Stalin Attenuates Experimental Anti-Glomerular Basement Membrane Glomerulonephritis Together with the Augmentation of Alternatively Activated Macrophages
Stalin Attenuates Experimental Anti-Glomerular Basement Membrane Glomerulonephritis Together with the Augmentation of Alternatively Activated Macrophages
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DOI：
10.2353/ajpath.2010.090608
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发表时间：
2010-09-01
影响因子：
6
通讯作者：
Fukuda, Yuh
中科院分区：
文献类型：
--
作者：
Fujita, Emiko;Shimizu, Akira;Fukuda, Yuh
巨噬细胞是异质性的，包括经典活化的M1和交替活化的M2巨噬细胞，其特征分别是促炎和抗炎功能。表达血红素加氧酶-1的巨噬细胞。还表现出抗炎作用。我们评估了他汀类药物在实验性抗肾小球基底膜肾炎和体外的抗炎作用，重点是巨噬细胞的异质性。诱导大鼠抗肾小球基底膜肾小球肾炎，并给予阿托伐他汀（20 mg/kg/天）或溶剂（对照）。对照组大鼠在第3天肾小球中出现巨噬细胞浸润，第7天出现新月体肾小球肾炎，M1巨噬细胞相关细胞因子、干扰素-γ、肿瘤坏死因子-α和白细胞介素-12的mRNA水平升高。相反，染色降低蛋白尿水平，减少肾小球中巨噬细胞的浸润，抑制单核细胞趋化蛋白-1的表达，并抑制坏死和新月体病变的形成。随着M1巨噬细胞相关细胞因子的下调，肾小球ED 3阳性巨噬细胞的数量减少。此外，他汀类增强ED 2阳性M2巨噬细胞与M2巨噬细胞相关的趋化因子和细胞因子，趋化因子（C-C基序）配体-17和白细胞介素-10的上调。他汀类药物也增加肾小球白细胞介素-10表达血红素氧合酶-1阳性巨噬细胞。他汀类药物抑制巨噬细胞的发展，并抑制ED 3阳性的巨噬细胞，但增加ED 2阳性的巨噬细胞在M2相关的细胞因子的环境中在体外。我们的结论是，他汀类药物在肾小球肾炎的抗炎作用是通过抑制巨噬细胞浸润以及增强抗炎巨噬细胞介导的。(Am J Pathol 2010，177：1143-1154; DOI：10.2353/ajpath.2010.090608）
Macrophages are heterogeneous and include classically activated M1 and alternatively activated M2 macrophages, characterized by pro- and anti-inflammatory functions, respectively. Macrophages that express heme oxygenase-1. also exhibit anti-inflammatory effects. We assessed the anti-inflammatory effects of statin in experimental anti-glomerular basement membrane glomerulonephritis and in vitro, focusing on the macrophage heterogeneity. Rats were induced anti-glomerular basement membrane glomerulonephritis and treated with atorvastatin (20 mg/kg/day) or vehicle (control). Control rats showed infiltration of macrophages in the glomeruli at day 3 and developed crescentic glomerulonephritis by day 7, together with increased mRNA levels of the M1 macrophage-associated cytokines, interferon-gamma, tumor necrosis factor-a, and interleukin-12. In contrast, stain reduced the level of proteinuria, reduced infiltration of macrophages in glomeruli with suppression of monocyte chemotactic protein-1 expression, and inhibited the formation of necrotizing and crescentic lesions. The number of glomerular ED3-positive macrophages decreased with down-regulation of M1 macrophage-associated cytokines. Furthermore, statin augmented ED2-positive M2 macrophages with up-regulation of the M2 macrophage-associated chemokines and cytokines, chemokine (C-C motif) ligand-17 and interleukin-10. Statin also increased the glomerular interleukin-10-expressing heme oxygenase-1-positive macrophages. Statin inhibited macrophage development, and suppressed ED3-positive macrophages, but augmented ED2-positive macrophages in M2-associated cytokine environment in vitro. We conclude that the anti-inflammatory effects of statin in glomerulonephritis are mediated through inhibition of macrophage infiltration as well as augmentation of anti-inflammatory macrophages. (Am J Pathol 2010, 177:1143-1154; DOI: 10.2353/ajpath.2010.090608)