Laboratory of Veterinary Pathology, Division of Veterinary Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58, Rinku-ourai-kita, Izumisano city, Osaka 598-8531, Japan.
Laboratory of Veterinary Pathology, Division of Veterinary Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58, Rinku-ourai-kita, Izumisano city, Osaka 598-8531, Japan.
Exp Mol Pathol. 2014 Jun;96(3):382-92. doi: 10.1016/j.yexmp.2014.04.003. Epub 2014 Apr 18.
Resident and exudate macrophages play an important role in the development of liver cirrhosis. Ionized calcium binding adaptor molecule 1(+) (Iba1(+)) and galectin-3(+) (Gal-3(+)) macrophages regulate liver fibrosis probably through pro-inflammatory and pro-fibrotic factors. Macrophages show polarized functions in liver fibrosis; however, M1-/M2-polarization of Iba1(+) and Gal-3(+) macrophages remains obscured. This study investigated the M1-/M2-polarized properties of Iba1(+) and Gal-3(+) macrophages in chemical-induced liver cirrhosis.
Cirrhosis was induced in F344 rats by repeated injections of thioacetamide (100mg/kg BW, twice a week for 25 weeks). Liver samples were collected from post-first-injection (PFI) week 5 to 25. Macrophage immunophenotypes and myofibroblasts in the fibrous bridges (FBs) and pseudolobules (PLs) were analyzed by immunohistochemistry. Expressions of M1- and M2-related factors were analyzed with RT-PCR, separately in FBs and PLs.
Activation of myofibroblasts was most pronounced in livers at week 15. CD68(+) (M1), CD204(+) (M2), Iba1(+) and Gal-3(+) macrophages in the FBs increased gradually and peaked at week 15, consistent with the upregulation of both M1-(MCP-1, IFN-γ, IL-1β, IL-6, and TNF-α) and M2-(TGF-β1, IL-4, and IL-10) related factors. Iba1(+) and Gal-3(+) macrophages showed both M1- and M2-immunophenotypes. CD163(+) macrophages showed a persistent increase, consistent with TGF-β1 upregulation. MHC class II(+) macrophages increased in the developing fibrotic lesions, and then reduced in the advanced stage cirrhosis.
Both M1- and M2-macrophage polarizations occur during development of liver cirrhosis. Iba1(+) and Gal-3(+) macrophages participate in liver cirrhosis through production of both M1- and M2-related factors.
驻留和渗出巨噬细胞在肝硬化的发展中起着重要作用。离子钙结合衔接分子 1（+）（Iba1（+））和半乳糖凝集素-3（+）（Gal-3（+））巨噬细胞可能通过促炎和促纤维化因子调节肝纤维化。巨噬细胞在肝纤维化中表现出极化功能；然而，Iba1（+）和 Gal-3（+）巨噬细胞的 M1-/M2 极化仍然不清楚。本研究探讨了化学诱导性肝硬化中 Iba1（+）和 Gal-3（+）巨噬细胞的 M1-/M2 极化特性。
通过重复注射硫代乙酰胺（100mg/kg BW，每周两次，共 25 周）在 F344 大鼠中诱导肝硬化。从首次注射后第 5 周到第 25 周采集肝组织样本。通过免疫组织化学分析纤维桥（FBs）和假小叶（PLs）中的巨噬细胞免疫表型和肌成纤维细胞。分别在 FBs 和 PLs 中用 RT-PCR 分析 M1-和 M2 相关因子的表达。
在第 15 周时，肌成纤维细胞的激活最为明显。CD68（+）（M1）、CD204（+）（M2）、Iba1（+）和 Gal-3（+）巨噬细胞在 FBs 中逐渐增加，并在第 15 周时达到峰值，与 M1-（MCP-1、IFN-γ、IL-1β、IL-6 和 TNF-α）和 M2-（TGF-β1、IL-4 和 IL-10）相关因子的上调一致。Iba1（+）和 Gal-3（+）巨噬细胞均表现出 M1-和 M2-免疫表型。CD163（+）巨噬细胞持续增加，与 TGF-β1 的上调一致。在纤维化病变的发展过程中，MHC Ⅱ类（+）巨噬细胞增加，然后在肝硬化的晚期减少。
在肝硬化的发展过程中，既发生 M1-极化，也发生 M2-极化。Iba1（+）和 Gal-3（+）巨噬细胞通过产生 M1-和 M2 相关因子参与肝硬化的发生。
