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Am J Physiol Lung Cell Mol Physiol (November 21, 2003). doi:10.1152/ajplung.00296.2003
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Submitted on August 28, 2003
Accepted on November 17, 2003

Enhancement of the Endotoxin Recognition Pathway by Ventilation with a Large Tidal Volume in Rabbits

Kiyoshi Moriyama1, Akitoshi Ishizaka2*, Morio Nakamura3, Hiroshi Kubo4, Toru Kotani1, Shinichi Yamamoto1, Eileen N. Ogawa1, Osamu Kajikawa3, Charles W. Frevert3, Yoshifumi Kotake1, Hiroshi Morisaki1, Hidefumi Koh5, Sadatomo Tasaka5, Thomas R. Martin3, and Junzo Takeda1

1 Department of Anesthesiology, Keio university School of medicine, Tokyo, Japan
2 Department of Medicine, Tokyo Electric Power Company Hospital, Tokyo, Japan
3 Department of Medicine, Medical Research Service of the U.S. Department of Veterans Affairs, VA Puget Sound Medical Center, and the Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA, USA
4 Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Tohoku, Japan
5 Department of Medicine, Keio University School of Medicine, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: ishiz{at}attglobal.net.

Ventilation with a small tidal volume (VT) is associated with better clinical outcomes than with a large VT, particularly in critical settings, including acute lung injury. To determine whether VT influences the lipopolysaccaharide (LPS) recognition pathway, we studied the CD14 expression in rabbit lungs and the release of TNF-{alpha} by cultured alveolar macrophages after 240 min of ventilation with a large (20 ml/kg) versus a small (5 ml/kg) VT. We also applied small or large VT to lungs instilled with LPS, 50 µg/kg. The alveolar macrophages collected after large VT ventilation revealed a 20-fold increase in LPS-induced TNF-{alpha} release, compared with those collected after small VT ventilation, whereas TNF-{alpha} was undetectable without LPS stimulation. In the animals ventilated with a large VT, the expression of CD14 mRNA in whole lung homogenates and the expression of CD14 protein on alveolar macrophages, assessed by immunohistochemistry, were both significantly increased in absence of LPS stimulation. A large VT applied to LPS-instilled lungs increased the pulmonary albumin permeability and TNF-{alpha} release into the plasma. These results suggest that mechanical stress caused by a large VT sensitizes the lungs to endotoxin, a phenomenon that may occur partially via the upregulation of CD14.




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