Rabbani Zahid N, Salahuddin Fawzia K, Yarmolenko Pavel, Batinic-Haberle Ines, Thrasher Bradley A, Gauter-Fleckenstein Benjamin, Dewhirst Mark W, Anscher Mitchell S, Vujaskovic Zeljko
Department of Radiation Oncology, Durham Regional Hospital/Duke University Medical Center, Durham, NC 27710, USA.
Free Radic Res. 2007 Nov;41(11):1273-82. doi: 10.1080/10715760701689550.
The objective of this study was to determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL10150, reduces the severity of long-term lung injury induced by fractionated radiation (RT). Fisher 344 rats were randomized into five groups: RT+AEOL10150 (2.5 mg/kg BID), AEOL10150 (2.5 mg/kg BID) alone, RT+ AEOL10150 (5 mg/kg BID), AEOL10150 (5 mg/kg BID) alone and RT alone. Animals received five 8 Gy fractions of RT to the right hemithorax. AEOL10150 was administered 15 min before RT and 8 h later during the period of RT treatment (5 days), followed by subcutaneous injections for 30 days, twice daily. Lung histology at 26 weeks revealed a significant decrease in lung structural damage and collagen deposition in RT+AEOL10150 (5 mg/kg BID) group, in comparison to RT alone. Immunohistochemistry studies revealed a significant reduction in tissue hypoxia (HIF1alpha, CAIX), angiogenic response (VEGF, CD-31), inflammation (ED-1), oxidative stress (8-OHdG, 3-nitrotyrosine) and fibrosis pathway (TGFbeta1, Smad3, p-Smad2/3), in animals receiving RT+ AEOL10150 (5 mg/kg BID). Administration of AEOL10150 at 5 mg/kg BID during and after RT results in a significant protective effect from long-term RT-induced lung injury. Low dose (2.5 mg/kg BID) delivery of AEOL10150 has no beneficial radioprotective effects.
本研究的目的是确定给予催化抗氧化剂四（N，N'-二乙基咪唑-2-基）卟啉锰（III）（AEOL10150）是否能减轻分次放疗（RT）所致长期肺损伤的严重程度。将Fisher 344大鼠随机分为五组：RT+AEOL10150（2.5mg/kg，每日两次）组、单独使用AEOL10150（2.5mg/kg，每日两次）组、RT+AEOL10150（5mg/kg，每日两次）组、单独使用AEOL10150（5mg/kg，每日两次）组和单独放疗组。动物接受对右侧半胸的五次8Gy分次放疗。在放疗前15分钟及放疗期间（5天）放疗后8小时给予AEOL10150，随后皮下注射30天，每日两次。26周时的肺组织学检查显示，与单独放疗组相比，RT+AEOL10150（5mg/kg，每日两次）组的肺结构损伤和胶原沉积显著减少。免疫组织化学研究显示，接受RT+AEOL10150（5mg/kg，每日两次）的动物，其组织缺氧（HIF1α、CAIX）、血管生成反应（VEGF、CD-31）、炎症（ED-1）、氧化应激（8-羟基脱氧鸟苷、3-硝基酪氨酸）和纤维化途径（TGFβ1、Smad3、p-Smad2/3）显著降低。放疗期间及放疗后给予5mg/kg每日两次的AEOL10150可对长期放疗所致肺损伤产生显著保护作用。低剂量（2.5mg/kg，每日两次）给予AEOL10150无有益的放射保护作用。
