REGULATION OF ACUTE LUNG INJURY BY ACUTE PHASE PROTEINS

中性粒细胞被认为是许多疾病的主要细胞介质。 急性肺损伤的形式，包括成人呼吸窘迫 综合症(ARDS)是由于他们有能力隔离在 肺血管系统，并导致随后的内皮损伤 通过释放活性氧和蛋白水解酶。然而， 控制中性粒细胞介导的炎症的事件知之甚少 而人们对急性时相蛋白的能力了解更少 调节导致急性肺损伤的炎症过程。这个 拟议研究的目的是检验这样一个假设，即 急性时相蛋白，C反应蛋白和铜蓝蛋白，调节 中性粒细胞介导的急性肺损伤，导致通透性水肿。 实验方法侧重于对控制的检查 这些急性时相蛋白介导的中性粒细胞损伤机制 培养内皮细胞和离体兔肺灌流培养 就像在表达兔反应蛋白的转基因小鼠中一样。具体的 目标是：1)。检测C反应蛋白和铜蓝蛋白降低或 预防中性粒细胞介导的兔离体肺损伤 在肺和转基因小鼠中；2.研究其抑制机制。 这些急性时相蛋白介导的中性粒细胞急性肺损伤； 确定抑制中性粒细胞活化的机制和 C反应蛋白和铜蓝蛋白在体外的作用；4.检测 C反应蛋白和铜蓝蛋白在中性粒细胞介导的内皮损伤中的作用 在体外改变内皮细胞的功能。通过以下方式调整机制 每一种急性期蛋白都将通过其影响的测量来确定 关于中性粒细胞激活和激活的选择性但不同的步骤 功能。纯化的兔急性时相蛋白及其对兔的影响 中性粒细胞对内皮细胞完整性的改变也将 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，C反应蛋白和铜蓝蛋白的特定区域 中性粒细胞对内皮细胞损伤的调控作用 可导致急性肺损伤的疾病将被确定。这些措施的结果 研究应该提供关于这些急性呼吸道疾病的作用的有用的新信息。 时相蛋白在急性肺损伤发病机制和治疗中的作用 也应该为预防和治疗提供新的可能性 急性呼吸窘迫综合征的应对措施。

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.