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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

基本信息

批准号：
9779107
负责人：
Thomas Edward Taylor-Clark
金额：
$ 37.38万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-25 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9779107
关键词：
ANK1 gene Acute Air Pollutants Anesthetics Animals Antihypertensive Agents Atenolol Atropine Biochemical Biological Neural Networks Bradycardia C Fiber Cardiac Cardiovascular Diseases Cardiovascular Models Cardiovascular system Cessation of life Chronic Clinical Dangerousness Data Development Efferent Pathways Electrophysiology (science)Event Fiber Functional disorder Goals Health Health Care Costs Hypertension Individual Inhalation Irritants Lead Link Lung Mediating Mission Modeling Molecular Morbidity - disease rate Myocardial Ischemia National Heart, Lung, and Blood Institute Nerve Neurobiology Neurons Outcome Ozone Particulate Matter Patients Pharmacology Pollution Population Prevention therapy Public Health Pulmonary Heart Disease Rattus Reflex action Renin-Angiotensin System Research Risk Risk Factors Sensory Signal Transduction Stimulus TRPV1 gene Tachyarrhythmias Tachycardia Techniques Testing Time Vanilloid Ventricular Premature Complexes afferent nerve airway remodeling base biomarker development biomarker identification effective therapy improved innovation neurophysiology novel pollutant receptor recruit respiratory treatment choice

项目摘要

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.

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