title: High vascular pressure-induced lung injury requires P450 epoxygenase-dependent activation of TRPV4.
abstract: High vascular pressure targets the lung septal network, causing acute lung injury. While calcium entry in septal endothelium has been implicated, the channel involved is not known. This study tested the hypothesis that the vanilloid transient receptor potential channel, TRPV4, is a critical participant in the permeability response to high vascular pressure. Isolated lungs from TRPV4(+/+) or TRPV4(-/-) mice were studied at baseline or during high pressure challenge. Permeability was assessed via the filtration coefficient. Endothelial calcium transients were assessed using epifluorescence microscopy of the lung subpleural network. Light microscopy and point counting were used to determine the alveolar fluid volume fraction, a measure of alveolar flooding. Baseline permeability, calcium intensity, and alveolar flooding were no different in TRPV4(+/+) versus TRPV4(-/-) lungs. In TRPV4(+/+) lungs, the high pressure-induced permeability response was significantly attenuated by low calcium perfusate, the TRPV antagonist ruthenium red, the phospholipase A(2) inhibitor methyl arachidonyl fluorophosphonate, or the P450 epoxygenase inhibitor propargyloxyphenyl hexanoic acid. Similarly, the high pressure-induced calcium transient in TRPV4(+/+) lungs was attenuated with ruthenium red or the epoxygenase inhibitor. High vascular pressure increased the alveolar fluid volume fraction compared with control. In lungs from TRPV4(-/-) mice, permeability, calcium intensity, and alveolar fluid volume fraction were not increased. These data support a role for P450-derived epoxyeicosatrienoic acid-dependent regulation of calcium entry via TRPV4 in the permeability response to high vascular pressure.
authors.affiliation: Department of Physiology, University of South Alabama, 307 University Blvd., Mobile, AL 36688, USA.
authors.forename: Ming-Yuan
authors.initials: MY
authors.lastname: Jian
authors.forename: Judy A
authors.initials: JA
authors.lastname: King
authors.forename: Abu-Bakr
authors.initials: AB
authors.lastname: Al-Mehdi
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Liedtke
authors.forename: Mary I
authors.initials: MI
authors.lastname: Townsley
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D020013:Calcium Signaling; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004727:Endothelium / Q000201:enzymology / Q000473:pathology; D005260:Female; D006973:Hypertension / Q000150:complications*; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008171:Lung Diseases / Q000201:enzymology* / Q000209:etiology*; D008297:Male; D051379:Mice; D010477:Perfusion; D010539:Permeability; D010994:Pleura / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D050916:TRPV Cation Channels / Q000378:metabolism*; D013696:Temperature
chemical_list: D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D016718:Arachidonic Acid; D003577:Cytochrome P-450 Enzyme System