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，在理解上存在一个重大差距- 了解刺激诱发的肺心反射在心血管疾病中是如何重塑的。这一点意义重大，因为它是 反射重塑决定了污染的影响，从而决定了急性污染物的根本原因- 诱发的心血管(CV)事件，每年导致美国10万人死亡。因此，没有 识别或治疗高危个体的临床选择。刺激物通过激活剂触发肺心反射- 表达瞬时受体电位(TRP)的呼吸道传入神经--锚蛋白1和香草素1 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的传出信号及其机制探讨 CVD相关反射重塑的原因。基于强劲的初步数据，核心假设是 脑血管病患者异常的刺激诱发反射是由于交感神经在脑血管病的下游重新募集。 表达Trp的呼吸道传入网络的慢性重构。这一假设是创新的，因为这是 病理生理学的基础，即肺-心反射的重塑，第一次被 有针对性的。目的1：确定重塑的气道刺激物诱发的自主神经传出通路 脑血管病的反射。据推测，CVD将刺激性诱发的肺心反射从 交感神经起搏引起的快速性心律失常的交感神经介导的心动过缓 太紧张了。目的2：确定重塑刺激性肺损伤所需的呼吸道传入信号。 心血管疾病患者的心脏反射。CVD中刺激诱发的交感神经兴奋可能是由新生引起的。 呼吸道A类纤维传入中TRPs的表达。目标3：确定心脏重塑的机制 脑血管病患者的肺心反射。推测反射性重构是由肾素-血管紧张素系统引起的。 (RAS)激活等对RAS抑制敏感，但对其他降压药不敏感。这项研究是签名的- 具有重要意义，因为它是精制药理和电疗法的绝对要求。 PIES用于治疗污染诱导的心血管事件；识别对CVD诱导的反射至关重要的新靶点 重塑；以及为肺心反射改变的高危个体开发生物标记物。 这种方法是创新的，因为研究机制将在没有麻醉剂的情况下进行，麻醉剂会改变肺- 心脏反射，使用最先进的电生理技术。因此，这些研究将具有跨- 对我们对刺激诱发的反射的理解的形成影响，并有望导致一种范式 改变我们的方法，以减少异常的呼吸道反射对临床人群的影响。

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 understand- ing 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 identify or treat at-risk individuals. Irritants trigger pulmonary-cardiac reflexes via the activa- tion of 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 reflexes in CVD are due to de novo recruitment of sympathetic nerves downstream of chronic 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. It is hypothesized that CVD switches irritant-evoked pulmonary-cardiac reflexes from para- sympathetic-mediated bradycardia towards tachyarrhythmia due to de novo recruitment of cardiac sympathetic nerves. Aim 2: Determine the airway afferent signaling required for the remodeled irritant-evoked pulmonary- cardiac reflexes in CVD. It is hypothesized that irritant-evoked sympathoexcitation in CVD is due to de novo expression of TRPs in airway A-fiber afferents. Aim 3: Determine the mechanism underlying the remodeling of pulmonary-cardiac reflexes in CVD. It is hypothesized that reflex remodeling is due to renin-angiotensin system (RAS) activation and so will be sensitive to RAS inhibition but not to other antihypertensives. This study is sig- nificant because it is an absolute requirement for the refinement of pharmacological and electroceutical thera- pies to treat pollution-induced CV events; the identification of novel targets critical to the CVD-induced reflex remodeling; and the development of biomarkers for at-risk individuals with altered pulmonary-cardiac reflexes. The approach is innovative because mechanisms will be studied free of anesthetics, which alter pulmonary- cardiac reflexes, using state-of-the-art electrophysiological techniques. Thus, these studies will have a trans- formative impact upon our understanding of irritant-evoked reflexes, and are expected to lead to a paradigm shift in our approach to reduce the impact of aberrant airway reflexes on the clinical population.