Testosterone-dependent sex differences in red blood cell hemolysis in storage, stress, and disease
Testosterone-dependent sex differences in red blood cell hemolysis in storage, stress, and disease
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DOI：
10.1111/trf.13745
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发表时间：
2016-10-01
期刊：
影响因子：
2.9
通讯作者：
Gladwin, Mark T.
中科院分区：
文献类型：
--
作者：
Kanias, Tamir;Sinchar, Derek;Gladwin, Mark T.
背景：红细胞(RBC)溶血是人类血管疾病的内在机制。血管内溶血释放血红蛋白和其他代谢物，抑制一氧化氮信号转导，推动氧化和炎症应激。虽然这些途径在疾病发病机制中很重要，但包括性别在内的溶血的遗传和种群修饰物尚未建立。研究设计和方法我们使用溶血测量方法研究了来自美国和加拿大的22个近交系小鼠和镰状细胞病(SCD)患者中来自美国和加拿大的RBC单位在储存或应激诱导溶血方面的性别差异，这些患者来自Walk-PHASST队列，其中315名患者具有纯合子SS血红蛋白。结果基于性别的溶血易感性分析表明，在常规冷藏、渗透或氧化应激、小鼠输血后和SCD患者中，男性红细胞比女性更容易发生溶血。这种性别差异是红细胞固有的，不受血浆因素或女性性激素的调节。重要的是，睾丸切除改善了小鼠红细胞的储存稳定性和输血后的恢复，而睾酮补充疗法则加剧了对渗透或氧化应激的溶血反应。结论未发现睾酮增加了人类疾病中溶血的易感性，提示男性可能调节血液储存和SCD的临床结果，并确立供者遗传变量在储存的红细胞的生存能力和人类溶血性疾病中的作用。
BACKGROUNDRed blood cell (RBC) hemolysis represents an intrinsic mechanism for human vascular disease. Intravascular hemolysis releases hemoglobin and other metabolites that inhibit nitric oxide signaling and drive oxidative and inflammatory stress. Although these pathways are important in disease pathogenesis, genetic and population modifiers of hemolysis, including sex, have not been established.STUDY DESIGN AND METHODSWe studied sex differences in storage or stress-induced hemolysis in RBC units from the United States and Canada in 22 inbred mouse strains and in patients with sickle cell disease (SCD) using measures of hemolysis in 315 patients who had homozygous SS hemoglobin from the Walk-PHASST cohort. A mouse model also was used to evaluate posttransfusion recovery of stored RBCs, and gonadectomy was used to determine the mechanisms related to sex hormones.RESULTSAn analysis of predisposition to hemolysis based on sex revealed that male RBCs consistently exhibit increased susceptibility to hemolysis compared with females in response to routine cold storage, under osmotic or oxidative stress, after transfusion in mice, and in patients with SCD. The sex difference is intrinsic to the RBC and is not mediated by plasmatic factors or female sex hormones. Importantly, orchiectomy in mice improves RBC storage stability and posttransfusion recovery, whereas testosterone repletion therapy exacerbates hemolytic response to osmotic or oxidative stress.CONCLUSIONOur findings suggest that testosterone increases susceptibility to hemolysis across human diseases, suggesting that male sex may modulate clinical outcomes in blood storage and SCD and establishing a role for donor genetic variables in the viability of stored RBCs and in human hemolytic diseases.