# Role of TRPV4 channel signaling in lung ischemia-reperfusion injury

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2024 · $689,589

## Abstract

Project Summary
The success of lung transplantation is limited by high rates of primary graft dysfunction due to
ischemia-reperfusion injury (IRI) characterized by robust inflammation, vascular permeability,
and alveolar damage. IRI is also a risk factor for late graft rejection (bronchiolitis obliterans), the
major cause of mortality beyond one year of transplant. TRPV4 is a transmembrane calcium
channel expressed in numerous cell types including vascular endothelial cells (ECs), alveolar
epithelial cells, macrophages, and neutrophils. TRPV4 activation can induce lung
endothelial/epithelial barrier dysfunction, a critical feature of IRI, and our data suggests that
TRPV4 activity in endothelial cells (ECs) is a significant mediator of lung IRI and that inhibition
of TRPV4 activity is significantly protective. We also show that TRPV4 activity may be affected
by ATP released by pannexin (Panx1) channels on ECs. Thus, our proposal will test the overall
hypothesis that endothelial TRPV4 channel signaling is a critical mediator of lung IRI by
inducing endothelial barrier disruption, vascular permeability and leukocyte infiltration. Aim 1 will
determine if TRPV4 activity on ECs mediates lung IRI leading to endothelial/epithelial barrier
dysfunction, vascular inflammation, and leukocyte infiltration. A potential role for TRPV4 in
alveolar epithelial cells, macrophages, and neutrophils will also be evaluated during lung IRI.
Aim 2 will define mechanisms for a Panx1/TRPV4 axis in ECs that mediates lung IRI by testing
the hypothesis that TRPV4 is activated by ATP released by Panx1 channels after IR. We will
also determine if TRPV4 activity is induced by NADPH oxidase-derived reactive oxygen species
after IR. Aim 3 will utilize a murine orthotopic lung transplant model to decipher the role of
TRPV4 in donor versus recipient cells as well as in ECs after transplantation. In addition, a
clinically relevant, large animal porcine lung transplant model will be used to determine if
pharmacologic inhibition of Panx1 will prevent lung IRI after transplantation. There currently are
no preventative therapies for IRI, and our studies will provide novel insight into mechanisms of
lung IRI and will define TRPV4 channels as a novel therapeutic target for the prevention of IRI
after lung transplantation.

## Key facts

- **NIH application ID:** 10819199
- **Project number:** 5R01HL157407-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Victor E Laubach
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $689,589
- **Award type:** 5
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819199

## Citation

> US National Institutes of Health, RePORTER application 10819199, Role of TRPV4 channel signaling in lung ischemia-reperfusion injury (5R01HL157407-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10819199. Licensed CC0.

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