Hemolysis-induced Lung Vascular Leakage Contributes to the Development of Pulmonary Hypertension
Hemolysis-induced Lung Vascular Leakage Contributes to the Development of Pulmonary Hypertension
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DOI：
10.1165/rcmb.2017-0308oc
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发表时间：
2018-09-01
影响因子：
6.4
通讯作者：
Rafikov, Ruslan
中科院分区：
文献类型：
--
作者：
Rafikova, Olga;Williams, Elissa R.;Rafikov, Ruslan
虽然溶血性贫血相关性肺动脉高压(PH)和肺动脉高压(PAH)比特发性PAH更常见，但溶血性在PAH发生发展中的作用尚不清楚。我们假设，溶血通过内皮屏障功能障碍导致血管周围水肿和炎症，独立地促进PAH的发病。用右心导管术证实的PAH患者和非PAH患者的血浆样本测定游离血红蛋白(Hb)及其与PAH严重程度的相关性。采用SUGEN(50 mg/kg)/低氧(3wk)/常氧(2wk)大鼠模型，探讨Hb/Hb途径在PAH中的作用。用人肺微血管内皮细胞研究了血红素介导的内皮屏障作用。我们的数据表明，PAH患者血浆中游离Hb水平升高，与PAH严重程度相关。在大鼠模型中，也有大量的游离Hb积聚和结合珠蛋白的耗竭。在大鼠中，早期观察到血管周围水肿，并伴有炎性细胞的增加。血红素诱导的人肺微血管内皮细胞通透性涉及p38/HSP27通路的激活。事实上，在PH的初始阶段，大鼠模型也表现出p38/HSP27的激活增加。令人惊讶的是，尽管溶血和血红素介导的信号转导水平增加，但没有发现血红素加氧酶-1的激活。这可以由观察到的HIF-1a在PH的前2周内的不稳定来解释，无论低氧条件如何。我们的数据表明，溶血可能在PAH的病理生物学中起重要作用。
Although hemolytic anemia-associated pulmonary hypertension (PH) and pulmonary arterial hypertension (PAH) are more common than the prevalence of idiopathic PAH alone, the role of hemolysis in the development of PAH is poorly characterized. We hypothesized that hemolysis independently contributes to PAH pathogenesis via endothelial barrier dysfunction with resulting perivascular edema and inflammation. Plasma samples from patients with and without PAH (both confirmed by right heart catheterization) were used to measure free hemoglobin (Hb) and its correlation with PAH severity. A sugen (50 mg/kg)/hypoxia (3 wk)/normoxia (2 wk) rat model was used to elucidate the role of free Hb/heme pathways in PAH. Human lung microvascular endothelial cells were used to study heme-mediated endothelial barrier effects. Our data indicate that patients with PAH have increased levels of free Hb in plasma that correlate with PAH severity. There is also a significant accumulation of free Hb and depletion of haptoglobin in the rat model. In rats, perivascular edema was observed at early time points concomitant with increased infiltration of inflammatory cells. Heme-induced endothelial permeability in human lung microvascular endothelial cells involved activation of the p38/HSP27 pathway. Indeed, the rat model also exhibited increased activation of p38/HSP27 during the initial phase of PH. Surprisingly, despite the increased levels of hemolysis and heme-mediated signaling, there was no heme oxygenase-1 activation. This can be explained by observed destabilization of HIF-1a during the first 2 weeks of PH regardless of hypoxic conditions. Our data suggest that hemolysis may play a significant role in PAH pathobiology.