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ALPHA ADRENERGIC REGULATION OF AIRWAY BLOOD FLOW

气道血流的 ALPHA 肾上腺素调节

基本信息

批准号：
6183929
负责人：
Adam Wanner
金额：
$ 21.87万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-01 至 2002-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from the applicant's abstract): Asthma is considered to be an inflammatory airway disease. The airway circulation is therefore likely to participate in some of its manifestations including exercise induced bronchoconstriction, airway wall edema and the clearance of locally released spasmogens. However, in contrast to airway smooth muscle responsiveness, information on the effect of inflammation on airway vascular smooth muscle responsiveness is lacking. The airway vasculature is part of the systemic circulation and norepinephrine (NE) is the principal neurotransmitter for the local adrenergic regulation of airway blood flow. In recent studies, the principal investigator has shown that asymptomatic asthmatics have an exaggerated vasoconstrictor response in the airway to an inhaled adrenergic agonist and that repeated antigen challenge potentiates NE-induced contraction of small bronchial arterial rings in sensitized rabbits. These observations indicated that inflammation causes alpha-adrenergic hyperresponsiveness of the airway vasculature, possibly as an adaptive mechanism to counteract inflammatory vasodilation. The present proposal is based on the hypothesis that the inflammatory increase in alpha-adrenergic vascular responsiveness is due to upregulated alpha-adrenergic signaling in vascular smooth muscle or decreased alpha-adrenergic generation of endothelial relaxing factors, or both. This will be tested by 1) assessing the effects of short-term and long-term inflammatory stimulation on alpha1 and alpha2-receptor expression and adrenergic signal transduction in rabbit bronchial arterial smooth muscle and in endothelium, 2) correlating these findings with NE-induced bronchial arterial contraction and its endothelial modulation, 3) comparing alpha-adrenergic responsiveness of airway blood flow between asthmatics and normals, and 4) determining the effect of glucocorticosteroids on enhanced alpha-adrenergic responsiveness. These experiments are expected to yield new information on the regulation of the airway circulation in bronchial asthma and possibly identify novel therapeutic approaches.

描述(改编自申请者的摘要)：哮喘被考虑是一种炎症性呼吸道疾病。因此，呼吸道循环可能参与其中的一些表现，包括锻炼诱发的支气管收缩、气道壁水肿和局部的清除释放出痉挛物质。然而，与呼吸道平滑肌相反，反应性，关于炎症对呼吸道血管影响的信息平滑肌反应性缺乏。呼吸道血管系统是体循环和去甲肾上腺素(NE)是主要的局部肾上腺素能调节呼吸道血流的神经递质。在最近的研究中，首席研究人员表明，没有症状的哮喘患者呼吸道血管收缩反应被夸大吸入肾上腺素能激动剂和反复抗原挑战会增强 NE对致敏小鼠支气管动脉环的收缩作用兔子。这些观察表明，炎症导致呼吸道血管系统的α-肾上腺素能高反应性，可能是一种抗炎性血管扩张的适应性机制。现在这一提议是基于这样一种假设，即 α-肾上腺素能血管反应性是由于上调 α-肾上腺素能信号在血管平滑肌或减弱 α-肾上腺素能产生内皮松弛因子，或两者兼而有之。这将通过1)评估短期和长期影响进行测试炎症刺激对α1和α2受体表达的影响兔支气管动脉平滑肌的肾上腺素能信号转导在内皮方面，2)这些发现与去甲肾上腺素诱导的支气管动脉收缩及其内皮调节，3)比较哮喘患者和哮喘患者呼吸道血流的α-肾上腺素能反应性正常，以及4)测定糖皮质激素对增强的影响 α-肾上腺素能反应。这些实验预计将产生支气管呼吸道循环调节的新进展哮喘，并可能找到新的治疗方法。