Effect of iron chelators on methemoglobin and thrombin preconditioning.
Effect of iron chelators on methemoglobin and thrombin preconditioning.
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DOI：
10.1007/s12975-012-0195-4
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发表时间：
2012-12
影响因子：
6.9
通讯作者：
Regan, Raymond F.
中科院分区：
文献类型：
--
作者：
Chen-Roetling, Jing;Sinanan, Jesse;Regan, Raymond F.
紧邻脑出血的细胞损失可能部分是由细胞外血红蛋白 (Hb) 和凝血酶的毒性介导的。然而，在低浓度下，这些蛋白质会诱导对血红素和铁的耐受，随着红细胞裂解的进行，可能会限制血肿周围的进一步损伤。介导这些预处理作用的机制尚未完全确定，但血红素加氧酶 (HO)-1 和铁结合蛋白表达的增加可能有所贡献。在本研究中，我们假设铁螯合剂疗法会减弱这种保护反应。用 3 μM 高铁血红蛋白 (metHb) 或 5 单位/ml 凝血酶预处理皮质神经胶质培养物 (> 90 % GFAP+) 24 小时本身是无毒的，并且会增加 HO-1 和铁蛋白的表达。当受到有毒浓度的血红素挑战时，在预处理的培养物中细胞氧化还原活性铁的增加减弱，细胞存活率增加。然而，如果用metHb或凝血酶加去铁胺或2,2'-联吡啶对培养物进行预处理，铁蛋白诱导就会被阻止，并且细胞氧化还原活性铁会随着氯高铁血红素处理而增加。去铁胺持续降低预处理介导的细胞保护作用，而 2,2'-联吡啶则具有不同的作用。两种螯合剂均不会改变 HO-1 表达。当螯合剂治疗仅限于 24 小时预处理间隔中的 11 小时时，细胞保护反应得以保留。这些结果表明脑出血后连续铁螯合剂治疗可能产生有害影响。间歇治疗可以去除血肿周围的铁，而不会抵消暴露于低浓度血红蛋白或凝血酶的益处。
Cell loss immediately adjacent to an intracerebral hemorrhage may be mediated in part by the toxicities of extracellular hemoglobin (Hb) and thrombin. However, at low concentrations, these proteins induce tolerance to hemin and iron that may limit further peri-hematomal injury as erythrocyte lysis progresses. The mechanisms mediating these preconditioning effects have not been completely defined, but increased expression of both heme oxygenase (HO)-1 and iron binding proteins likely contributes. In the present study, we hypothesized that iron chelator therapy would attenuate this protective response. Pretreatment of cortical glial cultures (> 90 % GFAP+) with 3 μM methemoglobin (metHb) or 5 units/ml thrombin for 24 h was nontoxic per se, and increased HO-1 and ferritin expression. When challenged with a toxic concentration of hemin, the increase in cellular redox-active iron was attenuated in preconditioned cultures and cell survival was increased. However, if cultures were pretreated with metHb or thrombin plus deferoxamine or 2,2′-bipyridyl, ferritin induction was prevented and cellular redox-active iron increased with hemin treatment. Preconditioning-mediated cytoprotection was consistently reduced by deferoxamine, while 2,2′-bipyridyl had a variable effect. Neither chelator altered HO-1 expression. A cytoprotective response was preserved when chelator therapy was limited to 11 hours of the 24 h preconditioning interval. These results suggest a potentially deleterious effect of continuous iron chelator therapy after ICH. Intermittent therapy may remove peri-hematomal iron without negating the benefits of exposure to low concentrations of Hb or thrombin.
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