Sheen-Chen Shyr-Ming, Hung Kuo-Sheng, Ho Hsin-Tsung, Chen Wei-Jen, Eng Hock-Liew
Department of Surgery, Chang Gung Memorial Hospital, Kaohsiung, 123 Ta-Pai Road, Niao-Sung Hsiang, Kaohsiung Hsien, Taiwan.
World J Surg. 2004 May;28(5):457-60. doi: 10.1007/s00268-004-7189-7. Epub 2004 Apr 19.
Apoptosis is an important process in a wide variety of biologic systems. Cholestasis, or impaired bile formation, occurs in a wide variety of human liver diseases. Retention and accumulation of toxic hydrophobic bile salts in hepatocytes may cause hepatocyte toxicity by inducing apoptosis. In addition, the translocation of bacteria and endotoxin, well documented in patients with obstructive jaundice, contribute to the induction of hepatocyte apoptosis. We hypothesized that oral bile acid replacement, glutamine administration, or both can attenuate or abolish hepatocyte apoptosis. Male Sprague-Dawley rats weighing 250 to 300 g were randomized to four groups (10 in each group). Group 1 underwent a sham operation and was simultaneously treated with normal saline. Group 2 underwent common bile duct (CBD) ligation and was simultaneously treated with normal saline. Group 3 underwent CBD ligation and was simultaneously treated with oral glutamine. Group 4 underwent CBD ligation and was simultaneously treated with oral bile acid replacement. After 3 days (n = 5) and 7 days (n = 5), liver tissues were harvested for histopathologic analysis and apoptosis measurements. When compared with the sham operation group, significantly increased hepatocyte apoptosis and ductular proliferation occurred after CBD ligation for either 3 or 7 days. After administration of either glutamine or bile acid, the increased hepatocyte apoptosis and ductular proliferation after CBD ligation for 3 days were significantly diminished. However, both failed to diminish the changes after CBD ligation for 7 days. Significantly increased hepatocyte apoptosis and ductular proliferation occurred after CBD ligation. The administration of either glutamine or bile acid effectively diminished the hepatocyte apoptosis and ductular proliferation after CBD ligation for 3 days, whereas both failed to show the same effect after CBD ligation for 7 days.
细胞凋亡是多种生物系统中的一个重要过程。胆汁淤积，即胆汁形成受损，发生在多种人类肝脏疾病中。有毒疏水性胆汁盐在肝细胞中的潴留和积累可能通过诱导细胞凋亡而导致肝细胞毒性。此外，在梗阻性黄疸患者中已得到充分证实的细菌和内毒素易位，也有助于诱导肝细胞凋亡。我们推测口服胆汁酸替代物、给予谷氨酰胺或两者联合使用可减轻或消除肝细胞凋亡。将体重250至300克的雄性Sprague-Dawley大鼠随机分为四组（每组10只）。第1组接受假手术，并同时用生理盐水治疗。第2组接受胆总管（CBD）结扎，并同时用生理盐水治疗。第3组接受CBD结扎，并同时口服谷氨酰胺治疗。第4组接受CBD结扎，并同时口服胆汁酸替代物治疗。3天（n = 5）和7天（n = 5）后，采集肝脏组织进行组织病理学分析和细胞凋亡检测。与假手术组相比，CBD结扎3天或7天后肝细胞凋亡和小胆管增生显著增加。给予谷氨酰胺或胆汁酸后，CBD结扎3天后增加的肝细胞凋亡和小胆管增生显著减少。然而，两者均未能减轻CBD结扎7天后的变化。CBD结扎后肝细胞凋亡和小胆管增生显著增加。给予谷氨酰胺或胆汁酸均可有效减轻CBD结扎3天后的肝细胞凋亡和小胆管增生，而两者在CBD结扎7天后均未显示相同效果。
