High-mobility group box 1: role in ARDS

Extracellular high-mobility group box 1 (HMGB-1), first isolated approximately 30 years ago from the thymus as a chromosomal protein and recognized as a transcriptional factor, has recently been proposed as one of the late mediators of sepsis and lipopolysaccharide (LPS) endotoxin acute lung injury (ALI) [1, 2]. In recent studies, HMGB-1 has been implicated in the development of arthritis, activation of human monocytes, smooth muscle cell chemotaxis, and induction of adhesion molecules in endothelial cells. These observations suggest that HMGB-1 is a key mediator of cell injury, and that its inhibition may be key in improving clinical outcomes. We conducted a translational study to examine the participation of HMGB-1 in the pathogenesis of ALI caused by sepsis. To test the hypothesis that HMGB-1 plays a key role as a late mediator, we first measured its concentrations and those of its related compound, HMGB-2, in the blood and lungs of patients presenting with septic ALI/ARDS, and in a murine model of LPS-induced lung injury. We then studied the localization of the extracellular HMGB-1 protein and examined the anti-inflammatory effects of anti-HMGB-1 antibodies in our LPS-induced lung injury murine model. The direct effects of HMGB-1 and HMGB-2 on the lung were also examined. This study was performed to examine the putative role of HMGB protein in the pathogenesis of ALI. Observations were made (1) in 21 septic patients with ALI and 15 patients with normal lung function, and (2) in a mouse model, 24 hours after intratracheal instillation of lipopolysaccharide. The concentrations of HMGB-1 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-HMGB-1 antibody. Although this protein was not detected in the plasma of control humans or mice, the concentrations of HMGB-1 in lung epithelial lining fluid or in bronchoalveolar lavage fluid were unexpectedly high. The nuclear expression of HMGB-1 was apparent in epithelial cells surrounding terminal bronchioles in normal mice, while its nuclear and cytoplasmic expression was observed in alveolar macrophages in LPS-instilled mice. Lung instillation of HMGB-2 did not cause as much inflammation as HMGB-1. Extracellular HMGB-1 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.