Z α1-Antitrypsin Confers a Proinflammatory Phenotype That Contributes to Chronic Obstructive Pulmonary Disease
Z α1-Antitrypsin Confers a Proinflammatory Phenotype That Contributes to Chronic Obstructive Pulmonary Disease
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DOI：
10.1164/rccm.201308-1458oc
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发表时间：
2014-04-15
影响因子：
24.7
通讯作者：
Mahadeva, Ravi
中科院分区：
文献类型：
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作者：
Alam, Samuel;Li, Zhenjun;Mahadeva, Ravi
原理：由Z变体（Glu 342 Lys; ZZ-AT）引起的严重α（1）-抗胰蛋白酶缺乏是众所周知的肺气肿遗传原因。虽然严重缺乏抗蛋白酶保护是ZZ-AT相关慢性阻塞性肺疾病（COPD）的关键病因，但一些报道认为肺部炎症增强是ZZ-AT纯合子的一个因素。目的：提供ZZ-AT炎症的分子特征。炎症细胞和细胞因子谱（核因子-kB，IL-6，肿瘤坏死因子-α），Z-AT的细胞内聚合，和内质网（ER）应激标志物（蛋白激酶RNA样ER激酶，激活转录因子4）在转基因小鼠和转染细胞中响应于香烟烟雾，以及在来自患有严重COPD的ZZ和MM个体的受损肺中进行评估。与M-AT相比，暴露于香烟烟雾的转基因Z-AT小鼠肺具有更高水平的肺细胞因子、中性粒细胞和巨噬细胞以及夸大的ER应激。类似地，ER超载反应在患有COPD的ZZ-AT纯合子的肺中更大，特别是在肺上皮细胞中发现。香烟烟雾增加细胞内Z-AT聚合物，ER超载反应，和促炎细胞因子释放Z-AT表达肺上皮细胞，这可以防止与聚合抑制剂，抗氧化剂，和蛋白激酶RNA样ER kinase.Conclusions的抑制剂：Weshow在这里，聚集的细胞内突变Z-AT调用一个特定的有害细胞炎症表型在COPD。上皮细胞中氧化剂诱导的Z-AT的细胞内聚合引起ER应激，并促进过量的细胞因子和细胞炎症。该通路可能有助于ZZ-AT纯合子中COPD的发展，因此值得进一步研究。
Rationale: Severe alpha(1)-antitrypsin deficiency caused by the Z variant (Glu342Lys; ZZ-AT) is a well-known genetic cause for emphysema. Although severe lack of antiproteinase protection is the critical etiologic factor for ZZ-AT-associated chronic obstructive pulmonary disease (COPD), some reports have suggested enhanced lung inflammation as a factor in ZZ-AT homozygotes.Objectives: To provide molecular characterization of inflammation in ZZ-AT.Methods: Inflammatory cell and cytokine profile (nuclear factor-kB, IL-6, tumor necrosis factor-alpha), intracellular polymerization of Z-AT, and endoplasmic reticulum (ER) stress markers (protein kinase RNA-like ER kinase, activator transcription factor 4) were assessed in transgenic mice and transfected cells in response to cigarette smoke, and in explanted lungs from ZZ and MM individuals with severe COPD.Measurements and Main Results: Compared with M-AT, transgenic Z-AT mice lungs exposed to cigarette smoke had higher levels of pulmonary cytokines, neutrophils, and macrophages and an exaggerated ER stress. Similarly, the ER overload response was greater in lungs from ZZ-AT homozygotes with COPD, and was particularly found in pulmonary epithelial cells. Cigarette smoke increased intracellular Z-AT polymers, ER overload response, and proinflammatory cytokine release in Z-AT-expressing pulmonary epithelial cells, which could be prevented with an inhibitor of polymerization, an antioxidant, and an inhibitor of protein kinase RNA-like ER kinase.Conclusions: Weshow here that aggregation of intracellular mutant Z-AT invokes a specific deleterious cellular inflammatory phenotype in COPD. Oxidant-induced intracellular polymerization of Z-AT in epithelial cells causes ER stress, and promotes excess cytokine and cellular inflammation. This pathway is likely to contribute to the development of COPD in ZZ-AT homozygotes, and therefore merits further investigation.