title: Nafamostat mesilate inhibits high-mobility group box 1 by lipopolysaccharide stimulation in murine macrophage RAW 264.7.
abstract: In recent investigations, high-mobility group box 1 (HMGB1) has been recognized to be an important factor in the development of sepsis. On the other hand, a serine protease inhibitor, nafamostat mesilate (NM) inhibits the enzyme activities of various protease and coagulation factors. We examined whether NM could inhibit HMGB1 in a rat sepsis model and thus could potentially be useful for treating sepsis. We administered NM to rats before administering lipopolysaccharide and thereafter measured the HMGB1 levels of the serum and lung tissue. We used a mouse macrophage cell line and we performed lipopolysaccharide stimulation under NM administration and thereafter measured the quantity of HMGB1 and cytokines in the supernatant, and cell signal in the cells. We were thereby able to reduce the degree of injury to pulmonary tissue by administering NM. The HMGB1 levels of the serum and lung tissue were thus found to be inhibited. This action was confirmed at the cell level, and the release of HMGB1 and cytokines from the cell decreased. Regarding the cell signal in each cell, we observed the inhibition of the phosphorylation of IkappaB. We thus concluded that it is possible to prevent the occurrence of pulmonary disorders in an endotoxic shock model by administering NM, however, this also inhibits the cell signal in a cell, mainly by the phosphorylation of IkappaB, thereby inhibiting the HMGB1 levels. Our findings thus suggest that the administration of NM may therefore potentially improve the condition of patients who have septic shock.
authors.affiliation: Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medicine, Yufu City, Oita, Japan. saku@med.oita-u.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hagiwara
authors.forename: Hideo
authors.initials: H
authors.lastname: Iwasaka
authors.forename: Sigekiyo
authors.initials: S
authors.lastname: Matumoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D001550:Benzamidines; D002460:Cell Line; D006146:Guanidines / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D046509:Tissue Culture Techniques
chemical_list: D001550:Benzamidines; D006146:Guanidines; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D015842:Serine Proteinase Inhibitors; C032855:nafamostat