期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 293, 期 4, 页码 L923-L932出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00221.2007
关键词
pulmonary edema; P-450 epoxygenases; stretch-activated cation channel; vascular permeability; Ca2+ channels; epoxyeicosatrienoic acids; temperature
资金
- NHLBI NIH HHS [P01-HL-66299] Funding Source: Medline
- NIMH NIH HHS [K08-MH-64702] Funding Source: Medline
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 (K-f) in isolated perfused lungs of C57BL/6 mice after 30-min ventilation periods of 9, 25, and 35 cmH(2)O PIP at both 35 degrees C and 40 degrees C. Ventilation with 35 cmH2O PIP increased K-f by 2.2-fold at 35 C and 3.3-fold at 40 degrees C compared with baseline, but K-f increased significantly with time at 40 C with 9 cmH(2)O 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.
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