Wakabayashi Yasuo, Shimizu Hiroaki, Kimura Fumio, Yoshidome Hiroyuki, Ohtsuka Masayuki, Kato Atsushi, Miyazaki Masaru
Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
Hepatogastroenterology. 2008 Jul-Aug;55(85):1179-83.
BACKGROUND/AIMS: Polymorphonuclear neutrophil (PMN) infiltration represents a potential source of liver injury, but the precise mechanisms of PMN infiltration in cholestatic liver are not fully understood.
This study investigated hepatic expression of cytokine-induced neutrophil chemoattractant (CINC) 14 days after bile duct ligation, as well as the number of infiltrated PMNs in livers. Portal venous endotoxin levels were also evaluated. Furthermore, in vitro CINC production by isolated liver cells from obstructive jaundice (OJ) liver or sham-treated liver was evaluated after stimulation with tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta) or LPS.
The number of infiltrated PMNs in sinusoids significantly increased in OJ liver, as compared to sham-treated liver. CINC mRNA expression was also increased in OJ liver. Immunohistochemical study revealed that the majority of the CINC-positive cells were hepatocytes. In vitro study proved that CINC production by isolated hepatocytes was markedly enhanced by IL-1beta stimulation in OJ liver. Furthermore, IL-1beta production by LPS-stimulated Kupffer cells isolated from OJ liver was significantly increased, compared to those from sham-treated liver. Portal venous endotoxin was detectable only in OJ rats.
Excessive production of IL-1beta by activated Kupffer cells, as a result of portal endotoxemia, may play an important role for increased CINC release from hepatocytes in cholestatic liver, leading to PMN infiltration.
背景/目的：多形核中性粒细胞（PMN）浸润是肝损伤的一个潜在来源，但胆汁淤积性肝病中PMN浸润的确切机制尚未完全明确。
本研究调查了胆管结扎14天后肝脏中细胞因子诱导的中性粒细胞趋化因子（CINC）的表达情况以及肝脏中浸润的PMN数量。还评估了门静脉内毒素水平。此外，在用肿瘤坏死因子-α（TNFα）、白细胞介素-1β（IL-1β）或脂多糖（LPS）刺激后，评估了阻塞性黄疸（OJ）肝脏或假手术处理肝脏分离出的肝细胞的体外CINC产生情况。
与假手术处理的肝脏相比，OJ肝脏中肝血窦内浸润的PMN数量显著增加。OJ肝脏中CINC mRNA表达也增加。免疫组织化学研究显示，大多数CINC阳性细胞是肝细胞。体外研究证明，OJ肝脏中分离出的肝细胞经IL-1β刺激后CINC产生明显增强。此外，与假手术处理肝脏分离出的细胞相比，OJ肝脏分离出的LPS刺激的库普弗细胞产生的IL-1β显著增加。仅在OJ大鼠中检测到门静脉内毒素。
门静脉内毒素血症导致活化的库普弗细胞过度产生IL-1β，这可能在胆汁淤积性肝病中肝细胞CINC释放增加从而导致PMN浸润方面发挥重要作用。
