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1 Physiology, University of South Alabama, Mobile, Alabama, United States; Center for Lung Biology, University of South Alabama, Mobile, Alabama, United States
2 Physiology, University of South Alabama, Mobile, Alabama, United States
3 Center for Lung Biology, University of South Alabama, Mobile, Alabama, United States; Physiology, University of South Alabama, Mobile, Alabama, United States
4 Pharmacology, University of South Alabama, Mobile, Alabama, United States; Center for Lung Biology, University of South Alabama, Mobile, Alabama, United States
5 Departments of Pharmacology and Pathology, University of South Alabama, Mobile, Alabama, United States; Center for Lung Biology, University of South Alabama, Mobile, Alabama, United States
6 Neurobiology, Duke University, Durham, North Carolina, United States
* To whom correspondence should be addressed. E-mail: jparker{at}usouthal.edu.
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 P450 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 minute 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 to baseline, but Kf increased significantly with time at 40 °C with 9 cmH2O PIP. Pretreatment with the inhibitors of TRPV4 (ruthenium red), arachidonic acid production (methanandamide) or P450 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 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.
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