Hemopexin dosing improves cardiopulmonary dysfunction in murine sickle cell disease.
Hemopexin dosing improves cardiopulmonary dysfunction in murine sickle cell disease.
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DOI：
10.1016/j.freeradbiomed.2021.08.238
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发表时间：
2021-11-01
影响因子：
7.4
通讯作者：
Irwin, David C.
中科院分区：
文献类型：
--
作者：
Buehler, Paul W.;Swindle, Delaney;Pak, David, I;Ferguson, Scott K.;Majka, Susan M.;Karoor, Vijaya;Moldovan, Radu;Sintas, Chantal;Black, Jennifer;Gentinetta, Thomas;Buzzi, Raphael M.;Vallelian, Florence;Wassmer, Andreas;Edler, Monika;Bain, Joseph;Schu, Daniel;Hassell, Kathryn;Nuss, Rachelle;Schaer, Dominik J.;Irwin, David C.
血红素结合蛋白（Hemopexin，Hpx）是一种重要的防御蛋白，能抵抗溶血过程中血红蛋白降解释放的血红素.高血红素应激导致Hpx生物利用度失衡，有利于血红素积累和下游病理生理反应，导致镰状细胞病（SCD）患者的心肺疾病进展。在这里，我们评估了一种小鼠SCD模型，该模型旨在通过将小鼠暴露于中度低压缺氧来加速红细胞镰状化、肺动脉高压、右心室功能障碍和运动不耐受。该模型中的病理生理学顺序跟踪循环血红素积累、脂质氧化、肺血管系统的广泛重塑和纤维化。我们假设，延长Hpx替代治疗时间将改善运动耐量（通过临界速度测量），作为具有临床意义的治疗终点。此外，我们试图确定Hpx对上游心肺功能、组织病理学和组织氧化的影响。我们的数据表明，三周一次给予Hpx三个月，剂量依赖性地减少血红素暴露和肺动脉高压，同时改善心脏压力-容量关系和运动耐量。此外，Hpx给药剂量依赖性地减弱肺纤维化和肺和右心室心肌的氧化修饰。在我们的SCD鼠模型中的观察结果与患有严重肺动脉高压、右心室功能障碍和心源性猝死的SCD患者尸检时的肺血管和右心室病理学一致。本研究提供了一项翻译评价，该评价得到了严格的结局分析的支持，证明了SCD中Hpx替代治疗的概念验证。
Hemopexin (Hpx) is a crucial defense protein against heme liberated from degraded hemoglobin during hemolysis. High heme stress creates an imbalance in Hpx bioavailability, favoring heme accumulation and downstream pathophysiological responses leading to cardiopulmonary disease progression in sickle cell disease (SCD) patients. Here, we evaluated an model of murine SCD, which was designed to accelerate red blood cell sickling, pulmonary hypertension, right ventricular dysfunction, and exercise intolerance by exposure of the mice to moderate hypobaric hypoxia. The sequence of pathophysiology in this model tracks with circulatory heme accumulation, lipid oxidation, extensive remodeling of the pulmonary vasculature, and fibrosis. We hypothesized that Hpx replacement for an extended period would improve exercise tolerance measured by critical speed as a clinically meaningful therapeutic endpoint. Further, we sought to define the effects of Hpx on upstream cardiopulmonary function, histopathology, and tissue oxidation. Our data shows that tri-weekly administrations of Hpx for three months dose-dependently reduced heme exposure and pulmonary hypertension while improving cardiac pressure-volume relationships and exercise tolerance. Furthermore, Hpx administration dose-dependently attenuated pulmonary fibrosis and oxidative modifications in the lung and myocardium of the right ventricle. Observations in our SCD murine model are consistent with pulmonary vascular and right ventricular pathology at autopsy in SCD patients having suffered from severe pulmonary hypertension, right ventricular dysfunction, and sudden cardiac death. This study provides a translational evaluation supported by a rigorous outcome analysis demonstrating therapeutic proof-of-concept for Hpx replacement in SCD.
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影响因子：
37.8
作者：
Andersen, Stine;Nielsen-Kudsk, Jens Erik;de Man, Frances S.
通讯作者：
de Man, Frances S.
DOI：
10.1073/pnas.1600311113
发表时间：
2016-08-30
影响因子：
11.1
作者：
Bakeer, Nihal;James, Jeanne;Malik, Punam
通讯作者：
Malik, Punam
影响因子：
3.3
作者：
Hirai, Daniel M.;Copp, Steven W.;Poole, David C.
通讯作者：
Poole, David C.
影响因子：
158.5
作者：
Niihara, Yutaka;Miller, Scott T.;Vichinsky, Elliott P.
通讯作者：
Vichinsky, Elliott P.
DOI：
10.1152/ajplung.00074.2012
发表时间：
2012-08-01
影响因子：
4.9
作者：
Buehler, Paul W.;Baek, Jin Hyen;Irwin, David C.
通讯作者：
Irwin, David C.