Remodeled airway irritant reflexes as a cause of serious cardiovascular events

空气污染物/刺激物引起心血管疾病患者危险的交感神经兴奋性反射 (CVD)但在健康受试者中引起交感神经抑制反射。然而，在认识上存在重大差距 刺激物诱发的肺心反射在CVD中如何重塑。这很重要，因为这是反射， 重塑决定了污染的影响，从而急性污染诱发的根本原因 心血管（CV）事件，每年导致> 10万例美国死亡。因此，没有临床 治疗或识别高危个体的选择。刺激性吸入通过激活呼吸道刺激触发肺心反射。 表达瞬时受体电位（TRP）锚蛋白1和香草素1的迷走气道传入神经的支配。 TRP通常在C纤维上表达，但在A纤维上不表达，这可以触发副交感神经和交感神经反射， 分别长期目标是全面了解负责 心血管疾病中的异常肺心反射。这里的目的是确定特定的传入和 在两种CVD大鼠模型中由气道TRP激活诱发的传出信号并确定机制原因 与心血管疾病相关的反射重塑基于强有力的初步数据的中心假设是， CVD中刺激物诱发的肺心反射是由于交感神经效应的从头反射募集， TRP表达的气道传入网络的神经营养因子依赖性重塑下游的传入神经。 这一假设是创新的，因为这是第一次，病理生理学的基础-重塑 肺心反射-已经成为目标。目的1：确定负责的自主传出通路 用于CVD中重塑的气道刺激诱发反射。我们假设心血管疾病改变了刺激诱发的 从副交感神经介导的心动过缓到由DE引起的快速性心律失常的肺心反射 心脏交感传出神经的新生募集。目的2：确定所需的气道传入信号 用于CVD中重塑的刺激物诱发的肺心反射。我们假设刺激诱发的对称性 CVD中的病理性兴奋是由于气道迷走神经A纤维传入中TRP的重新表达。目标3：确定 心血管疾病中肺心反射重建的机制。我们假设改造- CVD患者肺心反射的形成依赖于迷走神经传入神经营养因子TrkB受体的激活 在慢性激活的肾素-血管紧张素系统（RAS）的下游。所有目标都得到初步支持， 数据这项研究是重要的，因为它将提供药理学原理（例如RAS抑制，TrkB 抑制，鼻薄荷醇）和电疗法，以减少重塑的影响或逆转重塑， 在临床研究中。我们的创新方法将针对独特的伤害性子集和机制， 使用最先进的电生理技术的无美感条件。因此，这些研究将有一个 这对我们理解CVD中刺激诱发的反射产生了变革性的影响，并有望导致 我们在减少污染物/刺激物对易受影响人群的影响方面的做法发生了实质性转变。

Air pollutants/irritants evoke dangerous sympathoexcitatory reflexes in individuals with cardiovascular disease (CVD) but evoke sympathoinhibitory reflexes in healthy subjects. However, there is a major gap in understanding how irritant-evoked pulmonary-cardiac reflexes are remodeled in CVD. This is significant because it is the reflex remodeling that determines the impact of pollution and thus the fundamental cause of acute pollutant-evoked cardiovascular (CV) events, which are responsible for >100k US deaths annually. Thus, there are no clinical options to treat or identify at-risk individuals. Irritant inhalation triggers pulmonary-cardiac reflexes via the acti- vation of vagal airway afferent nerves that express transient receptor potential (TRP) ankyrin 1 and vanilloid 1. TRPs are typically expressed on C- but not A-fibers, which can trigger parasympathetic and sympathetic reflexes, respectively. The long-term goal is a complete understanding of the mechanisms and networks responsible for the aberrant pulmonary-cardiac reflexes in CVD. The objective here is to determine the specific afferent and efferent signaling evoked by airway TRP activation in two CVD rat models and determine the mechanistic cause of the CVD-linked reflex remodeling. The central hypothesis, based upon strong preliminary data, is that aberrant irritant-evoked pulmonary-cardiac reflexes in CVD are due to the de novo reflex recruitment of sympathetic ef- ferent nerves downstream of neurotrophin-dependent remodeling of TRP-expressing airway afferent networks. The hypothesis is innovative because this is the first time that the basis of the pathophysiology – the remodeling of pulmonary-cardiac reflexes – has been targeted. Aim 1: Identify the autonomic efferent pathways responsible for the remodeled airway irritant-evoked reflexes in CVD. We hypothesize that CVD switches irritant-evoked pulmonary-cardiac reflexes from parasympathetic-mediated bradycardia towards tachyarrhythmia due to de novo recruitment of cardiac sympathetic efferent nerves. Aim 2: Determine the airway afferent signaling required for the remodeled irritant-evoked pulmonary-cardiac reflexes in CVD. We hypothesize that irritant-evoked sym- pathoexcitation in CVD is due to de novo expression of TRPs in airway vagal A-fiber afferents. Aim 3: Determine the mechanism underlying the remodeling of pulmonary-cardiac reflexes in CVD. We hypothesize that remodel- ing of pulmonary-cardiac reflexes in CVD is dependent on vagal afferent neurotrophin TrkB receptor activation downstream of chronic activation of the renin-angiotensin system (RAS). All aims are supported by preliminary data. This study is significant because it will provide the rationale for pharmacological (e.g. RAS inhibition, TrkB inhibition, nasal menthol) and electroceutical therapies to reduce the impact of remodeling or reverse the remod- eling in clinical studies. Our innovative approach will target unique nociceptive subsets and mechanisms in an- esthetic-free conditions using state-of-the-art electrophysiological techniques. Thus, these studies will have a transformative impact upon our understanding of irritant-evoked reflexes in CVD, and are expected to lead to a substantive shift in our approach to reduce the impact of pollutants/irritants on susceptible populations.