NEUTROPHILS & ACUTE INFLAMMATORY RESPONSES TO TRAUMATIC BRAIN INJURY

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Secondary processes exacerbate brain injury after trauma. Recent studies suggest that neutrophils in the local acute inflammatory response to traumatic brain injury contribute to this process, however, their role remains largely undefined. We HYPOTHESIZE that neutrophils accumulate in brain and contribute to injury extension after traumatic brain injury. Related to this, we also propose studies to define changes in expression of adhesion receptors for neutrophils on the cerebrovascular endothelium after cerebral trauma, and to examine the effect of hypothermia on posttraumatic neutrophil accumulation and adhesion molecule expression. Our SPECIFIC AIMS are: 1) To quantitate and localize neutrophil accumulation (myeloperoxidase, immunohistochemistry, rhodamine-labeled neutrophils) and endothelial expression of neutrophil adhesion receptor (ICAM-1) in brain after controlled cortical contusion in rats, 2) To assess the effect of neutrophil depletion (mouse monoclonal anti-rat neutrophil antibody [RP-3]) on markers of secondary brain injury including hyperemia (autoradiography), edema (proton-density MRI), intracranial pressure (cisternal catheter), and lesion volume (T2- weighted MRI) after controlled cortical contusion in rats, 3) To define the contribution of the integrin and selectin adhesion pathways to posttraumatic neutrophil accumulation in brain, 4) To determine if transient (4h), moderate (32degreesC) hypothermia delays posttraumatic neutrophil accumulation and endothelial expression of adhesion molecules in brain, 5) To determine if more prolonged hypothermia (8 h or 12 h) produces a more sustained or permanent effect on posttraumatic neutrophil accumulation, and 6) To determine if transient, moderate cerebral hypothermia reduces secondary brain injury in our model. The cellular and molecular events in the acute inflammatory response are highly dependent on both the nature of the stimulus and the tissue involved. Trauma is a unique, complex, and important inflammatory stimulus, and the brain is a similarly unique tissue, particularly related to the highly differentiated endothelium (blood-brain barrier). Thus, to develop effective anti-neutrophil strategies targeting the acute inflammatory response to cerebral trauma, the specific cellular and molecular events involved must be defined. Recent developments in our ability to modify inflammation and in the clinical use of hypothermia make the proposed research timely and clinically relevant