Published ahead of print on August 25, 2005, doi:10.1165/rcmb.2005-0133OC
© 2005 American Thoracic Society DOI: 10.1165/rcmb.2005-0133OC Sequence of Endothelial Signaling during Lung ExpansionDepartment of Physiology and Cellular Biophysics, and Department of Pediatrics, 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 Correspondence and requests for reprints should be addressed to Sunita Bhattacharya, M.D., St. Luke's-Roosevelt Hospital Center, AJA #510, 1000 10th Avenue, New York, NY 10019. E-mail: sb80{at}columbia.edu Although high tidal volume ventilation exacerbates lung injury, the mechanisms underlying the inflammatory response are not clear. Here, we exposed isolated lungs to high or low tidal volume ventilation, while perfusing lungs with whole blood, or blood depleted of leukocytes and platelets. Then, we determined signaling responses in freshly isolated lung endothelial cells by means of immunoblotting and immunofluorescence approaches. In depleted blood perfusion, high tidal volume induced modest increases in both P-selectin expression on the endothelial surface, and in endothelial protein tyrosine phosphorylation. Both high tidal volume–induced responses were markedly enhanced in the presence of whole blood perfusion. However, a P-selectin–blocking antibody given together with whole blood perfusion inhibited the responses down to levels corresponding to those for depleted blood perfusion. These findings indicate that the full proinflammatory response occurs in two stages. First, lung distension causes modest endothelial activation. Second, subsequent endothelial–inflammatory cell interactions augment P-selectin expression and tyrosine phosphorylation. We conclude that interactions of circulating inflammatory cells with P-selectin critically determine proinflammatory endothelial activation during high tidal volume ventilation.
Key Words: leukocytes • lung • mechanical • P-selectin • phosphorylation This article has been cited by other articles:
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