Anti-tryptase treatment using nafamostat mesilate has a therapeutic effect on experimental colitis.
OBJECTIVE
Mast cell tryptase has been proposed to be involved in the pathogenesis of human inflammatory bowel disease (IBD). Recently, it was reported that a low dose of nafamostat mesilate (NM), a serine protease inhibitor that is widely used to treat disseminated intravascular coagulation (DIC) and acute pancreatitis, can selectively inhibit human tryptase activity. The aim of this study was to investigate the anti-inflammatory effects of NM on experimental colitis in rats.


METHODS
Colitis was induced in male Wistar rats using an enema of trinitrobenzene sulfonic acid (TNBS) dissolved in 50% ethanol. NM or 5-aminosalicylic acid (5-ASA), foundation therapy for mild-to-moderate IBD, was administered via the anus once a day on each of the 6 days after administration of TNBS. Colonic inflammation was assessed 1 week after TNBS administration.


RESULTS
Intracolonic administration of TNBS resulted in the infiltration of numerous tryptase-positive cells in the colonic mucosa. The colonic mucosal injury induced by TNBS was significantly decreased by treatment with NM or 5-ASA. The increases in thiobarbituric acid-reactive substances (TBA-RS), myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractants-1 (CINC-1) in the colonic mucosa were inhibited in the NM group and the 5-ASA group, without significant differences between them.


CONCLUSIONS
These results indicate that a low dose of NM can inhibit the colonic mucosal inflammation induced by TNBS in rats, which suggests that anti-tryptase therapy using low doses of NM has excellent potential to become a new therapeutic strategy for IBD.
Isozaki
Yutaka
Y
Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Yoshida
Norimasa
N
Kuroda
Masaaki
M
Handa
Osamu
O
Takagi
Tomohisa
T
Kokura
Satoshi
S
Ichikawa
Hiroshi
H
Naito
Yuji
Y
Okanoue
Takesi
T
Yoshikawa
Toshikazu
T
D000636:Aminosalicylic Acids / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001550:Benzamidines; D054360:Chemokine CXCL1; D019743:Chemokines, CXC / Q000032:analysis; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D006146:Guanidines / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014302:Trinitrobenzenesulfonic Acid; D053802:Tryptases / Q000032:analysis / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001550:Benzamidines; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; C513297:Cxcl1 protein, rat; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D053802:Tryptases; C032855:nafamostat