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（根据申请人的摘要改编）：哮喘被考虑成为炎症性气道疾病。因此，气道循环是可能参与其中的某些表现形式，包括锻炼诱导的支气管收缩，气道壁水肿和局部清除释放痉挛。但是，与气道平滑肌相反响应能力，有关炎症对气道血管影响的信息缺乏平滑肌反应能力。气道脉管系统是全身循环和去甲肾上腺素（NE）是主要的用于气道血流的局部肾上腺素能调节的神经递质。在最近的研究中，主要研究者表明无症状哮喘患者在呼吸道中有夸张的血管收缩反应吸入肾上腺素能激动剂，并重复抗原挑战增强剂敏化的小支气管动脉环的NE诱导的收缩兔子。这些观察结果表明炎症是原因气道脉管系统的α-肾上腺素能过度反应性应对炎症血管舒张的一种自适应机制。现在提案基于以下假设 α-肾上腺素能血管反应是由于上调的血管平滑肌中的α-肾上腺素能信号传导或减少 α-肾上腺素能的内皮放松因子或两者兼而有之。这将通过1）评估短期和长期的影响对α1和α2受体表达的炎症刺激以及兔支气管动脉平滑肌的肾上腺素能信号转导在内皮中，2）将这些发现与NE诱导的支气管相关联动脉收缩及其内皮调节，3）比较哮喘患者与气道血流的α-肾上腺素能反应正态和4）确定糖皮质激素对增强的影响 α-肾上腺素能反应。这些实验有望产生关于支气管中气道循环调节的新信息哮喘，并可能识别出新颖的治疗方法。