State Key Laboratory of Infectious Disease Diagnosis and Treatment, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
Mol Med Rep. 2013 Sep;8(3):757-62. doi: 10.3892/mmr.2013.1575. Epub 2013 Jul 8.
Activation of hepatic macrophages and systemic immunoparesis are prominent features of acute liver failure (ALF). However, the specific mechanism linking macrophage-associated inflammation and immunoparesis remains to be elucidated. The present study investigated the functional status and fate of hepatic macrophages, as well as their association with immunoparesis in ALF. Intravenous injection of concanavalin A (con A) was administered to develop a mouse model of ALF. Flow cytometry was performed to determine toll-like receptor 4 (TLR4) expression and the apoptotic rates of isolated hepatic macrophages in mice exposed to con A. The levels of TNF-α, IL-6 and IL-12p40 in serum and cell cultures were determined with enzyme-linked immunosorbent assay. TLR4 peak expression in hepatic macrophages was observed at ~0.5 h following exposure to con A and rapidly decreased at 1-3 h. The apoptotic rates of hepatic macrophages increased significantly with the exposure time of con A. The dysfunctional hepatic macrophages associated with apoptosis were observed earlier than the biochemical and histopathological changes of ALF. In addition, the production of macrophage-related inflammatory cytokines following exposure to con A in vivo or in vitro increased significantly. These observations indicated that the deactivation and apoptosis of hepatic macrophages may be a potential link between inflammation and immunoparesis in ALF.
肝巨噬细胞的激活和全身免疫功能低下是急性肝衰竭（ALF）的突出特征。然而，将巨噬细胞相关炎症与免疫功能低下联系起来的具体机制仍有待阐明。本研究探讨了 ALF 中肝巨噬细胞的功能状态和命运及其与免疫功能低下的关系。尾静脉注射刀豆蛋白 A(con A)建立 ALF 小鼠模型。采用流式细胞术检测 TLR4 表达和 Con A 作用后分离的肝巨噬细胞的凋亡率。采用酶联免疫吸附试验检测血清和细胞培养上清液中 TNF-α、IL-6 和 IL-12p40 的水平。TLR4 在肝巨噬细胞中的表达峰值在接触 Con A 后约 0.5 h 出现，并在 1-3 h 内迅速下降。随着 Con A 作用时间的延长，肝巨噬细胞的凋亡率显著增加。与 ALF 的生化和组织病理学变化相比，凋亡相关的功能失调肝巨噬细胞出现得更早。此外，体内或体外接触 Con A 后，巨噬细胞相关炎症细胞因子的产生显著增加。这些观察结果表明，肝巨噬细胞的失活和凋亡可能是 ALF 中炎症和免疫功能低下之间的潜在联系。
