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Departments of 1Physiology, 2Pharmacology, and 3Pathology and 4Center for Lung Biology, University of South Alabama, Mobile, Alabama; and 5Department of Medicine, Neurology, and Neurobiology, Duke University, Durham, North Carolina
Submitted 4 June 2007 ; accepted in final form 21 July 2007
We have previously implicated calcium entry through stretch-activated cation channels in initiating the acute pulmonary vascular permeability increase in response to high peak inflation pressure (PIP) ventilation. However, the molecular identity of the channel is not known. We hypothesized that the transient receptor potential vanilloid-4 (TRPV4) channel may initiate this acute permeability increase because endothelial calcium entry through TRPV4 channels occurs in response to hypotonic mechanical stress, heat, and P-450 epoxygenase metabolites of arachidonic acid. Therefore, permeability was assessed by measuring the filtration coefficient (Kf) in isolated perfused lungs of C57BL/6 mice after 30-min ventilation periods of 9, 25, and 35 cmH2O PIP at both 35°C and 40°C. Ventilation with 35 cmH2O PIP increased Kf by 2.2-fold at 35°C and 3.3-fold at 40°C compared with baseline, but Kf increased significantly with time at 40°C with 9 cmH2O PIP. Pretreatment with inhibitors of TRPV4 (ruthenium red), arachidonic acid production (methanandamide), or P-450 epoxygenases (miconazole) prevented the increases in Kf. In TRPV4–/– knockout mice, the high PIP ventilation protocol did not increase Kf at either temperature. We have also found that lung distention caused Ca2+ entry in isolated mouse lungs, as measured by ratiometric fluorescence microscopy, which was absent in TRPV4–/– and ruthenium red-treated lungs. Alveolar and perivascular edema was significantly reduced in TRPV4–/– lungs. We conclude that rapid calcium entry through TRPV4 channels is a major determinant of the acute vascular permeability increase in lungs following high PIP ventilation.
pulmonary edema; P-450 epoxygenases; stretch-activated cation channel; vascular permeability; Ca2+ channels; epoxyeicosatrienoic acids; temperature
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