NEUTROPHIL APOPTOSIS IN ACUTE LUNG INJURY

项目3：急性肺损伤中的中性粒细胞凋亡 尽管在阐明这些机制方面已经取得了相当大的进展 急性肺炎性中性粒细胞募集的影响因素 在体内调节移行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天生的局限性 组织中的寿命(即，结构性程序性细胞死亡)，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的影响，包括黏附、细胞因子和 趋化因子。中性粒细胞在肺中的持久性可能是一个重要的 急性肺损伤的决定因素，因为中性粒细胞持续的时间越长 在肺组织中存在时，它们可能 蛋白水解酶和活性氧的释放引发肺损伤 中间体。虽然急性肺部炎症的最终解决 取决于中性粒细胞的清除，清除的机制(S) 也可能影响肺部炎症的持续时间和严重程度。坏死性 中性粒细胞在细胞外释放有毒物质，从而 使炎症反应永久化，并进一步破坏组织。在……里面 相比之下，中性粒细胞的凋亡及其随后的吞噬作用 常驻巨噬细胞或诱导的单核细胞来源的巨噬细胞可能 终止炎症反应。这背后的假设是 认为中性粒细胞的凋亡决定了其严重程度和持续时间 急性肺炎症；促进中性粒细胞凋亡的因子和 巨噬细胞吞噬将导致肺更快的消退 炎症，而那些阻止细胞凋亡的物质会延长 炎症反应和增加急性肺损伤的可能性。 这一假设将在以下具体目标中得到检验：1) 确定表达的结构性和诱导性抗细胞凋亡蛋白 在体外和体内成熟的中性粒细胞中；2)测定其功能 中性粒细胞存活过程中亲和型和抗凋亡型蛋白的研究 急性肺炎症模型；3)确定黏附受体 介导小鼠对凋亡中性粒细胞的吞噬/清除 急性肺炎症模型；以及4)确定急性肺炎症的后果 促进或减少中性粒细胞凋亡在小鼠肺损伤中的作用 急性肺炎症模型。希望这些研究能够 获得了关于涉及到的分子机制的新信息 急性肺部炎症的解决，也许会产生新的治疗方法 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.