Macrophages Expressing Heme Oxygenase-1 Improve Renal Function in Ischemia/Reperfusion Injury
Macrophages Expressing Heme Oxygenase-1 Improve Renal Function in Ischemia/Reperfusion Injury
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DOI：
10.1038/mt.2010.100
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发表时间：
2010-09-01
影响因子：
12.4
通讯作者：
Kluth, David C.
中科院分区：
文献类型：
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作者：
Ferenbach, David A.;Ramdas, Vasudev;Kluth, David C.
急性肾损伤病死率高，缺乏特异的治疗方法，缺血再灌注损伤(IRI)是其主要原因。巨噬细胞(M Phi)已成功地用于炎症性肾病模型的细胞治疗，以传递靶向治疗基因。血红素加氧酶-1(HO-1)催化血红素分解，具有重要的细胞保护功能。我们假设，给予MPhi修饰过表达HO-1可以保护肾脏免受IRI。使用腺病毒载体(Ad-HO-1)，HO-1在原代骨髓来源的M Phi(BMDM)中高表达。在体外，Ad-HO-1 M-Phi显示出抗炎表型，内毒素/干扰素-1诱导的巨噬细胞(ACS)吞噬功能增强，白细胞介素10(IL-10)升高，而肿瘤坏死因子-α和一氧化氮(NO)水平降低。(干扰素-γ)刺激与转导或未修饰的对照M-Phi进行比较。在体内，与未损伤的对照组相比，静脉注射M Phi优先于IRI后的肾脏。在伤后24小时，尽管各组之间肾小管坏死、细胞凋亡和毛细血管密度水平相同，但注射Ad-HO-1M Phi可使肾功能得到保护(血肌酐下降46%)，并减少微血管血小板沉积。这些数据表明，转基因MF改善了在结构性损伤建立后给予IRI的结果，增加了靶向细胞治疗以支持急性损伤肾脏的功能的前景。
Acute kidney injury has a high mortality and lacks specific therapies, with ischemia/reperfusion injury (IRI) being the predominant cause. Macrophages (M Phi) have been used successfully in cell therapy to deliver targeted therapeutic genes in models of inflammatory kidney disease. Heme oxygenase-1 (HO-1) catalyzes heme breakdown and has important cytoprotective functions. We hypothesized that administration of M Phi modified to overexpress HO-1 would protect from renal IRI. Using an adenoviral construct (Ad-HO-1), HO-1 was overexpressed in primary bone marrow-derived M Phi (BMDM). In vitro Ad-HO-1 M Phi showed an anti-inflammatory phenotype with increased phagocytosis of apoptotic cells (ACs) and increased interleukin (IL)-10 but reduced TNF-alpha and nitric oxide (NO) following lipopolysaccharide/interferon-. (IFN gamma) stimulation compared to control transduced or unmodified M Phi. In vivo, intravenously (IV) injected M Phi homed preferentially to the post-IRI kidney compared to uninjured control following experimental IRI. At 24 hours postinjury, despite equivalent levels of tubular necrosis, apoptosis, and capillary density between groups, the injection of Ad-HO-1 M Phi resulted in preserved renal function (serum creatinine reduced by 46%), and reduced microvascular platelet deposition. These data demonstrate that genetically modified MF improve the outcomes in IRI when administered after the establishment of structural injury, raising the prospect of targeted cell therapy to support the function of the acutely injured kidney.