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呈上升趋势，在过去20年中，美国的发病率增加了250%。2001年，美国国立卫生研究院估计，有1700万美国人患有哮喘，1210万人患有慢性阻塞性肺病。越来越多的患有这些疾病的患者需要麻醉和支气管痉挛，特别是在麻醉诱导和苏醒期间，发病率很高。更好地了解在麻醉过程中将支气管痉挛降至最低的治疗方法，将使越来越多的哮喘和COPD患者的麻醉护理更加安全。诱导期间气管插管或麻醉苏醒期间气管插管会在呼吸道中引发神经介导的刺激性反射，促进支气管收缩。气道张力的神经控制由迷走神经内的胆碱能神经和伤害性感受性C纤维共同调节，C纤维向CMS发送传入信号，调节胆碱能流出，并局部将速激肽释放到气道壁。在大脑中，速激肽释放v-氨基丁酸(GABA)，这是主要的神经抑制性神经递质。这种反射的胆碱能成分已经在动物模型和人类中得到了广泛的研究，但关于C纤维、释放的速激肽或GABA在反射诱导的支气管收缩中的作用还知之甚少。已知异丙酚能变构增强大脑GABAA受体上的GABA活性，并被认为是有支气管痉挛风险的患者的首选静脉麻醉剂，但其保护呼吸道的机制尚不清楚。阐明异丙酚的气道保护作用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激动剂松弛气道平滑肌，[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，我们推测，气道刺激释放速激肽，速激肽激活气道神经上的NK2受体，释放GABA，从而允许异丙酚对气道平滑肌GABAA受体的变构增强，以促进松弛。

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.