Inflammatory Mechanisms in Cerebral Ischemia

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DESCRIPTION (provided by applicant): Stroke is a significant cause of death and disability in this country. Treatments are few and available to only a small percentage of stroke victims. We and others have shown that the stress inducible 70 kDa heat shock protein (HSP70) is neuroprotective. The mechanism of protection following cerebral ischemic events is not well known, but has largely been attributed to its chaperone functions whereby HSP70 improves cell survival by preventing protein aggregation. A few recent studies suggest that HSP70 may also have antiinflammatory properties. It is now known that inflammation participates in cerebral ischemic injury by contributing to brain tissue damage acutely, but it is unknown whether HSP70 plays an anti-inflammatory role in stroke. In this proposal, we will explore the effects of selective HSP70 overexpression in regulating the inflammatory response in brain ischemia and ischemia-like insults. In the intact brain, this response appears to be mediated by both the resident microglia and invading peripheral leukocytes. Inflammatory cells produce potentially damaging substances such as reactive oxygen and nitrogen species, cytokines, chemokines, glutamate and various proteases. Using a transgenic mouse model where HSPT0 is constitutively overexpressed, we will first test the hypothesis that HSP70 is associated with a reduction in this inflammatory response in a well characterized stroke model. Using mixed cultures of neurons, astrocytes and microglia, we have observed that microglia increase damage to ischemia-like insults. Therefore, we will examine whether selective overexpression of HSP70 in microglia may reverse the worsened injury, and explore potential mechanisms behind this observation such as suppression of inflammatory mediators and inhibition of the inflammatory transcription factor, nuclear factor kappa B (NFkB). In the final aim, we will then study the participation of peripheral inflammatory cells in a mouse stroke model using bone marrow chimeras, where wildtype animals are transplanted with marrow cells derived from the HSP70 transgenic mice. These studies should provide uniqae insights into a new mechanism by which HSP70 may protect against injury following cerebral ischemic and ischemia-like insults.