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Am J Physiol Lung Cell Mol Physiol. 2014 Jul 15;307(2):L158-72. doi: 10.1152/ajplung.00065.2014. Epub 2014 May 16.

TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut;
2
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama;
3
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut.
4
Heart Failure Discovery Performance Unit-Metabolic Pathways and Cardiovascular Therapy Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania;
5
Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana; and.
6
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut; sven.jordt@yale.edu.

Abstract

The treatment of acute lung injury caused by exposure to reactive chemicals remains challenging because of the lack of mechanism-based therapeutic approaches. Recent studies have shown that transient receptor potential vanilloid 4 (TRPV4), an ion channel expressed in pulmonary tissues, is a crucial mediator of pressure-induced damage associated with ventilator-induced lung injury, heart failure, and infarction. Here, we examined the effects of two novel TRPV4 inhibitors in mice exposed to hydrochloric acid, mimicking acid exposure and acid aspiration injury, and to chlorine gas, a severe chemical threat with frequent exposures in domestic and occupational environments and in transportation accidents. Postexposure treatment with a TRPV4 inhibitor suppressed acid-induced pulmonary inflammation by diminishing neutrophils, macrophages, and associated chemokines and cytokines, while improving tissue pathology. These effects were recapitulated in TRPV4-deficient mice. TRPV4 inhibitors had similar anti-inflammatory effects in chlorine-exposed mice and inhibited vascular leakage, airway hyperreactivity, and increase in elastance, while improving blood oxygen saturation. In both models of lung injury we detected increased concentrations of N-acylamides, a class of endogenous TRP channel agonists. Taken together, we demonstrate that TRPV4 inhibitors are potent and efficacious countermeasures against severe chemical exposures, acting against exaggerated inflammatory responses, and protecting tissue barriers and cardiovascular function.

KEYWORDS:

TRPV4; acute lung injury; chlorine

PMID:
24838754
PMCID:
PMC4152165
DOI:
10.1152/ajplung.00065.2014
[Indexed for MEDLINE]
Free PMC Article

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