An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions.
An innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions.
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人类尼古丁受体基因多态对COPD样皮损的先天贡献。
DOI：
10.1038/s41467-021-26637-6
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发表时间：
2021-11-04
影响因子：
16.6
通讯作者：
Maskos U
中科院分区：
文献类型：
--
作者：
Routhier J;Pons S;Freidja ML;Dalstein V;Cutrona J;Jonquet A;Lalun N;Mérol JC;Lathrop M;Stitzel JA;Kervoaze G;Pichavant M;Gosset P;Tournier JM;Birembaut P;Dormoy V;Maskos U
慢性阻塞性肺疾病通常是与吸烟相关的发病率和死亡率的主要原因。全基因组关联研究确定了一个基因座，包括CHRNA5的非同义单核苷酸多态性，rs16969968，编码烟碱乙酰胆碱受体α5亚基，易患吸烟和慢性阻塞性肺疾病。我们在此报告rs16969968非吸烟携带者的鼻息肉表现出气道上皮重塑和炎症。慢性阻塞性肺疾病的这些特征在表达人rs16969968的小鼠中自发发生。它们在暴露于猪胰弹性蛋白酶、肺气肿模型和氧化应激后显著扩增，并伴有肺功能的多态性依赖性改变。靶向rs16969968在上皮细胞中的表达导致体内气道重塑，通过减少钙进入和增加腺苷酸环化酶活性增加促炎细胞因子的增殖和产生。我们发现rs16969968直接导致慢性阻塞性肺病样病变，使肺对氧化应激和损伤的作用敏感，并代表了治疗靶点。人类烟碱乙酰胆碱受体基因的多态性与吸烟和肺部疾病如慢性阻塞性肺病（COPD）或肺癌有关。在这里，作者确定了人类编码多态性在COPD样病变中的直接作用，与吸烟或尼古丁暴露无关。
Chronic Obstructive Pulmonary Disease is a generally smoking-linked major cause of morbidity and mortality. Genome-wide Association Studies identified a locus including a non-synonymous single nucleotide polymorphism in CHRNA5, rs16969968, encoding the nicotinic acetylcholine receptor α5 subunit, predisposing to both smoking and Chronic Obstructive Pulmonary Disease. Here we report that nasal polyps from rs16969968 non-smoking carriers exhibit airway epithelium remodeling and inflammation. These hallmarks of Chronic Obstructive Pulmonary Disease occur spontaneously in mice expressing human rs16969968. They are significantly amplified after exposure to porcine pancreatic elastase, an emphysema model, and to oxidative stress with a polymorphism-dependent alteration of lung function. Targeted rs16969968 expression in epithelial cells leads to airway remodeling in vivo, increased proliferation and production of pro-inflammatory cytokines through decreased calcium entry and increased adenylyl-cyclase activity. We show that rs16969968 directly contributes to Chronic Obstructive Pulmonary Disease-like lesions, sensitizing the lung to the action of oxidative stress and injury, and represents a therapeutic target. Human polymorphisms in nicotinic acetylcholine receptor genes have been linked to both smoking and lung diseases like Chronic Obstructive Pulmonary Disease (COPD) or lung cancer. Here the authors identify a direct role for a human coding polymorphism in COPD-like lesions independent of smoke or nicotine exposure.
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DOI：
10.1152/ajplung.00050.2020
发表时间：
2020-05-01
影响因子：
4.9
作者：
Ghosh, Baishakhi;Park, Bongsoo;Sidhaye, Venkataramana K.
通讯作者：
Sidhaye, Venkataramana K.
影响因子：
3.7
作者：
Ghorani V;Boskabady MH;Khazdair MR;Kianmeher M
通讯作者：
Kianmeher M
影响因子：
82.9
作者：
Cloonan SM;Glass K;Laucho-Contreras ME;Bhashyam AR;Cervo M;Pabón MA;Konrad C;Polverino F;Siempos II;Perez E;Mizumura K;Ghosh MC;Parameswaran H;Williams NC;Rooney KT;Chen ZH;Goldklang MP;Yuan GC;Moore SC;Demeo DL;Rouault TA;D'Armiento JM;Schon EA;Manfredi G;Quackenbush J;Mahmood A;Silverman EK;Owen CA;Choi AM
通讯作者：
Choi AM
DOI：
10.1165/rcmb.2011-0353oc
发表时间：
2012-07-01
影响因子：
6.4
作者：
Herfs, Michael;Hubert, Pascale;Delvenne, Philippe
通讯作者：
Delvenne, Philippe
影响因子：
24.3
作者：
Giovannini-Chami, Lisa;Paquet, Agnes;Barbry, Pascal
通讯作者：
Barbry, Pascal