Toxic metals and ion channels in cigarette-smoke induced COPD

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疾病（COPD）和癌症。镉是CS中含量最丰富的有毒重金属。镉也存在于受污染的空气、食物和水中。据报道，镉吸入与COPD和肺癌的发展有关。重要的是，镉在宿主体内积累，半衰期为20至30年。CS显示出减少囊性纤维化跨膜传导调节因子（CFTR）的表达。CFTR是一种氯离子通道，主要在上皮细胞中表达，是维持肺表面水合作用的关键。功能性CFTR的缺乏导致囊性纤维化，这是一种以粘液纤毛清除受损以及肺中的慢性感染和炎症为特征的疾病。因此，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应进一步评估。这也给了我们一个机会来定义一个新的作用机制的发展和/或恶化的COPD。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，即镉降低了肺上皮细胞中CFTR的表达，导致氯离子转运减少，并增加了促炎细胞因子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COPD。在这里，我们提出（1）确定离子通道CFTR和ENaC的表达（由CFTR共调节的上皮钠通道）和促炎细胞因子IL-8，和（2）使用电感耦合等离子体质谱（ICP-MS）测量来自发展为COPD的吸烟者和来自非COPD的对照患者的肺样品中的重金属水平。吸烟者。这项研究将为了解重金属和离子通道CFTR在COPD发展中的作用奠定基础。公共卫生相关性：香烟烟雾（CS）含有镉等有毒重金属，CS和镉均可诱发COPD。我们发现，镉可以抑制囊性纤维化跨膜电导调节器，一个氯离子通道，当功能障碍导致囊性纤维化。(End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)