Cohen Children's Medical Center, North Shore-Long Island Jewish Health System, New Hyde Park, New York, United States of America.
Mol Med. 2012 Feb 10;18(1):38-46. doi: 10.2119/molmed.2011.00339.
Hypoxia leads to free radical production, which has a pivotal role in the pathophysiology of pulmonary hypertension (PH). We hypothesized that treatment with extracellular superoxide dismutase (EC-SOD) could ameliorate the development of PH induced by hypoxia. In vitro studies using pulmonary microvascular endothelial cells showed that cells transfected with EC-SOD had significantly less accumulation of xanthine oxidase and reactive oxygen species than nontransfected cells after hypoxia exposure for 24 h. To study the prophylactic role of EC-SOD, adult male wild-type (WT) and transgenic (TG) mice, with lung-specific overexpression of human EC-SOD (hEC-SOD), were exposed to fraction of inspired oxygen (FiO(2)) 10% for 10 d. After exposure, right ventricular systolic pressure (RVSP), right ventricular mass (RV/S + LV), pulmonary vascular wall thickness (PVWT) and pulmonary artery contraction/relaxation were assessed. TG mice were protected against PH compared with WT mice with significantly lower RVSP (23.9 ± 1.24 versus 47.2 ± 3.4), RV/S + LV (0.287 ± 0.015 versus 0.335 ± 0.022) and vascular remodeling, indicated by PVWT (14.324 ± 1.107 versus 18.885 ± 1.529). Functional studies using pulmonary arteries isolated from mice indicated that EC-SOD prevents hypoxia-mediated attenuation of nitric oxide-induced relaxation. Therapeutic potential was assessed by exposing WT mice to FiO(2) 10% for 10 d. Half of the group was transfected with plasmid containing cDNA encoding human EC-SOD. The remaining animals were transfected with empty vector. Both groups were exposed to FiO(2) 10% for a further 10 d. Transfected mice had significantly reduced RVSP (18.97 ± 1.12 versus 41.3 ± 1.5), RV/S + LV (0.293 ± 0.012 versus 0.372 ± 0.014) and PVWT (12.51 ± 0.72 versus 18.98 ± 1.24). On the basis of these findings, we concluded that overexpression of EC-SOD prevents the development of PH and ameliorates established PH.
缺氧导致自由基的产生，这在肺动脉高压 (PH) 的病理生理学中起着关键作用。我们假设，用细胞外超氧化物歧化酶 (EC-SOD) 治疗可能会改善由缺氧引起的 PH 的发展。在使用肺微血管内皮细胞的体外研究中，与未转染的细胞相比，在缺氧暴露 24 小时后，转染 EC-SOD 的细胞的黄嘌呤氧化酶和活性氧的积累明显减少。为了研究 EC-SOD 的预防作用，成年雄性野生型 (WT) 和转基因 (TG) 小鼠，肺特异性过表达人 EC-SOD (hEC-SOD)，在吸入氧分数 (FiO(2)) 10%下暴露 10 天。暴露后，评估右心室收缩压 (RVSP)、右心室质量 (RV/S + LV)、肺血管壁厚度 (PVWT) 和肺动脉收缩/舒张。与 WT 小鼠相比，TG 小鼠对 PH 有保护作用，RVSP 明显降低 (23.9 ± 1.24 与 47.2 ± 3.4)，RV/S + LV (0.287 ± 0.015 与 0.335 ± 0.022) 和血管重构，由 PVWT 表示 (14.324 ± 1.107 与 18.885 ± 1.529)。使用从小鼠分离的肺动脉进行的功能研究表明，EC-SOD 可防止缺氧介导的一氧化氮诱导的舒张减弱。通过将 WT 小鼠暴露于 FiO(2) 10% 10 天来评估治疗潜力。一半的组用含有编码人 EC-SOD 的 cDNA 的质粒转染。其余动物用空载体转染。两组均在 FiO(2) 10% 下再暴露 10 天。转染的小鼠的 RVSP (18.97 ± 1.12 与 41.3 ± 1.5)、RV/S + LV (0.293 ± 0.012 与 0.372 ± 0.014) 和 PVWT (12.51 ± 0.72 与 18.98 ± 1.24) 明显降低。基于这些发现，我们得出结论，EC-SOD 的过表达可预防 PH 的发展并改善已建立的 PH。
