NEUTROPHILS & ACUTE INFLAMMATORY RESPONSES TO TRAUMATIC BRAIN INJURY

继发过程加重创伤后的脑损伤。 最近的研究 提示中性粒细胞在局部急性炎症反应中 创伤性脑损伤有助于这一过程，然而，它们的作用 在很大程度上仍然不确定。 我们假设中性粒细胞聚集 并有助于创伤性脑损伤后的损伤扩展。 与此相关，我们还提出了研究，以定义表达的变化， 中性粒细胞粘附受体的表达 在脑外伤后，并检查低温对 创伤后中性粒细胞积聚和粘附分子表达。 我们的具体目标是：1）定量和定位中性粒细胞 蓄积（髓过氧化物酶，免疫组织化学，罗丹明标记 中性粒细胞）和内皮细胞表达中性粒细胞粘附受体 大鼠脑挫伤后脑内ICAM-1的表达; 2） 评估中性粒细胞耗竭（小鼠单克隆抗大鼠 中性粒细胞抗体[RP-3]）对继发性脑损伤标志物的影响 包括充血（放射自显影），水肿（质子密度MRI）， 颅内压（脑池导管）和病变体积（T2- 加权MRI）后，控制大鼠皮质挫伤，3）为了定义 整合素和选择素粘附途径对 脑中创伤后中性粒细胞积聚，4）为了确定是否 短暂（4小时）、中度（32 ℃）低温延迟创伤后 中性粒细胞聚集和粘附分子的内皮表达 5）确定是否更长时间的低温（8小时或12小时） 对创伤后中性粒细胞产生更持久或永久的影响 积累和 6)以确定是否有短暂的，中度的脑 低温降低了我们模型中的继发性脑损伤。 急性炎症反应中的细胞和分子事件是 高度依赖于刺激的性质和组织 涉案 创伤是一种独特的、复杂的、重要的炎症反应， 刺激，大脑是一个类似的独特的组织，特别是 与高度分化的内皮（血脑屏障）有关。 因此，为了开发针对急性淋巴细胞白血病的有效的抗中性粒细胞策略， 炎症反应脑外伤，具体的细胞和 必须定义所涉及的分子事件。 我国最近的事态发展 改变炎症的能力和低温的临床应用 使拟议的研究及时和临床相关

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