Reduction of activated macrophages after ischaemiareperfusion injury diminishes oxidative stress and ameliorates renal damage
Reduction of activated macrophages after ischaemiareperfusion injury diminishes oxidative stress and ameliorates renal damage
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DOI：
10.1093/ndt/gfr792
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发表时间：
2012-08-01
影响因子：
6.1
通讯作者：
Tolba, Rene H.
中科院分区：
文献类型：
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作者：
Fet, Ngwi G.;Fiebeler, Anette;Tolba, Rene H.
巨噬细胞是局部炎症反应综合征（LIRS）的主要效应物，影响缺血/再灌注损伤的程度，从而影响器官功能。存在几个巨噬细胞亚群，代表不同的作用模式。表达Fc γ受体（FcR）1的亚群在巨噬细胞活化状态中的具体作用尚不清楚，我们通过单侧肾切除大鼠（人FcR 1转基因）30分钟的缺血诱导了LIRS。再灌注6 h后，治疗组注射针对人FcR 1的重组免疫毒素（IT）H22（scFv）-ETA，诱导靶细胞凋亡。安慰剂组给予生理盐水（NS）。双侧肾脏作为健康对照（Ctr）。再灌注24小时后，对动物进行分析，IT靶向治疗可保护肾功能[NS vs IT治疗和基线（肌酐：69.2 ± 2.6、54.7 ± 3.4和27.3 ± 1.0 mol/L; P 0.001）]。所有浸润单核细胞的数量显著减少（每个视野的CD 68阳性细胞：NS 3.8 0.4，IT 2.5 0.2和Ctr 1.2 0.4; P 0.05），肾组织学改善，肾纤维连接蛋白表达减少（NS 4.0 0.4，IT 2.3 0.2和Ctr 1.1 0.1; P 0.001）。IT给药后，我们还观察到每个视野中肾单核细胞趋化蛋白-1阳性细胞的表达减少（NS 19.0 1，IT 10.1 0.8和Ctr 2.0 0.3; P 0.001）以及全身和局部氧化应激降低[血清丙二醛（MDA）：NS 340 30，IT 224 36 vs基线140 5 nmol/mL; P 0.01];肾MDA任意单位荧光强度：NS 3.7 0.2，IT 1.8 0.3和Ctr 0.4 0.2; P 0.001。在缺血触发的LIRS大鼠模型中，FcR 1上调的单核细胞减少导致肾功能和形态保留。我们的研究结果表明，针对活化的巨噬细胞是一种有价值的方法，改善缺血诱导的组织损伤。
Macrophages are major effectors of the local inflammatory response syndrome (LIRS) and influence the extent of ischaemia/reperfusion injury, thereby impacting organ function. Several subgroups of macrophages exist, representing distinct modes of action. The specific role of the subset expressing Fc gamma receptor (FcR) 1 in the activated state of macrophages is poorly defined.We induced a LIRS via 30 min of ischaemia in uninephrectomized rats, transgenic for the human FcR1. Six hours after reperfusion, the treatment group was injected with a recombinant immunotoxin (IT) H22(scFv)-ETA targeted against human FcR1, which induced apoptosis of target cells. The placebo group received normal saline (NS). Contralateral kidneys served as healthy controls (Ctr). After 24 h of reperfusion, the animals were analysed.Targeted treatment with IT resulted in preserved renal function [NS versus IT treatment and baseline (creatinine: 69.2 2.6, 54.7 3.4 and 27.3 1.0 mol/L; P 0.001)]. The number of all infiltrating monocytes were significantly reduced (CD68-positive cells per view field: NS 3.8 0.4, IT 2.5 0.2 and Ctr 1.2 0.4; P 0.05), renal histology improved and there was a reduced expression of renal fibronectin (NS 4.0 0.4, IT 2.3 0.2 and Ctr 1.1 0.1; P 0.001). Following IT administration, we also observed less expression of renal monocyte chemoattractant protein-1-positive cells per view field (NS 19.0 1, IT 10.1 0.8 and Ctr 2.0 0.3; P 0.001) as well as reduced systemic and local oxidative stress [serum malondialdehyde (MDA): NS 340 30, IT 224 36 versus baseline 140 5 nmol/mL; P 0.01]; renal MDA arbitrary units of fluorescence intensity: NS 3.7 0.2, IT 1.8 0.3 and Ctr 0.4 0.2; P 0.001.Reduction of FcR1-up-regulated monocytic cells leads to preserved renal function and morphology in a rat model of ischaemia-triggered LIRS. Our results show that targeting activated macrophages is a valuable approach for ameliorating ischaemia-induced tissue injury.