The Protective Effects of Long-Acting Recombinant Human Pancreatic Secretory Trypsin Inhibitor (R44S-PSTI) in a Rat Model of Cerulein-Induced Pancreatitis

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Abstract
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 μg/kg at 1 h intervals). Continuous intravenous infusion of R44S-PSTI began at a dose of 20 μg/kg/h 30 min before the first cerulein injection, and was completed 3 h after the last cerulein injection. Tumour necrosis factor (TNF-α) production by isolated peritoneal macrophages from rats with cerulein-induced pancreatitis increased following lipopolysac-charide stimulation, compared to control rats ( P < 0.01). R44S-PSTI administration significantly decreased the TNF-α 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.