Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodeling.
Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodeling.
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DOI：
10.1165/rcmb.2010-0065oc
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发表时间：
2011-04
影响因子：
6.4
通讯作者：
Zachary Van Rheen;C. Fattman;S. Domarski;S. Majka;D. Klemm;K. Stenmark;E. Nozik-Grayck
中科院分区：
文献类型：
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作者：
Zachary Van Rheen;C. Fattman;S. Domarski;S. Majka;D. Klemm;K. Stenmark;E. Nozik-Grayck
间质性肺病是人类的一种毁灭性疾病，可通过继发性肺动脉高压的发展而进一步复杂化。越来越多的证据表明，氧化剂超氧化物可能参与间质性肺病和肺动脉高压的发病机制。我们使用博来霉素诱导的肺纤维化继发性肺动脉高压模型来检验细胞外超氧化物及其抗氧化防御（细胞外超氧化物歧化酶）失衡将促进肺血管重塑和肺动脉高压的假设。我们将肺细胞外超氧化物歧化酶过度表达的转基因小鼠和野生型同窝小鼠暴露于单剂量的博莱霉素，每周对小鼠进行评估，持续35天。我们评估了肺血管重塑和几个对肺纤维化至关重要的基因的表达，以及肺动脉高压和死亡率。细胞外超氧化物歧化酶的过度表达保护了博莱霉素给药后血管壁的中膜、外膜和内膜层的晚期重塑，并在同一晚期时间点减弱了肺动脉高压。细胞外超氧化物歧化酶的过表达还阻断了肺中已知在肺纤维化和血管重塑中至关重要的两个关键基因的早期上调，即转录因子早期生长反应-1和转化生长因子-β。细胞外超氧化物歧化酶的过度表达减轻了晚期肺动脉高压，并显着提高了博莱霉素暴露后的生存率。这些数据表明，细胞外氧化剂/抗氧化剂失衡在肺血管重塑的发病机制中起重要作用，肺血管重塑与博来霉素诱导的肺纤维化引起的继发性肺动脉高压有关。
Interstitial lung disease is a devastating disease in humans that can be further complicated by the development of secondary pulmonary hypertension. Accumulating evidence indicates that the oxidant superoxide can contribute to the pathogenesis of both interstitial lung disease and pulmonary hypertension. We used a model of pulmonary hypertension secondary to bleomycin-induced pulmonary fibrosis to test the hypothesis that an imbalance in extracellular superoxide and its antioxidant defense, extracellular superoxide dismutase, will promote pulmonary vascular remodeling and pulmonary hypertension. We exposed transgenic mice overexpressing lung extracellular superoxide dismutase and wild-type littermates to a single dose of intratracheal bleomycin, and evaluated the mice weekly for up to 35 days. We assessed pulmonary vascular remodeling and the expression of several genes critical to lung fibrosis, as well as pulmonary hypertension and mortality. The overexpression of extracellular superoxide dismutase protected against late remodeling within the medial, adventitial, and intimal layers of the vessel wall after the administration of bleomycin, and attenuated pulmonary hypertension at the same late time point. The overexpression of extracellular superoxide dismutase also blocked the early up-regulation of two key genes in the lung known to be critical in pulmonary fibrosis and vascular remodeling, the transcription factor early growth response-1 and transforming growth factor-β. The overexpression of extracellular superoxide dismutase attenuated late pulmonary hypertension and significantly improved survival after exposure to bleomycin. These data indicate an important role for an extracellular oxidant/antioxidant imbalance in the pathogenesis of pulmonary vascular remodeling associated with secondary pulmonary hypertension attributable to bleomycin-induced lung fibrosis.