving oral anticoagulation therapy. J Intensive Care Med 30:63-78
Provencio, J Javier (2013) Inflammation in subarachnoid hemorrhage and delayed deterioration associated with vasospasm: a review. Acta Neurochir Suppl 115:233-8
Smithason, Saksith; Moore, Shari K; Provencio, J Javier (2013) Low-dose lipopolysaccharide injection prior to subarachnoid hemorrhage modulates Delayed Deterioration associated with vasospasm in subarachnoid hemorrhage. Acta Neurochir Suppl 115:253-8
Smithason, Saksith; Moore, Shari Korday; Provencio, J Javier (2012) Systemic administration of LPS worsens delayed deterioration associated with vasospasm after subarachnoid hemorrhage through a myeloid cell-dependent mechanism. Neurocrit Care 16:327-34
Provencio, J Javier; Altay, Tamer; Smithason, Saksith et al. (2011) Depletion of Ly6G/C(+) cells ameliorates delayed cerebral vasospasm in subarachnoid hemorrhage. J Neuroimmunol 232:94-100
Provencio, J J; Fu, X; Siu, A et al. (2010) CSF neutrophils are implicated in the development of vasospasm in subarachnoid hemorrhage. Neurocrit Care 12:244-51
Moskowitz, Shaye I; Ahrens, Christine; Provencio, J Javier et al. (2009) Prehemorrhage statin use and the risk of vasospasm after aneurysmal subarachnoid hemorrhage. Surg Neurol 71:311-7, discussion 317-8
Altay, Tamer; Smithason, Saksith; Volokh, Nina et al. (2009) A novel method for subarachnoid hemorrhage to induce vasospasm in mice. J Neurosci Methods 183:136-40