Yamada Yosuke, Tomaru Utano, Ishizu Akihiro, Ito Tomoki, Kiuchi Takayuki, Ono Ayako, Miyajima Syota, Nagai Katsura, Higashi Tsunehito, Matsuno Yoshihiro, Dosaka-Akita Hirotoshi, Nishimura Masaharu, Miwa Soichi, Kasahara Masanori
1] Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan [2] Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Lab Invest. 2015 Jun;95(6):625-34. doi: 10.1038/labinvest.2015.43. Epub 2015 Apr 27.
Chronic obstructive pulmonary disease (COPD) is a disease common in elderly people, characterized by progressive destruction of lung parenchyma and chronic inflammation of the airways. The pathogenesis of COPD remains unclear, but recent studies suggest that oxidative stress-induced apoptosis in alveolar cells contributes to emphysematous lung destruction. The proteasome is a multicatalytic enzyme complex that plays a critical role in proteostasis by rapidly destroying misfolded and modified proteins generated by oxidative and other stresses. Proteasome activity decreases with aging in many organs including lungs, and an age-related decline in proteasomal function has been implicated in various age-related pathologies. However, the role of the proteasome system in the pathogenesis of COPD has not been investigated. Recently, we have established a transgenic (Tg) mouse model with decreased proteasomal chymotrypsin-like activity, showing age-related phenotypes. Using this model, we demonstrate here that decreased proteasomal function accelerates cigarette smoke (CS)-induced pulmonary emphysema. CS-exposed Tg mice showed remarkable airspace enlargement and increased foci of inflammation compared with wild-type controls. Importantly, apoptotic cells were found in the alveolar walls of the affected lungs. Impaired proteasomal activity also enhanced apoptosis in cigarette smoke extract (CSE)-exposed fibroblastic cells derived from mice and humans in vitro. Notably, aggresome formation and prominent nuclear translocation of apoptosis-inducing factor were observed in CSE-exposed fibroblastic cells isolated from Tg mice. Collective evidence suggests that CS exposure and impaired proteasomal activity coordinately enhance apoptotic cell death in the alveolar walls that may be involved in the development and progression of emphysema in susceptible individuals such as the elderly.
慢性阻塞性肺疾病（COPD）是老年人常见的疾病，其特征是肺实质进行性破坏和气道慢性炎症。COPD的发病机制尚不清楚，但最近的研究表明，氧化应激诱导的肺泡细胞凋亡导致肺气肿性肺破坏。蛋白酶体是一种多催化酶复合物，通过快速降解由氧化应激和其他应激产生的错误折叠和修饰的蛋白质，在蛋白质稳态中起关键作用。在包括肺在内的许多器官中，蛋白酶体活性随年龄增长而降低，蛋白酶体功能的年龄相关性下降与各种年龄相关的病理过程有关。然而，蛋白酶体系统在COPD发病机制中的作用尚未得到研究。最近，我们建立了一种蛋白酶体胰凝乳蛋白酶样活性降低的转基因（Tg）小鼠模型，该模型表现出与年龄相关的表型。利用这个模型，我们在此证明蛋白酶体功能降低会加速香烟烟雾（CS）诱导的肺气肿。与野生型对照相比，暴露于CS的Tg小鼠表现出明显的气腔扩大和炎症灶增加。重要的是，在受影响的肺的肺泡壁中发现了凋亡细胞。蛋白酶体活性受损还增强了体外暴露于香烟烟雾提取物（CSE）的小鼠和人成纤维细胞的凋亡。值得注意的是，在从Tg小鼠分离的暴露于CSE的成纤维细胞中观察到聚集体形成和凋亡诱导因子的显著核转位。综合证据表明，CS暴露和蛋白酶体活性受损协同增强肺泡壁中的凋亡细胞死亡，这可能与老年人等易感个体肺气肿的发生和发展有关。
