Acute hyperhemolysis is a severe life-threatening complication in patients with sickle cell disease (SCD) that may occur during delayed hemolytic transfusion reaction (DHTR), or vaso-occlusive crises associated with multiorgan failure. Here, we developed in vitro and in vivo animal models to mimic endothelial damage during the early phase of hyperhemolysis in SCD. We then used the carbon monoxide (CO)-releasing molecule CORM-401 and examined its effects against endothelial activation, damage, and inflammation inflicted by hemolysates containing red blood cell membrane–derived particles. The in vitro results revealed that CORM-401: (1) prevented the upregulation of relevant proinflammatory and proadhesion markers controlled by the NF-κB enhancer of activated B cells, and (2) abolished the expression of the nuclear factor erythroid-2-related factor 2 (Nrf2) that regulates the inducible antioxidant cell machinery. We also show in SCD mice that CORM-401 protects against hemolysate-induced acute damage of target organs such as the lung, liver, and kidney through modulation of NF-κB proinflammatory and Nrf2 antioxidant pathways. Our data demonstrate the efficacy of CORM-401 as a novel therapeutic agent to counteract hemolysate-induced organ damage during hyperhemolysis in SCD. This approach might be considered as possible preventive treatment in high-risk situations such as patients with SCD with history of DHTR.

中文翻译：

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口服一氧化碳释放分子可预防镰状细胞病的急性高溶血

急性高溶血是镰状细胞病 (SCD) 患者的一种严重危及生命的并发症，可能发生在迟发性溶血性输血反应 (DHTR) 或与多器官衰竭相关的血管闭塞危象期间。在这里，我们开发了体外和体内动物模型来模拟 SCD 过度溶血早期阶段的内皮损伤。然后，我们使用一氧化碳 (CO) 释放分子 CORM-401 并检查其对含有红细胞膜衍生颗粒的溶血液引起的内皮活化、损伤和炎症的影响。体外结果显示，CORM-401：（1）阻止由活化 B 细胞的 NF-κB 增强子控制的相关促炎和促粘附标记物的上调，（2）消除核因子 erythroid-2 相关的表达调节诱导型抗氧化细胞机制的因子 2 (Nrf2)。我们还在 SCD 小鼠中证明，CORM-401 通过调节 NF-κB 促炎和 Nrf2 抗氧化途径，可防止溶血产物诱导的靶器官（如肺、肝和肾）的急性损伤。我们的数据证明了 CORM-401 作为一种新型治疗剂在 SCD 过度溶血过程中对抗溶血物引起的器官损伤的功效。这种方法可能被认为是高危情况下可能的预防性治疗，例如有 DHTR 病史的 SCD 患者。