Published ahead of print on May 25, 2006, doi:10.1164/rccm.200605-699OC Am. J. Respir. Crit. Care Med., Volume 174, Number 4, August 2006, 400-407 A more recent version of this article appeared on August 15, 2006
Submitted on September 1, 2005 Contribution of High Mobility Group Box-1 to the Development of Ventilator-induced Lung InjuryEileen N Ogawa1,1 Department of Anesthesiology, Keio University, School of Medicine, Tokyo, Japan, 2 Department of Medicine, Keio University, School of Medicine, Tokyo, Japan, 3 Department of Anesthesiology and Intensive Care, Kyoto Prefectural University of Medicine, Kyoto, Japan, 4 Respiratory Oncology and Molecular Medicine, Tohoku University, Institute of Development, Aging and Cancer, Sendai, Japan, 5 Central Institute, Shino-Test Corporation, Kanagawa, Japan, 6 Ono Pharmaceutical Co. Ltd., Osaka, Japan, 7 Department of Anesthesiology and Intensive Care, Tokyo Women's Medical University Daini Hospital, Tokyo, Japan, 8 Department of Medicine, University of Alabama, Birmingham, AL, USA * To whom correspondence should be addressed. E-mail: ishizaka{at}cpnet.med.keio.ac.jp.
Rationale: Proinflammatory cytokines play an important role in ventilator-induced lung injury. High mobility group box-1 (HMGB1) is a macrophage-derived proinflammatory cytokine that can cause lung injury.
Objectives: This study tested the hypothesis that HMGB1 is released in intact lungs ventilated with large tidal volumes. A second objective was to identify the source of HMGB1. A third objective was to examine the effects of blocking HMGB1 on the subsequent development of ventilator-induced lung injury.
Methods: Bronchoalveolar lavage fluid and lung tissues were obtained from rabbits mechanically ventilated for 4 hours with a small (8 ml/kg) versus a large (30 ml/kg) tidal volume. Bronchoalveolar lavage fluid was also obtained from rabbits with intra-tracheal instillation of anti-HMGB1 antibody before the initiation of large tidal volume ventilation.
Measurements and Main Results: The concentrations of HMGB1 in bronchoalveolar lavage fluid were 5-fold higher in the large than in the small tidal volume group. Immunohistochemistry and immunofluorescence studies revealed expression of HMGB1 in the cytoplasm of macrophages and neutrophils in lungs ventilated with large tidal volumes. Blocking HMGB1 improved oxygenation, limited microvascular permeability and neutrophil influx into the alveolar lumen, and decreased concentrations of tumor necrosis factor- Key words: high mobility group box-1, ventilator-induced lung injury, macrophage, rabbit model
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in bronchoalveolar lavage fluid.
Conclusions: These observations suggested that HMGB1 could be one of the deteriorating factors in the development of ventilator-induced lung injury.
