title: HMGB1 contributes to the development of acute lung injury after hemorrhage.
abstract: High mobility group box 1 (HMGB1) is a novel late mediator of inflammatory responses that contributes to endotoxin-induced acute lung injury and sepsis-associated lethality. Although acute lung injury is a frequent complication of severe blood loss, the contribution of HMGB1 to organ system dysfunction in this setting has not been investigated. In this study, HMGB1 was detected in pulmonary endothelial cells and macrophages under baseline conditions. After hemorrhage, in addition to positively staining endothelial cells and macrophages, neutrophils expressing HMGB1 were present in the lungs. HMGB1 expression in the lung was found to be increased within 4 h of hemorrhage and then remained elevated for more than 72 h after blood loss. Neutrophils appeared to contribute to the increase in posthemorrhage pulmonary HMGB1 expression since no change in lung HMGB1 levels was found after hemorrhage in mice made neutropenic with cyclophosphamide. Plasma concentrations of HMGB1 also increased after hemorrhage. Blockade of HMGB1 by administration of anti-HMGB1 antibodies prevented hemorrhage-induced increases in nuclear translocation of NF-kappa B in the lungs and pulmonary levels of proinflammatory cytokines, including keratinocyte-derived chemokine, IL-6, and IL-1 beta. Similarly, both the accumulation of neutrophils in the lung as well as enhanced lung permeability were reduced when anti-HMGB1 antibodies were injected after hemorrhage. These results demonstrate that hemorrhage results in increased HMGB1 expression in the lungs, primarily through neutrophil sources, and that HMGB1 participates in hemorrhage-induced acute lung injury.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
authors.forename: Jae Yeol
authors.initials: JY
authors.lastname: Kim
authors.forename: Jong Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Derek
authors.initials: D
authors.lastname: Strassheim
authors.forename: Ivor
authors.initials: I
authors.lastname: Douglas
authors.forename: Fernando
authors.initials: F
authors.lastname: Diaz del Valle
authors.forename: Karim
authors.initials: K
authors.lastname: Asehnoune
authors.forename: Sanchayita
authors.initials: S
authors.lastname: Mitra
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Kwak
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Ishizaka
authors.forename: Edward
authors.initials: E
authors.lastname: Abraham
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D024243:HMGB1 Protein / Q000276:immunology / Q000378:metabolism*; D006470:Hemorrhage / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: D000906:Antibodies; D016207:Cytokines; D024243:HMGB1 Protein; D016328:NF-kappa B