title: TRPV4: an exciting new target to promote alveolocapillary barrier function.
abstract: Transient receptor potential (TRP) channels are emerging as important players and drug targets in respiratory disease. Amongst the vanilloid-type TRP channels (which includes the six members of the TRPV family), target diseases include cough, asthma, cancer, and more recently, pulmonary edema associated with acute respiratory distress syndrome. Here, we critically evaluate a recent report that addresses TRPV4 as a candidate target for the management of acute lung injury that develops as a consequence of aspiration of gastric contents, or acute chlorine gas exposure. By use of two new TRPV4 inhibitors (GSK2220691 or GSK2337429A) and a trpv4(-/-) mouse strain, TRPV4 was implicated as a key mediator of pulmonary inflammation after direct chemical insult. Additionally, applied therapeutically, TRPV4 inhibitors exhibited vasculoprotective effects after chlorine gas exposure, inhibiting vascular leakage, and improving blood oxygenation. These observations underscore TRPV4 channels as candidate therapeutic targets in the management of lung injury, with the added need to balance these against the potential drawbacks of TRPV4 inhibition, such as the danger of limiting the immune response in settings of pathogen-provoked injury.
authors.affiliation: Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany; Department of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Giessen, Germany; rory.morty@mpi-bn.mpg.de.
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
authors.affiliation: Institute of Physiology, Charité Universitätsmedizin Berlin, Germany; Departments of Surgery and Physiology, University of Toronto, Toronto, Ontario, Canada; and The Keenan Research Center for Biomedical Science of St. Michael's, Toronto, Ontario, Canada.
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Kuebler
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D015824:Blood-Air Barrier / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D002713:Chlorine / Q000633:toxicity; D063388:Endocannabinoids / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000637:transplantation; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011015:Pneumonia, Aspiration / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011651:Pulmonary Artery / Q000378:metabolism; D063466:Respiratory Aspiration of Gastric Contents / Q000150:complications; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D001095:Arachidonic Acids; D002186:Cannabinoids; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D002713:Chlorine; D002118:Calcium; C078814:anandamide
keywords: ARDS; TRPV4; chlorine; edema; inflammation