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CONTRIBUTION OF INSPIRATORY FLOW TO ACTIVATION OF EGFR, RAS, MAPK, ATF-2 AND C-JUN DURING LUNG STRETCH
Citation:
Silbajoris, R, J M. Samet, Huang, YuhChin T, AND Z. Li. CONTRIBUTION OF INSPIRATORY FLOW TO ACTIVATION OF EGFR, RAS, MAPK, ATF-2 AND C-JUN DURING LUNG STRETCH. Presented at American Thoracic Society, Orlando, FL, May 21-26, 2004.
Description:
Contribution of Inspiratory Flow to Activation of EGFR, Ras, MAPK, ATF-2 and c-Jun during Lung Stretch
R. Silbajoris 1, Z. Li 2, J. M. Samet 1 and Y. C. Huang 1. 1 NHEERL, ORD, US EPA, RTP, NC and 2 CEMALB, UNC-CH, Chapel Hill, NC .
Mechanical ventilation with large tidal volume (Vt) activates signal transduction pathways related to lung inflammation, injury and repair. Mechanical factors in addition to large Vt may also be important in mechano-transduction during lung stretch. We previously showed that decreasing inspiratory flow attenuated IL-8 release and mitogen-activated protein kinase (MAPK) activation induced by large Vt. In this study we assessed the role of inspiratory flow rate in MAPK-related signaling pathways. Isolated buffer-perfused rabbit lungs were ventilated for 2 hr with 21%O2+5%CO2, PEEP of 2-3 cm H2O and one of four protocols: normal Vt (Vt 6 ml/kg, respiratory rate (RR) 30, I:E 1:1, flow 6 ml/kg/sec) or large Vt (12 ml/kg) with either high rate high inspiratory flow (HRHF) (RR30, I:E 1:1, flow 12 ml/kg/sec), low rate high inspiratory flow (LRHF) (RR15, I:E 1:2.3, flow 10 ml/kg/sec) or low rate low inspiratory flow (LRLF) (RR15, I:E 1:1, flow 6 ml/kg/sec). Activation of MAPK (ERK1/2, p38), transcription factors (ATF-2, c-Jun), Ras and epidermal growth factor receptor (EGFR) were assessed by Western blotting and/or immunohistochemistry using phospho (p)-specific antibodies. Phosphorylation of ERK1/2, p38, ATF-2 and c-Jun was enhanced only in the two higher inspiratory flow groups (HRHF and LRHF) while EGFR and Ras were activated in all three large Vt groups regardless of inspiratory flow rate. In HRHF, increased phosphorylation of ERK1/2, p38, ATF-2, c-Jun and EGFR was seen in different cells of bronchopulmonary bundles, including bronchial epithelial and smooth muscle cells as well as smooth muscles and adventitia of pulmonary arteries. Increased p-c-Jun and p-ATF-2 staining was also observed in pulmonary venules. We conclude that in buffer perfused lungs subjected to mild Vt stretch, inspiratory flow rate and Vt may differentially regulate MAPK-related signaling originating from cells in large airways and vessels. Abstract does not reflect USEPA policy.
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