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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：
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
项目类别：
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

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 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危险的交感神经兴奋性反射