Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea
Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea
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DOI：
10.1182/blood-2014-12-616250
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发表时间：
2015-08-06
期刊：
影响因子：
20.3
通讯作者：
Conran, Nicola
中科院分区：
文献类型：
--
作者：
Almeida, Camila Bononi;Botelho Souza, Lucas Eduardo;Conran, Nicola
溶血和随之释放的无细胞血红蛋白（CFHb）损害血管一氧化氮（NO）的生物利用度，并引起氧化和炎症过程。羟基脲（HU）是镰状细胞病（SCD）的常用疗法，可诱导胎儿Hb生成，并可作为NO供体。我们评估了C57BL/6小鼠静脉水诱导溶血的急性炎症效应，并确定了NO供体、二乙胺NONOate （DEANO）和单剂量HU调节这种炎症的能力。静脉注射水诱导C57BL/6小鼠急性溶血，达到与嵌合SCD小鼠相当的血浆Hb水平。这种溶血在15分钟内导致明显而迅速的全身炎症和血管白细胞募集，并伴有NO代谢物的产生。另一种有效的NO清除剂（2-苯基-4,4,5,5-四甲基咪唑啉-1-氧基-3-氧化物）给C57BL/6小鼠也诱导了白细胞募集的类似改变，而血红素诱导的炎症发生在更长的时间内。重要的是，同时给药DEANO或HU可以通过NO途径介导的方式消除水诱导溶血的急性炎症效应，而不改变CFHb。在体外，HU部分逆转了hb介导的内皮促炎细胞因子分泌和粘附分子表达。综上所述，病理生理水平的溶血触发了立即的炎症反应，可能是由血管NO消耗介导的。HU通过no依赖机制抑制快速发作的溶血性炎症，显示出有益的抗炎作用，独立于胎儿Hb升高。这些数据为溶血性炎症的机制提供了新的见解，并进一步支持了HU作为急性SCD和其他溶血性疾病治疗的观点。
Hemolysis and consequent release of cell-free hemoglobin (CFHb) impair vascular nitric oxide (NO) bioavailability and cause oxidative and inflammatory processes. Hydroxyurea (HU), a common therapy for sickle cell disease (SCD), induces fetal Hb production and can act as an NO donor. We evaluated the acute inflammatory effects of intravenous water-induced hemolysis in C57BL/6 mice and determined the abilities of an NO donor, diethylamine NONOate (DEANO), and a single dose of HU to modulate this inflammation. Intravenous water induced acute hemolysis in C57BL/6 mice, attaining plasma Hb levels comparable to those observed in chimeric SCD mice. This hemolysis resulted in significant and rapid systemic inflammation and vascular leukocyte recruitment within 15 minutes, accompanied by NO metabolite generation. Administration of another potent NO scavenger (2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) to C57BL/6 mice induced similar alterations in leukocyte recruitment, whereas hemin-induced inflammation occurred over a longer timeframe. Importantly, the acute inflammatory effects of water-induced hemolysis were abolished by the simultaneous administration of DEANO or HU, without altering CFHb, in an NO pathway mediated manner. In vitro, HU partially reversed the Hb-mediated induction of endothelial proinflammatory cytokine secretion and adhesion molecule expression. In summary, pathophysiological levels of hemolysis trigger an immediate inflammatory response, possibly mediated by vascular NO consumption. HU presents beneficial anti-inflammatory effects by inhibiting rapid-onset hemolytic inflammation via an NO-dependent mechanism, independently of fetal Hb elevation. Data provide novel insights into mechanisms of hemolytic inflammation and further support perspectives for the use of HU as an acute treatment for SCD and other hemolytic disorders.