REGULATION OF ACUTE LUNG INJURY BY ACUTE PHASE PROTEINS

中性粒细胞在许多肿瘤中被认为是主要的细胞介质。 急性肺损伤的形式，包括成人呼吸窘迫 （2）由于其能力，成为隔离在 肺血管系统并导致随后的内皮损伤 通过活性氧和蛋白酶的释放。然而，在这方面， 对控制嗜中性粒细胞介导的炎症的事件知之甚少 关于急性期蛋白质的能力， 调节导致急性肺损伤的炎症过程。的 拟议研究的目的是检验假设， 急性时相蛋白，C-反应蛋白（CRP）和铜蓝蛋白， 嗜酸性粒细胞介导的急性肺损伤，导致渗透性水肿。 实验方法的重点是检查控制 这些急性时相蛋白介导的损伤机制， 培养的内皮细胞和离体灌流的兔肺 如在表达兔反应蛋白的转基因小鼠中。具体 目标是：1）。检查CRP和铜蓝蛋白降低或 预防嗜酸性粒细胞介导的急性肺损伤的实验研究 肺和转基因小鼠; 2.检查抑制的机制， 由这些急性时相蛋白引起的嗜中性粒细胞介导的急性肺损伤; 3.到 确定抑制中性粒细胞活化的机制， 通过CRP和铜蓝蛋白在体外的功能;和4.检查的影响 CRP和铜蓝蛋白对嗜铬细胞介导的内皮损伤的影响 改变体外内皮细胞功能。调节机制 每种急性时相蛋白将通过测量它们的作用来确定 选择性但不同的步骤参与中性粒细胞活化， 功能纯化的兔急性时相蛋白与兔肝细胞凋亡的关系 中性粒细胞对内皮细胞完整性改变的影响也将是 使用培养的兔内皮细胞进行研究。最后，通过一系列 结构-功能研究，CRP和铜蓝蛋白的特定区域 参与调节嗜中性粒细胞介导的内皮细胞损伤 会导致急性肺损伤结果进行 研究应提供关于这些急性 时相蛋白在急性肺损伤发病机制和解决中的作用， 还应该为预防和治疗提供新的可能性 ARDS的措施。

Neutrophils have been implicated as the major cellular mediator in many forms of acute lung injury including the adult respiratory distress syndrome (ARDS) by virtue of their ability to become sequestered in the pulmonary vasculature and cause subsequent damage to the endothelium through the release of reactive oxygen species and proteases. However, events that control neutrophil-mediated inflammation are poorly understood and even less is known about the ability of acute phase proteins to regulate inflammatory processes resulting in acute lung injury. The objective of the proposed research is to test the HYPOTHESIS that the acute phase proteins, C-reactive protein (CRP) and ceruloplasmin, regulate neutrophil-mediated acute lung injury that results in permeability edema. The experimental approach focuses upon an examination of control mechanisms by these acute phase proteins of neutrophil-mediated injury to cultured endothelial cells and in isolated perfused rabbit lungs as well as in transgenic mice expressing rabbit reactive protein. The specific aims are: 1). to examine the ability of CRP and ceruloplasmin to reduce or prevent neutrophil-mediated acute lung injury in isolated perfused rabbit lungs and in transgenic mice; 2. to examine mechanisms of inhibition of neutrophil-mediated acute lung injury by these acute phase proteins; 3. to determine the mechanisms of inhibition of neutrophil activation and function by CRP and ceruloplasmin in vitro; and 4. to examine effects of CRP and ceruloplasmin on neutrophil-mediated endothelial injury and altered endothelial cell function in vitro. Mechanisms of regulation by each acute phase protein will be determined by measurement of their effect on selective but distinct steps involved in neutrophil activation and function. The effect of purified rabbit acute phase proteins and rabbit neutrophils on alterations of endothelial cell integrity will also be studied using cultured rabbit endothelial cells. Finally, through a series of structure-function studies, specific regions of CRP and ceruloplasmin involved in modulation of neutrophil-mediated injury to endothelial cells that can result in acute lung injury will be identified. Results of these studies should provide useful new information on the role of these acute phase proteins in the pathogenesis and resolution of acute lung injury and should also provide new possibilities for prophylactic and therapeutic measures for ARDS.