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

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 33; no. 4; pp. L583 - L590
• Main Authors: XINCHUN LIN, HUAN YANG, SAKURAGI, Tohru, MAOWEN HU, MANTELL, Lin L, HAYASHI, Shinichiro, AL-ABED, Yousef, TRACEY, Kevin J, ULLOA, Luis, MILLER, Edmund J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Physiological Society 01.10.2005
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Lungs; Medical disorders; Nitrogen; Proteins; Vertebrates: respiratory system; Acute; Lung; Mobility; Inflammation; Chemokine receptor; Respiratory system; Survival; acute lung injury; Protein; Chemokine; Vertebrata; Mammalia; Lesion; Neutrophil; polymorphonuclear neutrophils; α-chemokines
• ISSN: 1040-0605; 1522-1504

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 {alpha}-chemokine receptors in the HMGB1-induced inflammatory injury and show that {alpha}-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 {alpha}-chemokine macrophage inflammatory protein-2 and accompanied by injury and increased inflammatory potential within the air spaces. To investigate the role of {alpha}-chemokine receptors in the injury, we instilled recombinant HMGB1 (0.5 g) directly into the lungs and administered a subcutaneous {alpha}-chemokine receptor inhibitor, Antileukinate (200 µg). {alpha}-Chemokine receptor blockade reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 plus or minus 3.2 vs. 8.1 plus or minus 2.4 x 104 cells; total protein: 120 plus or minus 48 vs. 311 plus or minus 129 g/ml; reactive nitrogen species: 2.3 plus or minus 0.3 vs. 3.5 plus or minus 1.3 M; and macrophage migration inhibitory factor: 6.4 plus or minus 4.2 vs. 37.4 plus or minus 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1-induced inflammation and injury are {alpha}-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 {alpha}-chemokine receptor inhibition can reduce HMGB1-induced lung injury and lethality in established sepsis and may provide a novel treatment in this devastating disease.[PUBLICATION ABSTRACT]