RESOLUTION OF NEUROGENIC PULMONARY EDEMA

神经源性肺水肿的解决

基本信息

批准号：
2234922
负责人：
MICHAEL B MARON
金额：
$ 9.65万
依托单位：
NORTHEAST OHIO MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-06-14 至 1999-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (Applicant's abstract): Neurogenic pulmonary edema (NPE) is a form of edema that may develop after CNS trauma that massively activates the sympathetic nervous system (SNS). The long term objectives of this program are to determine (1) the basic mechanisms by which such excessive SNS activity affects lung blood flow and fluid balance and how these mechanisms act in concert to produce NPE, and (2) the mechanisms involved in the resolution of this form of edema. An understanding of both the mechanisms of development and recovery is important for the design of effective preventive and treatment measures. We have recently found that the rate of alveolar fluid reabsorption (AFR) is increased during recovery from NPE in a canine model of NPE in which the SNS is massively activated by the administration of veratrine. This project is designed to determine the mechanisms of the increased AFR and has 3 specific aims. The 1st aim is to determine if the increased AFR is mediated by beta-adrenergic stimulated alveolar epithelial sodium reabsorption, and if so, the role played by endogenous epinephrine in this process. Alveolar liquid clearance will be determined from the increase in protein concentration that occurs as fluid is reabsorbed from autologous plasma that has been instilled into the airways. Experiments will be done in adrenalectomized animals and using appropriate blockers to determine the role of adrenal catecholamines, beta2-adrenergic receptors (ICI 118,551), and active Na+ transport (amiloride) in this process. The second aim is designed to determine the dose-response relationship between plasma epinephrine concentration and AFR. This will be accomplished by determining AFR after infusing epinephrine concentrations ranging from those observed during mild to massive SNS activation. The 3rd aim is to determine if the increased AFR observed after massive SNS activation is the maximal attainable in the lung. This will be accomplished by determining if the SNS-induced increased in AFR can be further increased by the administration of drugs that increase intracellular cyclic AMP concentration independently (forskolin, theophylline) of beta2-adrenergic receptor activation.

描述（申请人的摘要）：神经源性肺水肿（NPE）是 CNS创伤后可能发展的水肿形式，大规模激活了交感神经系统（SNS）。该程序的长期目标确定（1）这种过多的SNS的基本机制活动会影响肺血流和液体平衡以及这些机制如何共同行动以生产NPE，以及（2）解决这种形式的水肿。对两种机制的理解发展和恢复对于有效的设计很重要预防和治疗措施。我们最近发现牙槽液的吸收（AFR）在从NPE恢复期间增加了 NPE的犬类模型，其中SNS大规模激活维拉汀的给药。该项目旨在确定 AFR增加的机制，具有3个具体目标。第一个目标是确定增加的AFR是否是由β-肾上腺素能刺激介导的肺泡上皮钠的吸收，如果是的，则在此过程中，内源性肾上腺素。肺泡液体清除将是由蛋白质浓度的增加确定为流体是从已灌输到的自体等离子体中吸收的航空公司。实验将在肾上腺切除动物中进行，并使用适当的阻滞剂来确定肾上腺儿茶酚胺的作用， β2-肾上腺素能受体（ICI 118,551）和主动Na+转运（Amiloride）在此过程中。第二个目标旨在确定血浆肾上腺素浓度和AFR之间的剂量反应关系。这将通过在注入肾上腺素后确定AFR来实现浓度范围从在轻度到大量SNS期间观察到的浓度不等激活。第三目的是确定是否在大规模SNS激活是肺中最大可达到的。这将是通过确定SNS诱导的AFR是否可以是通过增加细胞内的药物的给药进一步增加独立的环状AMP浓度（福斯科林，茶碱）的浓度 β2-肾上腺素受体激活。