Toblli Jorge E, Cao Gabriel, Giani Jorge F, Dominici Fernando P, Angerosa Margarita
Laboratory of Experimental Medicine, Hospital Alemán, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
Department of Biochemistry, School of Pharmacy, Institute of Chemistry and Biophysics-Biochemistry (UBA-CONICET), Buenos Aires, Argentina.
Drug Des Devel Ther. 2017 Aug 1;11:2251-2263. doi: 10.2147/DDDT.S132612. eCollection 2017.
Iron deficiency anemia is a frequent complication in clinical conditions such as chronic kidney disease, chronic heart failure, inflammatory bowel disease, cancer, and excessive blood loss. Given the ability of iron to catalyze redox reactions, iron therapy can be associated with oxidative stress. The lung is uniquely susceptible to oxidative stress, and little is known about the effects of intravenous iron treatment in this organ. This study characterized changes in markers of oxidative/nitrosative stress and inflammation in the lung of non-iron deficient, non-anemic rats treated with five weekly doses (40 mg iron per kg body weight) of low molecular weight iron dextran (LMWID), iron sucrose (IS), ferric carboxymaltose (FCM), ferumoxytol (FMX), iron isomaltoside 1000 (IIM), or saline (control). Rats treated with LMWID, FMX, or IIM showed significant changes in most measures of oxidative/nitrosative stress, inflammation, and iron deposition compared to the saline-treated controls, with greatest changes in the LMWID treatment group. Increases in products of lipid peroxidation (thiobarbituric acid reactive substances) and protein nitrosation (nitrotyrosine) were consistent with increases in the activity of antioxidant enzymes (catalase, Cu,Zn-SOD, GPx), decreases in antioxidative capacity (reduced:oxidized GSH ratio), increased levels of transcription factors involved in the inflammatory pathway (NF-κB, HIF-1α), inflammatory cytokines (TNF-α, IL-6), adhesion molecules (VCAM-1), markers of macrophage infiltration (ED-1), and iron deposition (Prussian blue, ferritin). Since changes in measured parameters in FCM- or IS-treated rats were generally modest, the results suggest that FCM and IS have a low propensity to induce lung inflammation. The relevance of these findings to clinical safety profiles of the tested intravenous iron products requires further investigation.
缺铁性贫血是慢性肾病、慢性心力衰竭、炎症性肠病、癌症和失血过多等临床病症中常见的并发症。鉴于铁具有催化氧化还原反应的能力，铁疗法可能与氧化应激相关。肺对氧化应激尤为敏感，而关于静脉铁剂治疗对该器官的影响却知之甚少。本研究对非缺铁、非贫血大鼠进行了特征分析，这些大鼠每周接受五次低分子量右旋糖酐铁（LMWID）、蔗糖铁（IS）、羧麦芽糖铁（FCM）、 ferumoxytol（FMX）、异麦芽糖酐铁1000（IIM）或生理盐水（对照）治疗（每千克体重40毫克铁），以观察氧化/亚硝化应激和炎症标志物的变化。与生理盐水处理的对照组相比，接受LMWID、FMX或IIM治疗的大鼠在氧化/亚硝化应激、炎症和铁沉积的大多数指标上均有显著变化，其中LMWID治疗组变化最大。脂质过氧化产物（硫代巴比妥酸反应性物质）和蛋白质亚硝化（硝基酪氨酸）的增加与抗氧化酶（过氧化氢酶、铜锌超氧化物歧化酶、谷胱甘肽过氧化物酶）活性的增加、抗氧化能力的降低（还原型谷胱甘肽与氧化型谷胱甘肽的比率）、炎症途径中涉及的转录因子（核因子κB、缺氧诱导因子-1α）、炎症细胞因子（肿瘤坏死因子-α、白细胞介素-6）、黏附分子（血管细胞黏附分子-1）、巨噬细胞浸润标志物（ED-1）和铁沉积（普鲁士蓝、铁蛋白）水平的升高一致。由于FCM或IS治疗的大鼠所测参数的变化通常较小，结果表明FCM和IS诱发肺部炎症的倾向较低。这些发现与所测试的静脉铁剂产品临床安全性的相关性需要进一步研究。
