Nafamostat mesilate, a serine protease inhibitor, suppresses lipopolysaccharide-induced nitric oxide synthesis and apoptosis in cultured human trophoblasts.
We investigated the effects of nafamostat mesilate, a synthetic protease inhibitor clinically used for patients with pancreatitis or disseminated intravascular coagulopathy, on NO synthesis and apoptosis in lipopolysaccharide (LPS)-treated human trophoblasts. Nafamostat mesilate or aminoguanidine, an inhibitor of NO synthase, suppressed NO synthesis and apoptosis in trophoblasts induced by LPS. Both agents also suppressed matrix metalloproteinase-2 activity induced by LPS. LPS also stimulated secretion of IL-6 and IL-8 in cultured trophoblasts, which was suppressed by nafamostat mesilate. Protease inhibitors including nafamostat mesilate may be therapeutic agents for chorioamnionitis and various diseases including septic shock, ischemia-reperfusion injury in brain and heart, graft rejection, and acute phase inflammatory diseases, in which overproduction of NO or peroxynitrite is involved in tissue injury.
Nakatsuka
M
M
Department of Obstetrics and Gynecology, Okayama University Medical School, Okayama-city, Japan. mikiya@cc.okayama-u.ac.jp
Asagiri
K
K
Noguchi
S
S
Habara
T
T
Kudo
T
T
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001550:Benzamidines; D002478:Cells, Cultured; D003470:Culture Media; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005780:Gelatin / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D011247:Pregnancy; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001550:Benzamidines; D003470:Culture Media; D006146:Guanidines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D005780:Gelatin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C032855:nafamostat