Gabexate mesilate inhibits the expression of HMGB1 in lipopolysaccharide-induced acute lung injury.
High mobility group box 1 (HMGB1) is an important late mediator of acute lung injury. Gabexate mesilate (GM) is a synthetic protease inhibitor with some anti-inflammatory action. We aimed to evaluate the effect of GM on HMGB1 in lipopolysaccharide (LPS)-induced lung injury in rats. Prior to the injection of LPS to induce lung injury, rats were administered saline or GM. Injury to the lung and expression of HMGB1, plasminogen activator inhibitor-1 (PAI-1), and protease-activated receptor-2 (PAR-2) were examined. In an accompanying in vitro study, we performed LPS stimulation under GM administration in a mouse macrophage cell line and measured the quantity of HMGB1 and cytokines in the supernatant, and cell signal in the cells. Histologic examination revealed that interstitial edema, leukocytic infiltration, and HMGB1 protein expression were markedly reduced in the GM+LPS group compared wih the LPS group. Furthermore, LPS-induced increases in PAI-1 and PAR-2 activity and in plasma HMGB1 concentrations were lower in the rats given both GM and LPS than in the rats given LPS alone. Release of HMGB1 and cytokines from the cell after the administration of LPS were decreased by GM. Phosphorylation of IκB was inhibited by GM. GM may have inhibited PAI-1 and PAR-2, thereby indirectly inhibiting HMGB1 and reducing tissue damage in the lung. This indicates that GM can inhibit lung injury induced by LPS in rats. GM is a candidate for use in novel strategies to prevent or minimize lung injury in sepsis.
Hidaka
Seigo
S
Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine, Oita University, Yufu City, Oita, Japan. sehidaka@med.oita-u.ac.jp
Iwasaka
Hideo
H
Hagiwara
Satoshi
S
Noguchi
Takayuki
T
D055371:Acute Lung Injury / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D004247:DNA / Q000378:metabolism; D016670:Gabexate / Q000494:pharmacology* / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D024243:HMGB1 Protein; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016670:Gabexate; D004247:DNA