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.

High mobility group box 1 as a mediator of endotoxin administration after hemorrhagic shock-primed lung injury

“…At the same time, lung HMGB1 levels increased significantly at 24 h after intratracheal LPS injection, a delayed event compared to hemorrhagic shock in mice. This result is consistent with a previously conducted study (20). However, lung HMGB1 levels increased notably within 4 h of LPS administration to hemorrhagic shock animals, an earlier event compared to ALI induced by hemorrhagic shock and intratracheal LPS injection (6,20).…”

Clinical Significance of Serum HMGB-1 and sRAGE Levels in Systemic Sclerosis: Association with Disease Severity

“…In this study, serum HMGB-1 and sRAGE levels correlated with various [8,[17][18][19][20][21][22]. HMGB-1 is actively secreted by damaged, necrotic, and apoptotic cells after translocation from the nucleus to secretory lysosomes [5,6].…”

“…HMGB-1 and RAGE are known to be causally involved in a variety of pathophysiological processes, such as rheumatoid arthritis, acute lung injury, disseminated intravascular coagulation, Alzheimer disease, tumorigenesis, abnormalities associated with diabetes, and impaired wound healing [8,[17][18][19][20][21][22]. Although HMGB-1 is regarded as a trigger of these immune/inflammatory disorders mediated via RAGE and TLR and also affects immunological abnormalities [5,6,9,12,23], correlation of serum…”

“…ELISA for serum HMGB-1 and serum sRAGE levels was performed as previously described [20,21,33] using a specific ELISA kit (Shino-Test Co., Sagamihara, Kanagawa, Japan. for HMGB-1 and R&D systems, Minneapolis, MN for sRAGE), according to the manufacturer's protocol.…”

“…Recently, increasing serum HMGB-1 levels have been reported in several immune/inflammatory disorders [8,[17][18][19][20][21][22]. However, it has been controversial whether sRAGE increases or decreases in immune/inflammatory conditions.…”