Remodeled airway irritant reflexes as a cause of serious cardiovascular events

空气污染物/刺激物在心血管疾病患者中引起危险的交感兴奋反射 (CVD)，但在健康受试者中引起交感神经抑制反射。然而，在理解上存在着重大差距。 刺激诱发的肺心反射在心血管疾病中是如何重塑的。这一点很重要，因为它是反射 重塑决定了污染的影响，从而是急性污染物诱发的根本原因 心血管(CV)事件，每年导致美国10万人死亡。因此，没有临床上的 治疗或识别高危个体的选项。刺激性吸入通过以下途径触发肺心反射-- 表达瞬时受体电位(Trp)的迷走神经传入神经--锚蛋白1和香草素1。 TRP通常表达在C-纤维上，但不表达在A-纤维上，这可以触发副交感和交感反射， 分别进行了分析。长期目标是完全了解负责的机制和网络 脑血管病患者的异常肺心反射。这里的目标是确定特定的传入和 两种CVD大鼠模型气道色氨酸激活诱发的传出信号及其机制探讨 脑血管疾病相关的反射重塑。基于强大的初步数据的核心假设是，这种反常 心血管疾病患者的刺激诱发的肺心反射是由于交感神经的从头反射募集所致。 神经营养素依赖于Trp表达的呼吸道传入网络重构的下游不同神经。 这一假说是创新的，因为这是第一次病理生理学的基础-重塑 肺-心脏反射-已经成为目标。目标1：确定负责的自主神经传出通路 用于CVD中重塑的呼吸道刺激性反射。我们假设CVD开关由刺激性刺激引起 副交感神经介导的心动过缓对De所致快速性心律失常的肺心反射 心脏交感神经传出神经的新募集。目标2：确定所需的呼吸道传入信号 用于CVD中重塑的刺激诱发的肺心反射。我们假设刺激性刺激诱发的综合征- 心血管疾病的病理性兴奋是由于呼吸道迷走神经A纤维传入中TRPs的从头表达所致。目标3：确定 心血管疾病中肺-心反射重塑的机制。我们假设重塑- 心血管疾病患者的肺心反射依赖于迷走神经传入神经营养素TrkB受体的激活 肾素-血管紧张素系统(RAS)慢性激活的下游。所有目标均由初选支持 数据。这项研究具有重要意义，因为它将为药理学(例如RAS抑制，TrkB)提供理论基础 抑制、鼻腔薄荷脑)和电疗以减少重塑的影响或逆转重塑- 埃林在临床研究中。我们的创新方法将针对一个独特的伤害感受子集和机制- 使用最先进的电生理技术的无美容条件。因此，这些研究将有一个 对我们对心血管疾病刺激诱发反射的理解产生了革命性的影响，并有望导致 我们在减少污染物/刺激物对易感人群的影响方面的方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.