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Contribution of High-Mobility Group Box-1 to the Development of Ventilator-induced Lung Injury

Departments of Anesthesiology and Medicine, School of Medicine, Keio University; Department of Anesthesiology and Intensive Care, Tokyo Women's Medical University Daini Hospital, Tokyo; Department of Anesthesiology and Intensive Care, Kyoto Prefectural University of Medicine, Kyoto; Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai; Central Institute, Shino-Test Corporation, Kanagawa; Ono Pharmaceutical Co. Ltd., Osaka, Japan; and Department of Medicine, University of Alabama, Birmingham, Alabama

Correspondence and requests for reprints should be addressed to Akitoshi Ishizaka, M.D., Ph.D., Department of Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: ishizaka{at}cpnet.med.keio.ac.jp

Rationale: Proinflammatory cytokines play an important role in ventilator-induced lung injury (VILI). 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 VT. 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 VILI.

Methods: Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained from rabbits mechanically ventilated for 4 h with a small (8 ml/kg) versus a large (30 ml/kg) VT. BALF was also obtained from rabbits with intratracheal instillation of anti-HMGB1 antibody before the initiation of large VT ventilation.

Measurements and Main Results: The concentrations of HMGB1 in BALF were fivefold higher in the large than in the small VT group. Immunohistochemistry and immunofluorescence studies revealed expression of HMGB1 in the cytoplasm of macrophages and neutrophils in lungs ventilated with large VT. Blocking HMGB1 improved oxygenation, limited microvascular permeability and neutrophil influx into the alveolar lumen, and decreased concentrations of tumor necrosis factor- in BALF.

Conclusions: These observations suggest that HMGB1 could be one of the deteriorating factors in the development of VILI.

Key Words: high-mobility group box-1 • macrophage, rabbit model • ventilator-induced lung injury

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