Chen Yan, Hanaoka Masayuki, Chen Ping, Droma Yunden, Voelkel Norbert F, Kubo Keishi
First Department of Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
Am J Physiol Lung Cell Mol Physiol. 2009 Apr;296(4):L648-56. doi: 10.1152/ajplung.90270.2008. Epub 2009 Feb 6.
Chronic inflammation, imbalance of proteolytic and anti-proteolytic activities, oxidative stress, and apoptosis of lung structural cells contribute to the pathogenesis of COPD. Prostacyclin protects cells against apoptosis, has anti-inflammatory properties, partially prevents cigarette smoke extract (CSE)-induced apoptosis of the pulmonary endothelium, and thus may be relevant in the pathogenesis of emphysema. We determined whether a synthetic stable prostacyclin analog, beraprost sodium (BPS), attenuates the development of CSE-induced emphysema and elucidated the molecular mechanisms involved in its effect. Sprague-Dawley rats were treated with BPS and injected with CSE once a week for 3 wk. We measured the DNA damage of cells, the expression of caspase-3, and the activity of matrix metalloproteinase (MMP)-2 and MMP-9. We also analyzed TNFalpha and IL-1beta concentrations and the serum antioxidant activity. BPS prevented the development of CSE-induced emphysema, resulting in significant attenuation in alveolar enlargement and pulmonary parenchymal destruction. BPS inhibited pulmonary apoptosis and induction of MMP-2 and MMP-9 activity. Moreover, the protective effect of BPS was associated with a reduction of the expression of proinflammatory cytokines including TNFalpha and IL-1beta and a normalized biological oxidant activity. BPS introduces all these events, probably by activating cAMP signaling through acting specific prostacyclin receptors. In conclusion, BPS protects against the development of CSE-induced emphysema by attenuating apoptosis, inhibiting proteolytic enzyme activity, reducing inflammatory cytokine levels, and augmenting antioxidant activity. BPS may potentially represent a new therapeutic option in the prevention of emphysema in humans in prospect.
慢性炎症、蛋白水解与抗蛋白水解活性失衡、氧化应激以及肺结构细胞凋亡均参与慢性阻塞性肺疾病（COPD）的发病机制。前列环素可保护细胞免于凋亡，具有抗炎特性，能部分预防香烟烟雾提取物（CSE）诱导的肺内皮细胞凋亡，因此可能与肺气肿的发病机制相关。我们研究了一种合成的稳定前列环素类似物贝拉前列腺素钠（BPS）是否能减轻CSE诱导的肺气肿的发展，并阐明其作用的分子机制。将Sprague-Dawley大鼠用BPS处理，每周注射一次CSE，共3周。我们测量了细胞的DNA损伤、半胱天冬酶-3的表达以及基质金属蛋白酶（MMP）-2和MMP-9的活性。我们还分析了肿瘤坏死因子α（TNFα）和白细胞介素-1β（IL-1β）的浓度以及血清抗氧化活性。BPS预防了CSE诱导的肺气肿的发展，导致肺泡扩大和肺实质破坏显著减轻。BPS抑制了肺细胞凋亡以及MMP-2和MMP-9活性的诱导。此外，BPS的保护作用与促炎细胞因子（包括TNFα和IL-1β）表达的降低以及生物氧化活性的正常化有关。BPS可能通过作用于特定的前列环素受体激活环磷酸腺苷（cAMP）信号传导来引发所有这些事件。总之，BPS通过减轻细胞凋亡、抑制蛋白水解酶活性、降低炎症细胞因子水平以及增强抗氧化活性来预防CSE诱导的肺气肿的发展。BPS可能有望成为预防人类肺气肿的一种新的治疗选择。
