Research and development of therapy for lung injury by activation of alveolar fluid and protein reabsorption mechanism

肺泡液激活及蛋白重吸收机制治疗肺损伤的研究进展

基本信息

批准号：
17591492
负责人：
SAKUMA Tsutomu
金额：
$ 2.52万
依托单位：
Kanazawa Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

The prognosis of acute lung injury is poor and a mew therapy is necessary to improve the outcome. Recently, alveolar fluid clearance has been considered to play an important role in the resolution of acute lung injury. To increase alveolar fluid clearance, an administration of a beta adrenergic agonist is a candidate, but the mechanism responsible for the beta agonist mediated alveolar fluid clearance is still uncertain. We studied mechanisms responsible for alveolar fluid and protein clearance in rots and excised human lungs and developed a therapy for lung injury. First, we found that CFTR plays a role in b_1-adrenergic agonist-stimulated alveolar fluid clearance in rat lungs. Second, endogenous catecholamine concentrations in pulmonary edema fluid are probably not sufficient to stimulate alveolar fluid clearance. In contrast, administration of exogenous catecholamines into the distal airspaces can stimulate alveolar fluid clearance in the human lung, an effect that is mediated in part by CH R. Therefore, exogenous cAMP-dependent stimulation will probably be required to accelerate the resolution of alveolar edema in the lungs of patients with pulmonary edema. Third, chronic pulmonary artery occlusion increases alveolar fluid clearance via a_1-Na, K-ATPase overexpression in rats. Fourth, endogenous catecholamine stimulated a-adrenoceptors and increased alveolar fluid clearance in rats with acute pancreatitis. Finally, basal alveolar fluid clearance in obese Zucker rat is mediated the increased function of b_2-adrenoceptor. The current study indicates that endogenous and exogenous catecholamines play an important role in the improvement of acute lung injury.

急性肺损伤的预后很差，需要新的治疗来改善预后。最近，肺泡液清除被认为在急性肺损伤的缓解中发挥重要作用。为了增加肺泡液清除率，可以使用β肾上腺素能激动剂，但β激动剂介导的肺泡液清除率的机制仍不确定。我们研究了腐烂和切除的人肺中负责肺泡液和蛋白质清除的机制，并开发了一种治疗肺损伤的疗法。首先，我们发现 CFTR 在 b_1-肾上腺素能激动剂刺激的大鼠肺部肺泡液清除中发挥作用。其次，肺水肿液中的内源性儿茶酚胺浓度可能不足以刺激肺泡液清除。相反，将外源性儿茶酚胺注入远端空腔可以刺激人肺中的肺泡液清除，这种作用部分是由 CH R 介导的。因此，可能需要外源性 cAMP 依赖性刺激来加速肺泡水肿的消退存在于肺水肿患者的肺部。第三，慢性肺动脉闭塞通过大鼠体内 a_1-Na、K-ATPase 过度表达增加肺泡液清除率。第四，内源性儿茶酚胺刺激急性胰腺炎大鼠的α-肾上腺素受体并增加肺泡液清除率。最后，肥胖 Zucker 大鼠的基础肺泡液清除率介导了 b_2-肾上腺素受体功能的增强。目前的研究表明，内源性和外源性儿茶酚胺在急性肺损伤的改善中发挥着重要作用。