Abstract：
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet.
we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice.
four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery.
iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus.
taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard.
we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice.
four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery.
iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus.
taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard.
摘要：
背景：慢性阻塞性肺疾病（COPD）是全球第三大死亡原因。除了慢性支气管炎和肺气肿,患者通常发展为至少轻度肺动脉高压(PH)。我们先前证明了诱导型一氧化氮合酶（iNOS）的抑制可以预防和逆转小鼠的肺气肿和PH。有趣的是,在肺气肿小鼠肺中的肺泡II型上皮细胞（AECII）中发现了强烈的iNOS上调，和过氧亚硝酸盐,可以由iNOS衍生的NO形成，显示在体外诱导AECII细胞凋亡。然而,在肺气肿/PH中驱动iNOS依赖性肺再生的特定细胞类型尚未被鉴定。
目的：我们测试了AECII中iNOS敲除是否影响已确定的弹性蛋白酶诱导的小鼠肺气肿。
方法：气管内滴注猪胰弹性蛋白酶4周后，诱导肺气肿和PH，我们在小鼠的AECII中诱导iNOS敲除，并给予了额外的12周的潜在恢复。
结果：AECII中的iNOS敲除并没有减少弹性蛋白酶诱导的肺功能和结构改变，例如肺顺应性增加，平均线性截获减少，空域增加，右心室功能下降，右心室收缩压升高和肺血管肌肉化增加。体外，在暴露于有害刺激后,iNOS抑制并不减少AECII的凋亡。
结论：合在一起，我们的数据表明，AECII中的iNOS缺失不足以再生肺气肿小鼠的肺，并提示iNOS在肺血管或基质细胞中的表达在这方面可能至关重要。
目的：我们测试了AECII中iNOS敲除是否影响已确定的弹性蛋白酶诱导的小鼠肺气肿。
方法：气管内滴注猪胰弹性蛋白酶4周后，诱导肺气肿和PH，我们在小鼠的AECII中诱导iNOS敲除，并给予了额外的12周的潜在恢复。
结果：AECII中的iNOS敲除并没有减少弹性蛋白酶诱导的肺功能和结构改变，例如肺顺应性增加，平均线性截获减少，空域增加，右心室功能下降，右心室收缩压升高和肺血管肌肉化增加。体外，在暴露于有害刺激后,iNOS抑制并不减少AECII的凋亡。
结论：合在一起，我们的数据表明，AECII中的iNOS缺失不足以再生肺气肿小鼠的肺，并提示iNOS在肺血管或基质细胞中的表达在这方面可能至关重要。
