NEUTROPHIL APOPTOSIS IN ACUTE LUNG INJURY

项目3：急性肺损伤中的神经细胞凋亡 虽然在阐明这些机制方面取得了相当大的进展， 急性肺部炎症中性粒细胞募集的影响因素 调节体内迁移的中性粒细胞的命运并不像 很好理解。中性粒细胞被认为具有固有的有限的 组织中的寿命（即，组成性程序性细胞死亡），但 最近的证据表明，它们在组织中的存活是可以调节的， 在一定程度上受局部因素影响，包括粘附、细胞因子和 趋化因子肺内神经元的持续存在可能是一个重要的 急性肺损伤的决定因素，因为中性粒细胞 存在于肺组织中，它们可能 通过释放蛋白酶和活性氧引起肺损伤 中间体的虽然急性肺部炎症的解决最终 取决于中性粒细胞的清除，清除机制 也可能影响肺部炎症的持续时间和严重程度。坏死 的中性粒细胞释放有毒产物的细胞外，从而 使炎症反应持续并进一步损伤组织。在 相反，中性粒细胞的凋亡及其随后的吞噬作用， 驻留的巨噬细胞或诱发的单核细胞衍生的巨噬细胞可 终止炎症反应。这背后的假设是 建议是中性粒细胞凋亡决定的严重性和持续时间 急性肺部炎症;促进中性粒细胞凋亡的因子， 巨噬细胞的吞噬将导致肺的更快消退 而那些阻止细胞凋亡的细胞会延长炎症， 炎症反应，增加急性肺损伤的概率。 这一假设将在以下具体目标中加以检验： 确定表达的组成性和诱导性抗凋亡蛋白 体外和体内成熟中性粒细胞; 2）确定功能 促凋亡蛋白和抗凋亡蛋白在小鼠神经元存活中的作用 急性肺部炎症模型; 3）粘附受体的定义 介导小鼠凋亡中性粒细胞的吞噬/清除 急性肺部炎症模型;和4）确定 肺损伤小鼠神经细胞凋亡的加速或减少 急性肺部炎症模型。希望这些研究将 产生新的信息的分子机制所涉及的 解决急性肺部炎症，并可能产生新的方法， ARDS的治疗。

Project 3: Neutrophil Apoptosis in Acute Lung Injury Although considerable progress has been made in elucidating the mechanisms of neutrophil recruitment in acute lung inflammation, the factors regulating the fate of the transmigrated neutrophils in vivo are not as well understood. Neutrophils were thought to have an inherently limited life-span in tissues (i.e., constitutive programmed cell death), but recent evidence suggests that their survival in tissues can be regulated to some extent by local factors including adhesion, cytokines, and chemokines. Neutrophil persistence in the lung may be an important determinant of acute lung injury since the longer that neutrophils are present in lung tissue, the greater is the possibility that they may provoke lung injury by release of proteases and reactive oxygen intermediates. While the resolution of acute lung inflammation ultimately depends upon the clearance of neutrophils, the mechanism(s) of clearance may also affect the duration and severity of lung inflammation. Necrosis of neutrophils releases toxic products extracellularly, thereby perpetuating the inflammatory response and further damaging tissue. In contrast, apoptosis of neutrophils with their subsequent phagocytosis by resident macrophages or elicited monocyte-derived macrophages may terminate the inflammatory reaction. The underlying hypothesis of this proposal is that neutrophil apoptosis determines the severity and duration of acute lung inflammation; factors that promote neutrophil apoptosis and engulfment by macrophages will lead to more rapid resolution of lung inflammation while those that prevent apoptosis will prolong the inflammatory response and increase the probability of acute lung injury. This hypothesis will be examined in the following Specific Aims: 1) To Determine the Constitutive and Induced Anti-Apoptotic Proteins Expressed in Mature Neutrophils In vitro and In Vivo; 2) To determine the Function of Pro and Anti-Apoptotic Proteins in Neutrophil Survival in a Murine Model of Acute Lung Inflammation; 3) To Define the Adhesion Receptors Mediating Phagocytosis/Clearance of Apoptotic Neutrophils in a Murine Model of Acute Lung Inflammation; and 4) To Determine the Consequences of Accelerated or Reduced Neutrophil Apoptosis on Lung Injury in a Murine Model of Acute Lung Inflammation. It is hoped that these studies will yield new information on the molecular mechanisms involved in the resolution of acute lung inflammation and perhaps yield new approaches to the therapy of ARDS.