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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 218-224, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.4763

High Tidal Volume Ventilation Induces Proinflammatory Signaling in Rat Lung Endothelium

Sunita Bhattacharya, Namita Sen, Maimaiti T. Yiming, Rashmi Patel, Kaushik Parthasarathi, Sadiqa Quadri, Andrew C. Issekutz and Jahar Bhattacharya

Departments of Pediatrics, Medicine, and Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University; and St. Luke's-Roosevelt Hospital Center, New York, New York; and Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada

Address correspondence to: Sunita Bhattacharya, St. Luke's-Roosevelt Hospital Center, 1000 10th Ave, New York, NY 10019. E-mail: sb80{at}columbia.edu

Alveolar overdistension during mechanical ventilation causes leukocyte sequestration, leading to lung injury. However, underlying endothelial cell (EC) mechanisms are undefined. In a new approach, we exposed isolated blood-perfused rat lungs to high tidal volume ventilation (HV) for 2 h, then obtained fresh lung endothelial cells (FLEC) by immunosorting at 4°C. Immunoblotting experiments indicated that as compared with FLEC derived from lungs ventilated at low volume (LV), HV markedly enhanced tyrosine phosphorylation (TyrP). The tyrosine kinase blocker, genistein, inhibited this response. HV also induced focal adhesion (FA) formation in FLEC, as detected by immunofluorescent aggregates of the {alpha}vß3 integrin that co-localized with aggregations of focal adhesion kinase (FAK). Immunoprecipitation and blotting experiments revealed that HV increased TyrP of the FA protein, paxillin. In addition, HV induced a paxillin-associated P-selectin expression on FLEC that was also inhibited by genistein. However, HV did not increase lung water. These results indicate that in HV, EC signaling in situ causes FA formation and induces TyrP-dependent P-selectin expression. These signaling mechanisms may promote leukocyte-mediated responses in HV.

Abbreviations: endothelial cell, EC • focal adhesions, FA • focal adhesion kinase, FAK • fresh lung endothelial cells, FLEC • high tidal volume ventilation, HV • immunoprecipitation, IP • low tidal volume ventilation, LV • phosphate-buffered saline, PBS • tyrosine phosphorylation, TyrP • Weibel-Palade bodies, WPB




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