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Contributions of High Mobility Group Box Protein in Experimental and Clinical Acute Lung Injury

Department of Anesthesiology and Intensive Care; Department of Anatomy, Kyoto Prefectural University of Medicine, Kyoto; Intensive Care Unit, Saiseikai Suita Hospital, Osaka; Department of Laboratory and Molecular Medicine, Faculty of Medicine, Kagoshima University, Kagoshima; and Department of Medicine, Keio University, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Satoru Hashimoto, M.D., Department of Intensive Care and Anesthesiology, Kyoto Prefectural University of Medicine, 465 Kajiicho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan, 602–8566. E-mail: satoru{at}koto.kpu-m.ac.jp

This study was performed to examine the putative role of high mobility group box (HMGB) protein in the pathogenesis of acute lung injury (ALI). Observations were made (1) in 21 patients who were septic with ALI and 15 patients with normal lung function and (2) in a mouse model 24 hours after intratracheal instillation of lipopolysaccharide (LPS). The concentrations of HMGB1 were increased in plasma and lung epithelial lining fluid of patients with ALI and mice instilled with LPS. LPS-induced ALI was mitigated by anti-HMGB1 antibody. Although this protein was not detected in the plasma of control humans or mice, the concentrations of HMGB1 in lung epithelial lining fluid or in bronchoalveolar lavage fluid were unexpectedly high. The nuclear expression of HMGB1 was apparent in epithelial cells surrounding terminal bronchioles in normal mice, whereas its nuclear and cytoplasmic expression was observed in alveolar macrophages in LPS-instilled mice. Lung instillation of HMGB2 did not cause as much inflammation as HMGB1. Extracellular HMGB1 may play a key role in the pathogenesis of clinical and experimental ALI. However, its expression in normal airways is noteworthy and suggests that it also plays a physiologic role in the lung.

Key Words: acute respiratory distress syndrome • endotoxin • high mobility group B-1 protein • high mobility group B-2 protein • lipopolysaccharide

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