Mechanisms of anesthetic effects on tachykinin induced airway tone

描述（由申请人提供）：哮喘的发病率在全球范围内增加，在过去的20年里，美国增加了250%。2001年，美国国立卫生研究院估计有1700万美国人患有哮喘，1210万美国人患有慢性阻塞性肺病。越来越多的这些疾病患者需要麻醉，特别是在诱导和麻醉后出现的支气管痉挛具有显著的发病率。更好地了解麻醉期间支气管痉挛最小化的治疗方法将使越来越多的哮喘和慢性阻塞性肺病患者的麻醉护理更加安全。在诱导过程中气管插管或在麻醉苏醒过程中气管内管的存在会在气道中引发神经介导的刺激反射，促进支气管收缩。神经系统对气道张力的控制由迷走神经内的胆碱能神经和伤害感觉C纤维共同调节，后者向CMS发送传入信号，调节胆碱能流出并局部释放速激素进入气道壁。在大脑中，速激素释放v-氨基丁酸（GABA），这是主要的神经元抑制性神经递质。这种反射的胆碱能成分已经在动物模型和人类中进行了广泛的探索，但关于C纤维，释放的速激肽或GABA对反射诱导的支气管收缩的贡献知之甚少。异丙酚已知能变异性地增强大脑中GABA受体的活性，被认为是支气管痉挛高危患者首选的静脉麻醉诱导剂，但其气道保护机制尚不清楚。阐明异丙酚保护气道作用的机制可能为多种原因引起的支气管收缩提供新的治疗方法。令人兴奋的初步数据表明，[1]GABA局部存在于气道平滑肌附近，[2]气道平滑肌表达GABAA受体，[3]GABAA激动剂放松气道平滑肌，[4]异丙酚选择性地通过GABAA受体减弱nk2介导的气道收缩。基于这些初步数据，我们假设气道刺激释放速激素，其激活气道神经上的NK2受体释放GABA，从而允许异丙酚在气道平滑肌GABAA受体上进行变构增强，以促进放松。

DESCRIPTION (provided by applicant): The incidence of asthma is increasing worldwide with a 250% increase in the US over the past 20 years. In 2001 the NIH estimated that 17 million Americans suffer from asthma and 12.1 million from COPD. An increasing number of patients with these diseases require anesthesia and bronchospasm especially during induction and emergence from anesthesia carries significant morbidity. A better understanding of therapies that minimize bronchospasm during anesthesia will make anesthetic care safer for a growing number of patients with asthma and COPD. Intubation of the trachea during induction or the presence of an endotracheal tube during emergence from anesthesia initiates a neurally-mediated irritant reflex in the airway promoting bronchoconstriction. Neural control of airway tone is modulated by both cholinergic nerves traveling within the vagus nerve and by nocioceptive C fibers that send afferent signals to the CMS that modulate cholinergic outflow and locally release tachykinins into the airway wall. In brain, tachykinins release v-amino butyric acid (GABA), the primary neuronal inhibitory neurotransmitter. The cholinergic component of this reflex has been extensively explored in animal models and humans but little is known regarding the contribution of C fibers, released tachykinins or GABA to reflex-induced bronchoconstriction. Propofol is known to allosterically enhance the activity of GABA at GABAA receptors in the brain and is recognized as the intravenous anesthetic induction agent of choice in patients at risk for bronchospasm but its mechanism of airway protection is poorly understood. Elucidating the mechanisms of propofol's protective airway effects may provide novel therapies for bronchoconstriction from many causes. Exciting preliminary data demonstrate that [1] GABA is locally present near airway smooth muscle, [2] airway smooth muscle expresses GABAA receptors, [3] GABAA agonists relax airway smooth muscle and [4] propofol selectively attenuates NK2-mediated airway constriction via GABAA receptors. Based on these preliminary data we hypothesize that airway irritation releases tachykinins which activate NK2 receptors on airway nerves to release GABA which allows for the allosteric potentiation at airway smooth muscle GABAA receptors by propofol to facilitate relaxation.