title: Sivelestat improves outcome of crush injury by inhibiting high-mobility group box 1 in rats.
abstract: Severe crush injury is associated with high mortality because of resulting hyperkalemia in early phase and multiorgan dysfunction in later phase. In this study, we investigated the effects of sivelestat administration 1 h before reperfusion on the outcome of crush injury. Crush injury was induced by 6 h of direct compression to both hindlimbs of anesthetized rats with blocks weighing 3.5 kg each side, followed by 3 h of reperfusion. Rats were randomly assigned to three groups. In the control group, rats were infused with normal saline at 1 mL/kg per hour throughout the experiment without compression. Rats in the positive control group were compressed for 6 h, followed by fluid resuscitation initiated 1 h before release with normal saline. The infusion rate was increased from 1 to 10 mL/kg per hour and continued for 4 h. Rats in the treated group underwent the same procedures as in the positive control group, but sivelestat was added to normal saline (concentration was adjusted to infuse 10 mg/kg per hour) during fluid resuscitation (for 4 h). Treatment with sivelestat significantly improved survival rate with P = 0.032. This was accompanied by lower serum high-mobility group box 1 (HMGB1) levels after 3-h reperfusion, attenuated lung injury (assessed using hematoxylin-eosin stain), and suppression of HMGB1 expression in the lung and the liver. These results suggest that treatment with sivelestat improves the outcome of crush injury, likely by inhibiting HMGB1 in rats.
authors.affiliation: Department of Emergency and Disaster Medicine, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Nguyen The
authors.initials: NT
authors.lastname: Cuong
authors.forename: Chikara
authors.initials: C
authors.lastname: Abe
authors.forename: Nguyen Huy
authors.initials: NH
authors.lastname: Binh
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.forename: Hironobu
authors.initials: H
authors.lastname: Morita
authors.forename: Shinji
authors.initials: S
authors.lastname: Ogura
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D015415:Biomarkers / Q000097:blood; D002245:Carbon Dioxide / Q000097:blood; D003131:Combined Modality Therapy; D003444:Crush Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005440:Fluid Therapy / Q000379:methods; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D012206:Rhabdomyolysis / Q000378:metabolism / Q000517:prevention & control; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D002245:Carbon Dioxide; C069195:sivelestat; D010100:Oxygen; D005998:Glycine