Published ahead of print on October 25, 2007, doi:10.1165/rcmb.2007-0192OC Am. J. Respir. Cell Mol. Biol., Volume 38, Number 4, April 2008, 386-392 A more recent version of this article appeared on April 1, 2008
Submitted on May 31, 2007 High Vascular Pressure-induced Lung Injury Requires P450 Epoxygenase-dependent Activation of TRPV4Ming-Yuan Jian1,1 Department of Physiology, University of South Alabama, Mobile, AL, USA, 2 Department of Pharmacology, University of South Alabama, Mobile, AL, USA; Department of Pathology, University of South Alabama, Mobile, AL, USA; Center for Lung Biology, University of South Alabama, Mobile, AL, USA, 3 Department of Pharmacology, University of South Alabama, Mobile, AL, USA; Center for Lung Biology, University of South Alabama, Mobile, AL, USA, 4 Departments of Medicine, Neurology and Neurobiology, Duke University, Durham, NC, USA, 5 Department of Physiology, University of South Alabama, Mobile, AL, USA; Center for Lung Biology, University of South Alabama, Mobile, AL, USA * To whom correspondence should be addressed. E-mail: mtownsley{at}usouthal.edu.
Rationale: 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. Objective: 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. Methods: 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. Results: Baseline permeability, calcium intensity and alveolar flooding were no different in TRPV4+/+ vs 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 A2 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 to control. In lungs from TRPV4-/- mice, permeability, calcium intensity and alveolar fluid volume fraction were not increased. Conclusion: 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.
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