STRESS PRECONDITIONING AND ALVEOLAR EPITHELIAL INJURY

描述：（逐字摘自申请人摘要）创伤和出血 休克是人类急性肺损伤的主要原因之一。二十到 25%的严重创伤患者发展为急性肺损伤， 创伤是继脓毒症之后第二常见的急性肺损伤原因。 内源性前列腺素E上调肺泡上皮细胞液体转运 儿茶酚胺是预防肺泡灌洗液的主要机制， 失血性休克然而，在严重出血后，这种保护机制 通过对肺泡的氧化应激的发展而被消除 上皮对肺屏障的氧化应激是由 大量的一氧化氮（NO）和自由基氧物种， 直接改变膜蛋白的功能， 肺泡上皮细胞中的β-肾上腺素能受体-cAMP信号通路， 通过肺中中性粒细胞的隔离放大氧化应激 在肺泡上皮中。 热休克或应激反应是一种高度保守的细胞防御 其特征在于应激蛋白的表达增加， “使细胞能够承受随后的致命伤害， 称为“耐热性”或“预处理”。“应力预处理， 热已经显示出保护肺免受缺血-再灌注损伤， 尽管对保护机制知之甚少。我们的初步 数据表明，无论是热诱导还是热诱导， 非热刺激恢复正常肺泡上皮细胞液体运输后， 大鼠严重出血。因此，我们建议测试假设， 保护肺泡上皮免受氧化应激， 用热进行的应激预处理通过以下方式介导：（a）降低 通过抑制肺中的炎症反应， 直接抑制离子的促炎介质（NO，过氧亚硝酸盐） 跨肺泡上皮的转运（aim 1）;（b 0） 严重出血后肺内中性粒细胞隔离， 从骨髓中释放中性粒细胞，并通过增加 中性粒细胞凋亡，以及通过减少粘附的表达， 肺内皮细胞表面的分子和空气释放 趋化因子CINC-1和/或MIP-2。(aim 2）。在本提案的目标3中，我们将 探讨如何应激预处理（使用临床相关策略，如 作为格尔德霉素或Hsp 32表达的直接诱导剂）， 出血后肺泡上皮细胞的氧化应激。

DESCRIPTION: (Verbatim from the applicant's abstract) Trauma and hemorrhagic shock are one of the major causes of acute lung injury in humans. Twenty to twenty-five percent of patients with severe trauma develop acute lung injury, and trauma is the second most common cause of acute lung injury after sepsis. Upregulation of alveolar epithelial fluid transport by endogenous catecholamines is a major mechanism that prevents alveolar flooding after hemorrhagic shock. However, after severe hemorrhage, this protective mechanism is abolished by the development of an oxidative stress to the alveolar epithelium. The oxidative stress to this lung barrier is caused by the release of a large quamtity of nitric oxide (NO) and radical oxygen species that directly alter the function of membrane proteins involved in the beta-adrenergic receptor-cAMP signaling pathway in the alveolar epithelium and by the sequestration of neutrophils in the lung that amplify oxidative stress in the alveolar epithelium. The heat shock or stress response is a highly conserved cellular defense mechanism characterized by the increased expression of stress proteins that "allows the cells to withstand a subsequent lethal insult, a phenomenon referred as "thermotolerance" or "preconditioning." Stress preconditioning with heat has been shown to protect against ischemia-reperfusion injury to the lung, although the mechanisms of protection are poorly understood. Our preliminary data indicated that induction of thermotolerance either with heat or non-thermal stimulus restored normal alveolar epithelial fluid transport after severe hemorrhage in rats. Therefore, we propose to test the hypothesis that the protection against oxidative stress to the alveolar epithelium provided by stress preconditioning with heat is mediated by: (a) a decrease of the inflammatory response in the lung by inhibition of expression of proinflammatory mediators (NO, peroxynitrite) that directly inhibit ion transport across the alveolar epithelium (aim 1); (b0 a decrease in the neutrophil sequestration in lung after severe hemorrhage by decreasing the release of neutrophils from the bone marrow and by increasing the rate of neutrophil apoptosis, as well as by decreasing the expression of adhesion molecules on the surface of the lung endothelium and the airspace release of chemokines CINC-1 and/or MIP-2. (aim 2). In aim 3 of this proposal we will explore how stress preconditioning ( using clinically relavant strategies, such as geldanamycin or direct inducers of Hsp 32 expression), protects against oxidative stress to the alveolar epithelium after hemorrhage.