Role of Kupffer cells on chronic liver injury

背景和目的：库普弗细胞是肝脏的常驻组织巨噬细胞，在肝脏炎症、肝细胞死亡和纤维化的调节中发挥关键作用，这些都是肝脏疾病的特征。然而，库普弗细胞是促进还是保护肝损伤仍存在争议。为了探讨这个问题，我们研究了库普弗细胞在肝损伤、细胞死亡、再生和胆汁淤积性肝损伤纤维化中的作用。方法：建立部分胆管结扎模型。用6-0丝结扎野生型C57BL/6雄性小鼠左肝管，术后10 d处死。比较结扎左叶和未结扎右叶的肝损伤、再生和纤维化情况。给药d -半乳糖胺和tnf -诱导PBDL小鼠肝细胞凋亡。研究了阿仑膦酸脂质体对Kupffer细胞耗竭和表达显性阴性AKT的腺病毒对AKT的抑制作用。结果：在胆汁淤积性肝损伤中，剩余的活细胞表现出对肿瘤坏死因子(TNF)-α-诱导的肝细胞凋亡的耐受和AKT激活的再生特征。AKT的抑制抑制了肝细胞的存活和再生能力。此外，Kupffer细胞缺失增加了结扎叶肝细胞损伤和TNF-α-诱导的肝细胞凋亡的敏感性。Kupffer细胞缺失减少肝细胞再生和肝纤维化，降低AKT激活。结论：库普弗细胞在胆汁淤积性肝病中对肝细胞损伤具有保护作用，促进细胞存活、肝脏再生和纤维化。Kupffer细胞对AKT激活肝细胞至关重要，而AKT激活是肝细胞存活和再生反应所必需的。

Background and Aims : Kupffer cells, resident tissue macrophages of the liver, play a key role in the regulation of hepatic inflammation, hepatocyte death, and fibrosis that characterize liver diseases. However, it is controversial whether Kupffer cell promotes or protects from liver injury. To explore this issue, we examined the role of Kupffer cell in liver injury, cell death, regeneration, and fibrosis on cholestatic liver injury. Methods : A model of partial bile duct ligation (PBDL) was developed. The left hepatic duct of wild-type C57BL/6 male mice was ligated with 6-0 silk, and the animals were sacrificed 10 days after the surgery. Liver injury, regeneration, and fibrosis were compared between the ligated left and non-ligated right lobes. Hepatocyte apoptosis was induced by administration of D-galactosamine and TNF-alpha to the PBDL mice. The effects of Kupffer cell depletion by alendronate liposomes, or inhibition of AKT by adenovirus expressing dominant-negative AKT were investigated. Results : In the cholestatic liver injury, remaining viable cells represented tolerance for tumor necrosis factor (TNF)-α-induced hepatocyte apoptosis and regenerative features along with AKT activation. Inhibition of AKT abolished the survival and regenerative properties in hepatocytes. Moreover, Kupffer cell depletion increased hepatocyte damage and the sensitivity of TNF-α-induced hepatocyte apoptosis in ligated lobes. Kupffer cell depletion decreased hepatocyte regeneration and liver fibrosis with reduced AKT activation. Conclusion: Kupffer cell has a protective role for hepatocyte damage, and promotes cell survival, liver regeneration, and fibrosis in cholestatic liver disease. Kupffer cell is crucial for AKT activation of hepatocytes that is required for the survival and regenerative responses.