Toxic metals and ion channels in cigarette-smoke induced COPD

香烟烟雾引起的慢性阻塞性肺病中的有毒金属和离子通道

基本信息

批准号：
7837630
负责人：
Estelle A Cormet-Boyaka
金额：
$ 7.5万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-11 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7837630
关键词：
Affect Air Apical Asthma Bacterial Infections Biopsy Breathing Cadmium Cells Chloride Channels Chloride Ion Chlorides Chronic Chronic Obstructive Airway Disease Cigarette Smoker Clinical Clinical Research Collaborations Coughing Coupled Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Development Disease Elements Epithelial Epithelial Cells Fluids and Secretions Food Functional disorder Genes Goals Half-Life Hand Heavy Metals Human Hydration status IL8 gene Immunohistochemistry In Situ Infection Inflammation Inflammatory Ion Channel Ions Iron Laboratory Research Letters Link Lung Maintenance Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Measures Mediating Nickel Nose Ohio Pathologist Pathology Patients Pattern Phenotype Physiological Plasma Polymerase Chain Reaction Production Recording of previous events Reporting Research Reverse Transcriptase Polymerase Chain Reaction Sampling Smoke Smoker Smoking History Sodium Channel Sputum Staging Surface Testing Time Tissues Tobacco smoke Trace Elements United States National Institutes of Health Universities Water Zinc abstracting acronyms cigarette smoke-induced cigarette smoking cigarette smoking clinical phenotype cytokine disorder control driving force epithelial Na+ channel human tissue innovation mortality non-smoker nornicotine novel prevent programs public health relevance stem toxic metal

项目摘要

DESCRIPTION (provided by applicant): Cigarette smoke (CS) is well known to induce chronic obstructive pulmonary disease (COPD) and cancer in humans. Cadmium is the most abundant toxic heavy metal that is present in CS. Cadmium is also present in contaminated air, food and water. Cadmium inhalation has been reported to be associated with development of COPD and lung cancer. Importantly, cadmium accumulates in the host with a half-life of 20 to 30 years. CS was shown to reduce the expression of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). CFTR is a chloride channel that is mostly expressed in epithelial cells and is key in maintaining the surface hydration of the lung. Absence of functional CFTR causes Cystic Fibrosis, a disease characterized by impaired mucocilliary clearance, and chronic infection and inflammation in the lung. Therefore, the potential importance of CS-induced CFTR abnormalities in the pathophysiology of smoking-related diseases should be further evaluated. It also gives us an opportunity to define a novel mechanism of action for the development and/or worsening of COPD. Indeed, over 80% of COPD patients have a smoking history. This proposal stems from our recent evidence that cadmium decreases CFTR expression in lung epithelial cells resulting in reduction of chloride transport, and increased secretion of the pro-inflammatory cytokine IL-8. Our hypothesis is that the toxic heavy metal cadmium inhibits the expression of the CFTR chloride channel, therefore leading to lung dysfunction and COPD. Here we propose (1) to determine the expression of the ion channels CFTR and ENaC (the epithelial sodium channel that is co-regulated by CFTR), and the pro- inflammatory cytokine IL-8 using quantitative RT-PCR, and (2) to measure the level of heavy metals using inductively coupled plasma mass spectroscopy (ICP-MS) in lungs samples from cigarette smokers that developed COPD and from control patients that are non-smokers. This study will set the stage to understanding the contribution of heavy metals and the ion channel CFTR in the development of COPD. PUBLIC HEALTH RELEVANCE: Cigarette smoke (CS) contains toxic heavy metals like cadmium, and both CS and cadmium can induce COPD. We found that cadmium can suppress the Cystic Fibrosis Transmembrane conductance Regulator, a chloride channel that when dysfunctional leads to cystic fibrosis. (End of Abstract)

描述（由申请人提供）：众所周知，香烟烟雾（CS）会诱发人类慢性阻塞性肺病（COPD）和癌症。镉是 CS 中含量最丰富的有毒重金属。镉还存在于受污染的空气、食物和水中。据报道，镉吸入与慢性阻塞性肺病和肺癌的发生有关。重要的是，镉在宿主体内积聚，半衰期为 20 至 30 年。 CS 被证明可以降低囊性纤维化跨膜电导调节因子 (CFTR) 的表达。 CFTR 是一种氯离子通道，主要在上皮细胞中表达，对于维持肺表面水合作用至关重要。功能性 CFTR 的缺失会导致囊性纤维化，这是一种以粘液纤毛清除受损、肺部慢性感染和炎症为特征的疾病。因此，应进一步评估CS诱导的CFTR异常在吸烟相关疾病的病理生理学中的潜在重要性。它还使我们有机会定义一种针对慢性阻塞性肺病的发展和/或恶化的新作用机制。事实上，超过80%的COPD患者有吸烟史。这一提议源于我们最近的证据，即镉降低肺上皮细胞中 CFTR 的表达，导致氯离子转运减少，并增加促炎细胞因子 IL-8 的分泌。我们的假设是有毒的重金属镉抑制CFTR氯离子通道的表达，从而导致肺功能障碍和慢性阻塞性肺病。在此，我们建议 (1) 使用定量 RT-PCR 确定离子通道 CFTR 和 ENaC（由 CFTR 共同调节的上皮钠通道）以及促炎细胞因子 IL-8 的表达，以及 (2)使用电感耦合等离子体质谱 (ICP-MS) 测量患有慢性阻塞性肺病 (COPD) 的吸烟者和非吸烟者对照患者的肺部样本中的重金属水平。这项研究将为了解重金属和离子通道 CFTR 在 COPD 发展中的贡献奠定基础。公众健康相关性：香烟烟雾 (CS) 含有镉等有毒重金属，CS 和镉均可诱发慢性阻塞性肺病 (COPD)。我们发现镉可以抑制囊性纤维化跨膜电导调节器，这是一种氯离子通道，当功能失调时会导致囊性纤维化。（摘要完）

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels.

GOLD4 COPD 肺部金属积聚与 CFTR 水平降低有关。

DOI：
发表时间：
2014-06-23
期刊：
影响因子：
5.8
作者：
Hassan, Fatemat;Xu, Xiaohua;Nuovo, Gerard;Killilea, David W;Tyrrell, Jean;Da Tan, Chong;Tarran, Robert;Diaz, Philip;Jee, Junbae;Knoell, Daren;Boyaka, Prosper N;Cormet
通讯作者：
Cormet

MiR-101 and miR-144 regulate the expression of the CFTR chloride channel in the lung.

miR-101 和 miR-144 调节肺中 CFTR 氯离子通道的表达。

DOI：
发表时间：
2012
期刊：
影响因子：
3.7
作者：
Hassan, Fatemat;Nuovo, Gerard J;Crawford, Melissa;Boyaka, Prosper N;Kirkby, Stephen;Nana;Cormet
通讯作者：
Cormet

Reduced expression of the Ion channel CFTR contributes to airspace enlargement as a consequence of aging and in response to cigarette smoke in mice.

由于衰老和小鼠对香烟烟雾的反应，离子通道 CFTR 表达的减少导致空腔扩大。

DOI：
发表时间：
2019-09-02
期刊：
影响因子：
5.8
作者：
Wellmerling, Jack H;Chang, Sheng;Kim, Eunsoo;Osman, Wissam H;Boyaka, Prosper N;Borchers, Michael T;Cormet
通讯作者：
Cormet