ALPHA ADRENERGIC REGULATION OF AIRWAY BLOOD FLOW

描述（改编自申请人摘要）：考虑哮喘 是一种炎症性气道疾病 因此， 有可能参与其某些表现形式，包括运动 诱导支气管收缩，气道壁水肿和清除局部 释放了痉挛素 然而，与气道平滑肌相比， 反应性，关于炎症对气道血管的影响的信息 缺乏平滑肌反应性。 气道脉管系统是 体循环和去甲肾上腺素（NE）是主要的 神经递质，用于气道血流的局部肾上腺素能调节。 在最近的研究中，主要研究者表明， 哮喘患者在气道中具有对哮喘的过度的血管收缩反应， 吸入肾上腺素能激动剂和重复抗原激发增强 NE引起致敏大鼠支气管小动脉环收缩 家兔 这些观察结果表明，炎症导致 气道血管系统的α-肾上腺素能高反应性，可能是因为 一种对抗炎症性血管舒张的适应性机制。 本 该提案是基于这样的假设，即炎症的增加， α-肾上腺素能血管反应性是由于 血管平滑肌中的α-肾上腺素能信号传导或降低 内皮松弛因子的α-肾上腺素能生成，或两者。 这 将通过1）评估短期和长期的影响进行测试 炎症刺激对α 1和α 2受体表达的影响， 兔支气管动脉平滑肌肾上腺素能信号转导 2）将这些发现与NE诱导的支气管炎相关， 动脉收缩及其内皮调节，3）比较 支气管哮喘患者与正常人气道血流α-肾上腺素能反应性的比较 正常人，以及4）确定糖皮质激素对增强的 α-肾上腺素能反应 这些实验有望产生 支气管哮喘气道循环调节的新信息 并可能发现新的治疗方法。

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.