Vasogenic edema is the most common form of brain edema observed in clinical practice. It is characterized by an increased permeability of brain capillary endothelial cells to macromolecules and by an increased extracellular space and brain water. Although the causes of vasogenic edema following brain ischemia and injury appear to be multifactorial, the basic mechanisms are dependent upon alteration sin the structural and functional integrity of brain endothelial cells. we have postulated that oxygen radicals, superoxide radicals in particular, are involved in the perturbation of the structural and functional integrity of the endothelial cells. We have demonstrated that cerebral edema and infarction induced by either cold injury or by focal cerebral ischemia and reperfusion are significantly reduced in transgenic (Tg) mice overexpressing human CuZn-superoxide dismutase (SOD-1) activity. We now propose to continue to investigate the role of oxidative stress in the pathogenesis of vasogenic edema using both in vivo mouse models of focal cerebral ischemia and reperfusion and in vitro cerebral capillary endothelial cell cultures.
Our specific aims are: 1) to elucidate the role of CuZn-SOD in vasogenic edema and infarction following focal cerebral ischemia and reperfusion in SOD-1 transgenic mice and in sod-1 knockout mutants; 2) to investigate the temporal pattern of bcl-2 and hsp 70 gene expression in neurons and endothelial cells in mice that overexpress SOD-1 transgene, wild-type or in mutant mice with reduced sod-1 expression following focal cerebral ischemia and reperfusion; 3) to elucidate the superoxide-dependent oxidative pathways involving the pathogenesis of vasogenic edema after focal cerebral ischemia using genetically modified mice with altered levels of glutathione peroxidase and nitric oxide synthase activities; 4) to investigate the role of oxidative stress in vasogenic edema and infarction in a newly developed mitochondrial manganese superoxide dismutase (sod-2) knockout mutant mouse; and 5) to study the role of superoxide dismutase on hypoxia-induced injury and degeneration in primary culture of cerebral endothelial cells of Tg and knockout mutants. These studies have therapeutic implications and will further shed light on molecular and cellular mechanisms underlying the pathogenesis of vasogenic edema following ischemia and reperfusion.
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