Lectin Complement Pathway in Emphysema.
Lectin Complement Pathway in Emphysema.
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肺气肿中的凝集素补体途径。
DOI：
10.1164/rccm.201807-1380le
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发表时间：
2019
影响因子：
24.7
通讯作者：
Petrache,Irina
中科院分区：
文献类型：
--
作者：
Serban,KarinaA;Mikosz,Andrew;Strange,Charlie;Janciauskiene,SabinaM;Stolk,Jan;Jonigk,Danny;Sandhaus,RobertA;Petrache,Irina
肺气肿和慢性阻塞性肺病（COPD）最常见的遗传原因是AAT（α-1抗胰蛋白酶）缺乏症（AATD）（1）。AATD患者的肺部疾病风险与循环AAT水平降低相关，AAT是一种对嗜酸性粒细胞衍生的丝氨酸蛋白酶（如弹性蛋白酶）具有高亲和力的蛋白酶抑制剂（2，3）。AAT靶向的其他蛋白酶的鉴定可能为肺气肿的发病机制提供进一步的见解。我们的工作表明，AAT靶向参与补体激活的蛋白酶MASP-2（MBL [甘露糖结合凝集素]相关丝氨酸蛋白酶2）。这些研究的一些结果以前已经以摘要的形式报道过（4）。与其他MASP-1或-3同种型相反，单独的MASP-2足以启动补体系统内的凝集素途径，补体系统是通过自身或酶促裂解激活的酶原酶（C1-C9）网络（图1A）（5）。虽然其主要功能是形成对病原体杀灭至关重要的膜攻击复合物（C5-C9），但补体最近已涉及无菌炎症和自身免疫（5）。尽管凝集素补体途径在COPD发病机制中的作用未得到充分研究，但新出现的报道指出了COPD和AATD患者血清中的补体活化（C4和C3）（6，7），以及香烟烟雾（CS）诱导的肺气肿模型中小鼠肺中的补体活化（8）。在这项研究中，我们研究了MASP-2和凝集素途径是否在COPD和AATD血浆和肺组织中活化。样本来自COPD受试者（n= 38，年龄= 64 ± 10岁，21例男性，FEV1%预测值= 45 ± 6 ± 27），AATD（n= 47）停止AAT增强治疗（AATD关闭，n= 30，年龄= 67 6 9岁，18例男性，FEV1%预测值= 73 6 32）或接受强化治疗（AATD-治疗，n= 17，年龄= 58 ± 14岁，8例男性，FEV1%预测值= 33 ± 11），和健康从不吸烟者（n= 23，年龄= 40 ± 8.5岁，5例男性）。排除了过去3个月内有活动性感染的受试者。受试者的吸烟状态记录为活跃吸烟者、既往吸烟者、从不吸烟者或未知（后一组从多变量分析中排除）。在R和Prism（GraphPad Software）中进行统计分析。从莱顿大学（n= 8）、汉诺威大学（n= 15）、南卡罗来纳州医科大学（n= 24）和国家犹太健康中心（n= 62）获得未识别的血浆样本，从肺组织研究联盟和汉诺威大学获得肺样本。国家犹太健康中心的机构审查委员会批准该研究为豁免人类受试者研究。
The most common genetic cause of emphysema and chronic obstructive pulmonary disease (COPD) is AAT (alpha-1 antitrypsin) deficiency (AATD)(1). The risk of lung disease in AATD is associated with decreased levels of circulating AAT, a proteinase inhibitor with high affinity for neutrophil-derived serine proteases such as elastase (2, 3). Identification of additional proteases targeted by AAT may provide further insight into the pathogenesis of emphysema. Our work suggests that AAT targets a protease involved in complement activation, MASP-2 (MBL [mannose-binding lectin]-associated serine protease 2). Some of the results of these studies have been previously reported in the form of an abstract (4). In contrast to other MASP-1 or-3 isoforms, MASP-2 alone is sufficient to initiate the lectin pathway within the complement system, a network of zymogen enzymes (C1–C9) activated by auto-or enzymatic cleavage (Figure 1A)(5). Whereas its main function is to form the membrane attack complex (C5–C9) that is critical for pathogen killing, the complement has been recently implicated in sterile inflammation and autoimmunity (5). Although the role of the lectin complement pathway in COPD pathogenesis is understudied, emerging reports point to complement activation (C4 and C3) in sera of patients with COPD and AATD (6, 7), and in lungs of mice in models of cigarette smoke (CS)-induced emphysema (8).In this study, we investigated whether MASP-2 and the lectin pathway are activated in COPD and AATD plasma and lung tissue. Samples were obtained from subjects with COPD (n= 38, age= 64 6 10 yr, 21 men, FEV1% predicted= 45 6 27), AATD (n= 47) off AAT augmentation therapy (AATD-off, n= 30, age= 67 6 9 yr, 18 men, FEV1% predicted= 73 6 32) or on augmentation therapy (AATD-on, n= 17, age= 58 6 14 yr, 8 men, FEV1% predicted= 33 6 11), and healthy never-smokers (n= 23, age= 40 6 8.5 yr, 5 men). Subjects with active infections in the past 3 months were excluded. The subjects’ smoking status was recorded as active smoker, ex-smoker, never smoker, or unknown (the latter group was excluded from multivariate analyses). Statistical analyses were performed in R and Prism (GraphPad Software). Deidentified plasma samples were obtained from Leiden University (n= 8), Hannover University (n= 15), the Medical University of South Carolina (n= 24), and National Jewish Health (n= 62), and lung samples were obtained from the Lung Tissue Research Consortium and Hannover University. The institutional review board at National Jewish Health approved the study as exempt human subjects research.