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lüll TRPV4 initiates the acute calcium-dependent permeability increase during ventilator-induced lung injury in isolated mouse lungs Hamanaka K; Jian MY; Weber DS; Alvarez DF; Townsley MI; Al-Mehdi AB; King JA; Liedtke W; Parker JCAm J Physiol Lung Cell Mol Physiol 2007[Oct]; 293 (4): L923-32We 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 cmH(2)O PIP increased K(f) by 2.2-fold at 35 degrees C and 3.3-fold at 40 degrees C compared with baseline, but K(f) increased significantly with time at 40 degrees 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 K(f). In TRPV4(-/-) knockout mice, the high PIP ventilation protocol did not increase K(f) at either temperature. We have also found that lung distention caused Ca(2+) 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.|*Capillary Permeability[MESH]|*Lung Injury[MESH]|*Pulmonary Circulation[MESH]|*Ventilators, Mechanical[MESH]|Animals[MESH]|Calcium/*metabolism[MESH]|In Vitro Techniques[MESH]|Lung/metabolism/pathology/physiopathology[MESH]|Male[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Mice, Knockout[MESH]|Microscopy, Electron[MESH]|Microscopy, Fluorescence[MESH]|Phosphorylation[MESH]|Positive-Pressure Respiration[MESH]|Pressure[MESH]|Pulmonary Edema/etiology[MESH]|Respiratory System/physiopathology[MESH]|TRPV Cation Channels/antagonists & inhibitors/deficiency/*metabolism[MESH]|Tyrosine/metabolism[MESH]|Wounds and Injuries/etiology/metabolism/pathology/physiopathology[MESH] |