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This Article Full Text Full Text (PDF) All Versions of this Article: 289/4/L583    most recent 00091.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Lin, X. Articles by Miller, E. J. Search for Related Content PubMed PubMed Citation Articles by Lin, X. Articles by Miller, E. J.

-Chemokine receptor blockade reduces high mobility group box 1 protein-induced lung inflammation and injury and improves survival in sepsis

¹Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center; Departments of ²Surgical Immunology and ³Biomedical Sciences, and ⁴Center for Immunology and Inflammation, Institute for Medical Research at North Shore-LIJ, Manhasset, New York; and Departments of ⁵Thoracic and Cardiovascular Surgery, and Pulmonary Medicine, Saga University, Saga, Japan

Submitted 28 February 2005 ; accepted in final form 25 May 2005

High mobility group box 1 (HMGB1) protein, a late mediator of lethality in sepsis, can induce acute inflammatory lung injury. Here, we identify the critical role of -chemokine receptors in the HMGB1-induced inflammatory injury and show that -chemokine receptor inhibition increases survival in sepsis, in a clinically relevant time frame. Intratracheal instillation of recombinant HMGB1 induces a neutrophilic leukocytosis, preceded by alveolar accumulation of the -chemokine macrophage inflammatory protein-2 and accompanied by injury and increased inflammatory potential within the air spaces. To investigate the role of -chemokine receptors in the injury, we instilled recombinant HMGB1 (0.5 µg) directly into the lungs and administered a subcutaneous -chemokine receptor inhibitor, Antileukinate (200 µg). -Chemokine receptor blockade reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 ± 3.2 vs. 8.1 ± 2.4 x 10⁴ cells; total protein: 120 ± 48 vs. 311 ± 129 µg/ml; reactive nitrogen species: 2.3 ± 0.3 vs. 3.5 ± 1.3 µM; and macrophage migration inhibitory factor: 6.4 ± 4.2 vs. 37.4 ± 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1-induced inflammation and injury are -chemokine mediated. Because HMGB1 can mediate late septic lethality, we administered Antileukinate to septic mice and observed increased survival (from 58% in controls to 89%) even when the inhibitor treatment was initiated 24 h after the induction of sepsis. These data demonstrate that -chemokine receptor inhibition can reduce HMGB1-induced lung injury and lethality in established sepsis and may provide a novel treatment in this devastating disease.

acute lung injury; -chemokines; polymorphonuclear neutrophils

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