Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Blood. 2010 Sep 2;116(9):1613-22. doi: 10.1182/blood-2010-01-267112. Epub 2010 May 28.
Pulmonary arterial hypertension (PAH) is suspected to be a strong mortality determinant of hemolytic disorders. However, direct contribution of acute intravascular hemolysis to fatal PAH has not been investigated. The roles of nitric oxide (NO) insufficiency and platelet activation in hemolysis-associated fatal PAH have been suspected but not been experimentally studied. We recently generated a unique intravascular hemolysis mouse model in which the membrane toxin, intermedilysin (ILY), exclusively lyses the erythrocytes of transgenically expressing human CD59 mice (ThCD59(RBC)), thereby inducing ILY-dose-dependent massive hemolysis. Using this murine hemolysis model, we found that the acute increase in pulmonary arterial pressure leading to right ventricle failure caused sudden death. Reduced NO bioavailability and massive platelet activation/aggregation leading to the formation of massive thrombosis specifically in the pulmonary microvasculature played the critical roles in pathogenesis of acute hemolysis-associated fatal PAH. Therapeutic interventions enhancing NO bioactivity or inhibiting platelet activation prevented sudden death or prolonged survival time via the suppression of the acute increase in pulmonary arterial pressure and improvement of right ventricle function. These findings further highlight the importance of the inhibition of platelet activation and the enhancement of NO bioavailability for the treatment and prevention of hemolysis-associated (fatal) PAH.
肺动脉高压（PAH）被怀疑是溶血性疾病的一个强有力的死亡决定因素。然而，急性血管内溶血对致命性 PAH 的直接作用尚未被研究。一氧化氮（NO）不足和血小板激活在溶血性致命 PAH 中的作用已被怀疑，但尚未进行实验研究。我们最近在小鼠中建立了一种独特的血管内溶血模型，该模型中的膜毒素，中介溶素（ILY）仅裂解转染表达人 CD59 的红细胞（ThCD59（RBC）），从而诱导ILY 剂量依赖性的大量溶血。使用这种鼠溶血模型，我们发现导致右心室衰竭的急性肺动脉压升高导致突然死亡。NO 生物利用度降低和大量血小板激活/聚集导致肺动脉微血管中形成大量血栓，在急性溶血性致命 PAH 的发病机制中起关键作用。通过抑制肺动脉压的急性升高和改善右心室功能，增强 NO 生物活性或抑制血小板激活的治疗干预可预防突然死亡或延长生存时间。这些发现进一步强调了抑制血小板激活和提高 NO 生物利用度在治疗和预防溶血性（致命）PAH 中的重要性。
