Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA.
Am J Respir Cell Mol Biol. 2011 Apr;44(4):500-8. doi: 10.1165/rcmb.2010-0065OC. Epub 2010 Jun 10.
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.
间质性肺病是一种严重的人类疾病，其发病过程可能会因继发性肺动脉高压而变得更加复杂。越来越多的证据表明，氧化剂超氧阴离子可能导致间质性肺病和肺动脉高压的发病。我们使用博来霉素诱导的肺纤维化继发肺动脉高压模型来验证以下假说，即细胞外超氧阴离子及其抗氧化防御（细胞外超氧化物歧化酶）的失衡会促进肺血管重构和肺动脉高压。我们将过表达肺细胞外超氧化物歧化酶的转基因小鼠和野生型同窝仔鼠暴露于单次气管内博来霉素，然后在长达 35 天的时间内每周对其进行评估。我们评估了肺血管重构和几个对肺纤维化至关重要的基因的表达情况，以及肺动脉高压和死亡率。博来霉素给药后，过表达细胞外超氧化物歧化酶可防止血管壁中层、外膜和内膜的晚期重构，并在同一晚期时间点减轻肺动脉高压。过表达细胞外超氧化物歧化酶还可阻断肺纤维化和血管重构两个关键基因的早期上调，这两个基因是转录因子早期生长反应-1 和转化生长因子-β。过表达细胞外超氧化物歧化酶可减轻晚期肺动脉高压，并显著提高博来霉素暴露后的生存率。这些数据表明，细胞外氧化剂/抗氧化剂失衡在与博来霉素诱导的肺纤维化相关的继发性肺动脉高压继发的肺血管重构发病机制中具有重要作用。
