TRPV4 inhibition counteracts edema and inflammation and improves pulmonary function and oxygen saturation in chemically induced acute lung injury.
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.
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut;
Shrilatha
S
Balakrishna
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama;
Weifeng
W
Song
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut;
Satyanarayana
S
Achanta
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama;
Stephen F
SF
Doran
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut;
Boyi
B
Liu
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut.
Melanie M
MM
Kaelberer
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama;
Zhihong
Z
Yu
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut;
Aiwei
A
Sui
Heart Failure Discovery Performance Unit-Metabolic Pathways and Cardiovascular Therapy Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania;
Mui
M
Cheung
Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana; and.
Emma
E
Leishman
Heart Failure Discovery Performance Unit-Metabolic Pathways and Cardiovascular Therapy Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania;
Hilary S
HS
Eidam
Heart Failure Discovery Performance Unit-Metabolic Pathways and Cardiovascular Therapy Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania;
Guosen
G
Ye
Heart Failure Discovery Performance Unit-Metabolic Pathways and Cardiovascular Therapy Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania;
Robert N
RN
Willette
Heart Failure Discovery Performance Unit-Metabolic Pathways and Cardiovascular Therapy Unit, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania;
Kevin S
KS
Thorneloe
Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana; and.
Heather B
HB
Bradshaw
Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama;
Sadis
S
Matalon
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut; sven.jordt@yale.edu.
Sven-Eric
SE
Jordt
D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002713:Chlorine / Q000633:toxicity; D057809:HEK293 Cells; D006801:Humans; D006851:Hydrochloric Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D011014:Pneumonia / Q000188:drug therapy; D051381:Rats; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000172:deficiency
D000893:Anti-Inflammatory Agents; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D002713:Chlorine; D006851:Hydrochloric Acid
TRPV4; acute lung injury; chlorine