SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice
SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice
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DOI：
10.1152/ajplung.00181.2013
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发表时间：
2013-12-01
影响因子：
4.9
通讯作者：
Benarafa, Charaf
中科院分区：
文献类型：
--
作者：
Cremona, Tiziana P.;Tschanz, Stefan A.;Benarafa, Charaf
慢性阻塞性肺疾病（COPD）的特征在于肺气肿和慢性支气管炎，并且是全世界发病率和死亡率的主要原因。吸烟和缺乏α 1-抗胰蛋白酶（AAT）分别是最突出的环境和遗传风险因素。然而，COPD的发病机制尚未完全阐明。疾病进展似乎包括由自我持续的肺部炎症、内皮和上皮细胞死亡以及细胞外基质蛋白的蛋白水解降解驱动的恶性循环。与AAT一样，serpinB 1是丝氨酸蛋白酶（包括中性粒细胞弹性蛋白酶和组织蛋白酶G）的有效抑制剂。由于serpinB 1在骨髓和肺上皮细胞中表达，并且在肺部感染期间具有保护作用，因此我们研究了serpinB 1在预防小鼠年龄相关性和香烟烟雾诱导的肺气肿中的作用。与年轻成年小鼠（3月龄）相比，15月龄小鼠的肺容量增加，肺功能降低，但在serpinB 1缺陷（KO）和野生型（WT）小鼠之间没有观察到差异。与相应的对照组小鼠相比，慢性暴露于二手烟烟雾导致结构性肺气肿的变化，但在基因型之间没有观察到肺形态学差异。值得注意的是，年龄和吸烟引起的体视学变化的不同模式表明导致气道容量增加的不同机制。最后，细胞内和细胞外蛋白酶抑制剂的表达在烟雾暴露后WT和KO小鼠的肺中受到不同的调节;然而，蛋白酶的活性没有显著改变。总之，我们发现，虽然AAT和serpinB 1是类似的有效的中性粒细胞蛋白酶抑制剂，serpinB 1缺乏症与更严重的肺气肿无关。
Chronic obstructive pulmonary disease (COPD) is characterized by emphysema and chronic bronchitis and is a leading cause of morbidity and mortality worldwide. Tobacco smoke and deficiency in alpha 1-antitrypsin (AAT) are the most prominent environmental and genetic risk factors, respectively. Yet the pathogenesis of COPD is not completely elucidated. Disease progression appears to include a vicious circle driven by self-perpetuating lung inflammation, endothelial and epithelial cell death, and proteolytic degradation of extracellular matrix proteins. Like AAT, serpinB1 is a potent inhibitor of serine proteases including neutrophil elastase and cathepsin G. Because serpinB1 is expressed in myeloid and lung epithelial cells and is protective during lung infections, we investigated the role of serpinB1 in preventing age-related and cigarette smoke-induced emphysema in mice. Fifteen-month-old mice showed increased lung volume and decreased pulmonary function compared with young adult mice (3 mo old), but no differences were observed between serpinB1-deficient (KO) and wild-type (WT) mice. Chronic exposure to secondhand cigarette smoke resulted in structural emphysematous changes compared with respective control mice, but no difference in lung morphometry was observed between genotypes. Of note, the different pattern of stereological changes induced by age and cigarette smoke suggest distinct mechanisms leading to increased airway volume. Finally, expression of intracellular and extracellular protease inhibitors were differently regulated in lungs of WT and KO mice following smoke exposure; however, activity of proteases was not significantly altered. In conclusion, we showed that, although AAT and serpinB1 are similarly potent inhibitors of neutrophil proteases, serpinB1 deficiency is not associated with more severe emphysema.