Remodeled airway irritant reflexes as a cause of serious cardiovascular events

重塑气道刺激反射是严重心血管事件的原因

• 批准号: 10334509
• 负责人: Thomas Edward Taylor-Clark
• 金额: $ 52.87万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-26 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10334509
• 关键词: ANK1 gene; Acute; Air Pollutants; Animals; Atenolol; Atropine; Bradycardia; C Fiber; Cardiac; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular system; Cessation of life; Chronic; Clinical; Clinical Research; Dangerousness; Data; Development; Efferent Neurons; Efferent Pathways; Electrophysiology (science); Esthetics; Event; Fiber; Functional disorder; Goals; Health; Health Care Costs; Heart failure; Hypertension; Individual; Inhalation; Irritants; Lead; Link; Lung; Mediating; Menthol; Mission; Modeling; Molecular; Morbidity - disease rate; Myocardial Infarction; National Heart, Lung, and Blood Institute; Nerve; Nerve Growth Factor Receptors; Neurobiology; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Nociception; Nose; Outcome; Ozone; Particulate Matter; Patients; Pharmacology; Pollution; Population; Prevention therapy; Public Health; Pulmonary Heart Disease; Rattus; Receptor Activation; Reflex action; Renin-Angiotensin System; Research; Risk; Risk Factors; Sensory; Signal Transduction; Stimulus; TRP channel; TRPA channel; Tachyarrhythmias; Tachycardia; Techniques; Testing; Time; Vanilloid; Ventricular Premature Complexes; afferent nerve; airway remodeling; base; biomarker identification; effective therapy; experience; hypertensive; improved; innovation; neural network; neurophysiology; neurotrophic factor; novel; pollutant; receptor; recruit; respiratory; treatment choice

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.

空气污染物/刺激物引起心血管疾病患者的危险交感神经反射 （CVD），但在健康受试者中引起交感抑制作用。但是，理解有一个重大差距 CVD中如何重塑了刺激性诱发的肺心反射。这很重要，因为它是反射 重塑决定污染的影响，从而决定急性污染物诱发的基本原因 心血管（CV）事件，每年造成> 100k美国死亡。那没有临床 治疗或识别高危个人的选择。刺激性吸入触发肺心反射的作用 传递瞬态受体电位（TRP）Ankyrin 1和Vanilloid 1的迷走神经传入神经的外观。 TRP通常在C-而不是A纤维上表达，这会触发副交感神经和交感反射， 长期目标是对负责机制和网络的完全理解 CVD中异常的肺心反射。这里的目的是确定特定传入和 气道TRP激活在两个CVD大鼠模型中引起的传出信号传导，并确定机械原因 CVD连接的反射重塑。基于强大初步数据的中心假设是异常 CVD中刺激性诱发的肺心反射是由于从头反射募集的交感神经EF- 表达TRP气道传入网络的神经营养素依赖性重塑的下游神经。 该假设具有创新性，因为这是病理生理学的第一次 - 重塑 肺心反射 - 已针对。目标1：确定负责的自主有效途径 对于CVD中的重塑气道刺激性诱发反射。我们假设CVD开关刺激性诱发 来自副交感神经介导的心动过缓朝向心律失常的肺心脏反射 Novo招募心脏交感神经有效神经。目标2：确定所需的气道传入信号 对于CVD中的重塑刺激性诱发的肺心反射。我们假设刺激性诱发的符号 CVD中的病理激发是由于气道迷走神经A纤维传入中TRP的从头表达所致。目标3：确定 CVD中肺心反射重塑的基础机制。我们假设重塑 - CVD中肺心反射的ING取决于迷走神经营养蛋白TRKB受体激活 肾素 - 血管紧张素系统（RAS）的慢性激活下游。所有目标均由初步支持 数据。这项研究很重要，因为它将为药物提供基本原理（例如RAS抑制，TRKB 抑制作用，鼻中半醇）和电疗法，以减少重塑或逆转重塑的影响 - 在临床研究中进行研究。我们的创新方法将以独特的伤害性子集和机制为目标 使用最先进的电生理技术的无美学条件。那就是这些研究将有一个 对我们对CVD中刺激性诱发反射的理解的变革性影响，并有望导致 我们减少污染物/刺激物对易感人群的影响的方法的实质性转变。