Ding Hong, Peng Renxiu, Reed Eddie, Li Qingdi Q
Wuhan University College of Pharmacy, Wuhan, Hubei 430071, P.R. China.
Int J Mol Med. 2003 Oct;12(4):549-57.
Kupffer cells are the tissue macrophages in the liver and play an important role in the defense mechanisms of the body. However, their role in liver function and hepatocellular activity remains unclear. This study was therefore undertaken to investigate the effect of gadolinium chloride-induced Kupffer cell dysfunction on liver function and hepatocellular signaling activity in mice and to establish an animal model for studying the role of Kupffer cells in vivo. Kunming mice were intraperitoneally injected with different doses of gadolinium chloride (GdCl3), a selective inhibitor of Kupffer cells, and the mice were sacrificed at different time periods following the drug administration. Hepatotoxicity and Kupffer cell function, as well as the levels of signaling molecules and inflammatory mediators in liver tissue, were measured. We demonstrated that the administration of 10-20 mg/kg GdCl3 caused apoptosis of Kupffer cells and blocked the Kupffer cell effector function, as shown by a decrease in CD68 expression and phagocytic activity. In addition, the NO, PGE2 and cAMP levels in the liver were also reduced significantly. Furthermore, 20 mg/kg GdCl3 decreased the levels of cNOS, PKC and NF-kappaB p65 expression by 26.6, 68 and 64%, respectively. In contrast, hepatotoxicity was not observed when the same doses of GdCl3 were used. Moreover, we found that Kupffer cell function and the NO, PGE2 and cAMP contents, as well as PKC and NF-kappaB p65 levels in the liver were only partially, but not fully recovered in up to six days following 20 mg/kg GdCl3 injection. However, the administration of higher doses of GdCl3 (40 mg/kg) caused both hepatotoxicity and Kupffer cell necrosis, as well as an increased release of TNF, NO, and PGE2 in the liver. These results indicate that administration of suitable doses of GdCl3 blocked the effector function of Kupffer cells selectively, but did not cause liver parenchymal cell toxicity, and provide a frame-work for the establishment of an animal model for studying the role of Kupffer cells in signaling in the liver. Lastly, the present study also provides evidence that shows there is a positive association between the expression of cAMP, PKC, or NF-kappaB and the levels of NO, PGE2 and TNF in the liver of Kupffer-cell-blocked mice, and suggests that Kupffer cells may play a part in mediating liver function and hepatocellular activity.
库普弗细胞是肝脏中的组织巨噬细胞，在机体防御机制中发挥重要作用。然而，它们在肝功能和肝细胞活性中的作用仍不清楚。因此，本研究旨在探讨氯化钆诱导的库普弗细胞功能障碍对小鼠肝功能和肝细胞信号活性的影响，并建立一种用于研究库普弗细胞在体内作用的动物模型。将不同剂量的氯化钆（GdCl3），一种库普弗细胞的选择性抑制剂，腹腔注射到昆明小鼠体内，并在给药后的不同时间段处死小鼠。检测肝毒性、库普弗细胞功能以及肝组织中信号分子和炎症介质的水平。我们证明，给予10 - 20mg/kg GdCl3会导致库普弗细胞凋亡并阻断库普弗细胞效应功能，如CD68表达和吞噬活性降低所示。此外，肝脏中的NO、PGE2和cAMP水平也显著降低。此外，20mg/kg GdCl3使cNOS、PKC和NF-κB p65表达水平分别降低26.6%、68%和64%。相比之下，使用相同剂量的GdCl3时未观察到肝毒性。此外，我们发现，在注射20mg/kg GdCl3后的长达六天内，库普弗细胞功能以及肝脏中的NO、PGE2和cAMP含量以及PKC和NF-κB p65水平仅部分恢复，但未完全恢复。然而，给予更高剂量的GdCl3（40mg/kg）会导致肝毒性和库普弗细胞坏死，以及肝脏中TNF、NO和PGE2释放增加。这些结果表明，给予合适剂量的GdCl3可选择性地阻断库普弗细胞的效应功能，但不会引起肝实质细胞毒性，并为建立用于研究库普弗细胞在肝脏信号传导中作用的动物模型提供了框架。最后，本研究还提供了证据表明，在库普弗细胞阻断的小鼠肝脏中，cAMP、PKC或NF-κB的表达与NO、PGE2和TNF的水平之间存在正相关，并表明库普弗细胞可能参与介导肝功能和肝细胞活性。
