LUNG VASCULAR /AIRWAY EFFECTS OF ADRENOMEDULLIN

本项目的总体目的是探讨肾上腺髓质素（ADM）在肺中的作用。ADM是一种内源性肽，普遍存在于包括血浆在内的人体组织中，并在运动过程中增加。ADM使血管平滑肌松弛。血管松弛作用在肺动脉比在主动脉更有效。ADM似乎在调节全身和肺动脉血压中起作用。心房利钠肽（Atrial Natriuretic Peptide， ANP）可增加ADM的释放，其血流动力学效应部分可能与心房利钠肽有关。除心血管组织、肾脏和肾上腺髓质外，心房利钠肽mrna在气道上皮基底细胞和肺ⅱ型肺细胞中高表达。ADM可能是在肺组织中合成并释放到外周血和气道管腔中。在充血性心力衰竭和肺部疾病中观察到血浆ADM水平升高。然而，在生理和病理生理条件下，ADM在肺中的作用尚不清楚，特别是ADM放松气道平滑肌的能力。具体目的是：1)研究ADM在支气管活性药物改变气道反应的离体灌注肺中的作用和效价。2)研究气道上皮特别是其中性内肽酶在ADM对肺力学作用中的作用。3)研究内皮源性松弛因子（EDRF）和环加氧酶抑制剂对ADM肺力学作用的影响。4)确定ADM是否通过cAMP作为第二信使作用于气道。5)确定ADM在气道内的作用部位。本研究的重要意义在于，通过确定ADM如何调节支气管扩张，可能为以气道阻塞为特征的肺部疾病提供新的治疗方法。

The overall objective of this project is to investigate the role of Adrenomedullin (ADM) in the lung. ADM is an endogenous peptide which is ubiquitously distributed in human tissues including plasma and it increases during physical exercise. ADM relaxes the smooth muscles of the blood vessels. The vasorelaxant effect is more potent in pulmonary artery than in the aorta. ADM appears to play a role in the regulation of systemic and pulmonary arterial blood pressure. Atrial Natriuretic Peptide (ANP) increases the release of ADM and the hemodynamic effects of ANP may be partially due to ADM. ADM-mRNA is highly expressed in the basal cells of the airway epithelium and Type II pneumocytes in the lung in addition to the cardiovascular tissue, kidney and adrenal medulla. It is possible that ADM is synthesized in the lung tissue and is released into the peripheral blood and airway lumen. An increase in plasma ADM levels has been observed in congestive heart failure and in pulmonary disorders. Yet, the role of ADM in the lung under physiologic and pathophysiologic conditions is not known, in particular the ability of ADM to relax the smooth muscles of the airways. The specific aims are: 1) To study the action and potency of ADM in isolated-perfused lungs where airway responses have been altered by bronchoactive agents. 2) To study the role of airway epithelium, particularly its neutral endopeptidases, on the action of ADM on lung mechanics. 3) To study the role of endothelial derived relaxing factor (EDRF) and cyclooxygenase inhibitors on the action of ADM on lung mechanics. 4) To determine if ADM acts on the airways through cAMP as the second messenger. 5) To determine the site of action of ADM within the airways. The proposed research is significant in that by establishing how ADM regulates bronchodilation it may lead to new therapies in pulmonary diseases characterized by airway obstruction.