<Original Articles>A New Experimental Model for Gallstone Pancreatitis : Short-Termed Pancreatico-Biliary Duct Obstruction and Exocrine Stimulation with Systemic Hypotension in Rats

Abstract

The effects of short-termed (2 hours) obstruction of pancreatico-biliary duct (PBDO) and exocrine stimulation (IDH) by caerulein infusion (0.2 μg/kg.hr) with systemic hypotension (SH) (30% reduction of mean arterial pressure for 30 min) on the exocrine pancreas were evaluated in the rat. PBDO and IDH with SH caused more significant rises in portal serum amylase, cathepsin B and malate dehydrogenase levels, and pancreatic water content as well as more significant redistribution of cathepsin B activity from the lysosomal fraction to the zymogen fraction in the subcellular fractionations than only PBDO, or PBDO with IDH, or PBDO with SH group. In addition, more accelerated lysosomal and mitochondrial fragility were observed in the PBDO and IDH with SH group. Moreover, PBDO and IDH with SH caused an activation of larger amount of trypsinogen in the pancreas compared with other groups (PBDO with IDH and PBDO with SH group). These results indicate that present model of short-termed PBDO and exocrine stimulation with systemic hypotension seems to be a pertinent model for gallstone pancreatitis in humans, and that redistribution of lysosomal enzymes and subcellular organellar fragility seem to play an important role in the pathogenesis of pancreatic injuries by PBDO, particularly with exocrine stimulation and pancreatic ischaemia, probably via activation of trypsinogen to trypsin by lysosomal enzyme such as cathepsin B.

ラットにおいて2週間の総膵胆管閉塞下, セルレイン投与(0. 2 μg/kg.hr)による外分泌刺激および脱血による低血圧(平均動脈圧を30% 低下)の膵外分泌におよぼす影響を検討した. このモデルにおいては, 門脈血清アミラーゼ, カテプシン B および林檎酸脱水素酵素レベルが単に総膵胆管閉塞や閉塞＋外分泌刺激や閉塞十低血圧群に比べ有意に上昇するのみならず, ライソゾーム酵素のチモーゲン分画への再分布, ライソゾームとミトコンドリア脆弱性の亢進が観察された. これらの結果は, 今回のこのモデルがヒトにおける胆石性膵炎の実験モデルとして有用であるのみならず, 胆石性膵炎の病態生理におけるライソゾーム酵素の再分布と細胞内小器官の脆弱性の亢進の重要な役割が示唆された.