# Remodeled airway irritant reflexes as a cause of serious cardiovascular events

> **NIH NIH R01** · UNIVERSITY OF SOUTH FLORIDA · 2021 · $541,038

## Abstract

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-
e...

## Key facts

- **NIH application ID:** 10121946
- **Project number:** 1R01HL152219-01A1
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Thomas Edward Taylor-Clark
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $541,038
- **Award type:** 1
- **Project period:** 2021-01-26 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121946

## Citation

> US National Institutes of Health, RePORTER application 10121946, Remodeled airway irritant reflexes as a cause of serious cardiovascular events (1R01HL152219-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10121946. Licensed CC0.

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