NEUTROPHILS & ACUTE INFLAMMATORY RESPONSES TO TRAUMATIC BRAIN INJURY

继发过程会加重创伤后的脑损伤。最新研究 提示中性粒细胞在局部急性炎症反应中 创伤性脑损伤促成了这一过程，然而，它们的作用 这在很大程度上仍然是未知数。我们假设中性粒细胞聚集在 并有助于颅脑损伤后损伤的扩展。 与此相关，我们还提出了定义表达变化的研究 脑血管内皮细胞中性粒细胞黏附受体的研究 并观察亚低温对脑损伤大鼠的影响。 创伤后中性粒细胞聚集和黏附分子表达。 我们的具体目标是：1)对中性粒细胞进行定量和定位 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黏附受体 (ICAM-1)在大鼠大脑皮质挫伤后的表达，2) 评估中性粒细胞去除(鼠单抗大鼠)的效果 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(质子密度磁共振)、 颅内压(脑池导管)和病变体积(T2- 加权磁共振成像)在大鼠大脑皮质挫伤后，3)确定 整合素和选择素黏附通路在细胞凋亡中的作用 创伤后中性粒细胞在脑内的堆积，4)确定 短暂(4小时)、中度(32摄氏度)低温延迟创伤后 中性粒细胞聚集与黏附分子的内皮表达 在大脑中，5)确定是否更长的低温(8小时或12小时) 对创伤后中性粒细胞产生更持久或持久的影响 蓄积，以及6)以确定一过性、中度大脑 在我们的模型中，低温减少了继发性脑损伤。 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 牵涉其中。创伤是一种独特、复杂、重要的炎症性疾病 刺激，而大脑也是一个同样独特的组织，特别是 与高度分化的内皮细胞(血脑屏障)有关。 因此，针对急性白血病患者制定有效的抗中性粒细胞策略 脑创伤的炎症反应，特异性细胞和 必须定义所涉及的分子事件。我们的最新发展 改善炎症的能力和低温在临床上的应用 使拟议的研究具有及时性和临床相关性

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