Nafamostat mesilate inhibits the expression of HMGB1 in lipopolysaccharide-induced acute lung injury.
OBJECTIVE
High mobility group box 1 (HMGB1) protein has recently been shown to be an important late mediator of acute lung injury and a promising therapeutic target. Nafamostat mesilate (NM) is a broad-range synthetic protease inhibitor with some anti-inflammatory action. The purpose of this study was to evaluate the effect of NM on HMGB1 in lipopolysaccharide (LPS)-induced lung injury in rats.


METHODS
Male Wistar rats were given either saline (LPS group) or NM (NM+LPS group) 30 min before the intravenous injection of a bolus of LPS (5 mg.kg(-1)). After the administration of LPS, injury to the lung and the expression of HMGB1, tumor necrosis factor-alpha (TNF-alpha), and plasminogen activator inhibitor-1 (PAI-1) were examined.


RESULTS
Histological examination revealed that interstitial edema, leukocytic infiltration, and HMGB1 protein expression were markedly reduced in the NM+LPS group compared to the LPS group. Furthermore, the LPS-induced increases in PAI-1 activity and in plasma TNF-alpha concentrations were also lower in the rats given both NM and LPS than in the rats given LPS alone.


CONCLUSIONS
The anticoagulatory activity of NM may have inhibited PAI-1, while its anti-inflammatory activity blockaded TNF-alpha, thereby indirectly inhibiting HMGB1 and reducing tissue damage in the lung. These findings indicate that NM can inhibit the lung injury induced by LPS in rats. NM is an excellent candidate for use in new therapeutic strategies to prevent or minimize lung injury.
Hagiwara
Satoshi
S
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan.
Iwasaka
Hideo
H
Noguchi
Takayuki
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001550:Benzamidines; D004195:Disease Models, Animal; D006146:Guanidines / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000096:biosynthesis* / Q000187:drug effects; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001550:Benzamidines; D006146:Guanidines; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D014409:Tumor Necrosis Factor-alpha; C032855:nafamostat