The protective effects of long-acting recombinant human pancreatic secretory trypsin inhibitor (R44S-PSTI) in a rat model of cerulein-induced pancreatitis.
The effects of pancreatic secretory trypsin inhibitor (PSTI) on cerulein-induced pancreatitis were studied in a rat model. Arg44 of PSTI was replaced by Ser using site-directed mutagenesis (R44S-PSTI). R44S-PSTI has a longer half-life than the natural form. Pancreatitis was induced by four intramuscular injections of cerulein (50 microgram/kg at 1 h intervals). Continuous intravenous infusion of R44S-PSTI began at a dose of 20 micrograms/kg/h 30 min before the first cerulein injection, and was completed 3 h after the last cerulein injection. Tumour necrosis factor (TNF-alpha) production by isolated peritoneal macrophages from rats with cerulein-induced pancreatitis increased following lipopolysaccharide stimulation, compared to control rats (P < 0.01). R44S-PSTI administration significantly decreased the TNF-alpha production by peritoneal macrophages from rats with cerulein-induced pancreatitis (P < 0.05). In addition, R44S-PSTI significantly reduced serum amylase activity (P < 0.01) and pancreatic wet weight after pancreatitis induction (P < 0.05). Histological examination revealed marked acinar cell vacuolization, interstitial oedema, and cellular infiltration in cerulein-induced pancreatitis, but a lesser degree of histological change in rats that were treated with R44S-PSTI. Prophylactic use of intravenous R44S-PSTI infusion may reduce the severity of acute pancreatitis either histologically or serologically.
Chen
Y Z
YZ
Department of Surgery II, Kumamoto University Medical School, Japan.
Ikei
S
S
Yamaguchi
Y
Y
Sameshima
H
H
Sugita
H
H
Moriyasu
M
M
Ogawa
M
M
D000681:Amylases / Q000097:blood; D000818:Animals; D002108:Ceruletide / Q000633:toxicity; D006801:Humans; D007262:Infusions, Intravenous; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016297:Mutagenesis, Site-Directed; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D014361:Trypsin Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014361:Trypsin Inhibitors; D014409:Tumor Necrosis Factor-alpha; D002108:Ceruletide; D000681:Amylases