Epithelial Sodium Channels and Pulmonary Toxicity of Zinc

上皮钠通道和锌的肺毒性

• 批准号: 7744689
• 负责人: Shaohu Sheng
• 金额: $ 27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-14 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744689
• 关键词: Address; Amiloride; Binding Sites; Breathing; Cells; Chronic; Conflict (Psychology); Culture Media; Cystic Fibrosis; Data; Defense Mechanisms; Disease; Dose; Dust; Ensure; Epithelial; Equilibrium; Exposure to; Figs - dietary; Frequencies; Height; Human; Knowledge; Lead; Link; Liquid substance; Lung; Measures; Metals; Methods; Minor; Molecular; Molecular Target; Mucociliary Clearance; Mucous body substance; Mus; Oocytes; Particulate; Particulate Matter; Pathogenesis; Peptide Hydrolases; Physiological; Principal Investigator; Protease Inhibitor; Reporting; Reproducibility; Role; Sodium; Sodium Channel; System; Testing; Toxic effect; Update; Xenopus oocyte; Zinc; airway epithelium; airway surface liquid; bronchial epithelium; epithelial Na+ channel; extracellular; lung injury; programs; research study; response; therapy development

DESCRIPTION (provided by applicant): Zinc, a major soluble component of particulate matter, may be a critical toxic agent in the cardiorespiratory pathophysiologic effects of exposure to atmospheric dusts. Nonetheless, the molecular targets that underlie zinc toxicity within lung remain unknown. We recently reported that extracellular zinc (1-100 ?M) increased amiloride-sensitive sodium currents of heterologously expressed murine epithelial Na+ channel (ENaC) subunits. Since a) ENaC-dependent sodium reabsorption across airway epithelia has a significant role in regulating the volume of airway surface liquids (and hence mucociliary transport); and b) activation of ENaC is essential in the pathogenesis of chronic airway disorders such as cystic fibrosis, we hypothesize that activation of ENaC by zinc is an important molecular determinant of the toxicity of inhaled particulate matter. Accordingly, the specific aims of this proposal are (i) to determine the effects of zinc on ENaC activity and its impact on periciliary liquid (PCL) height, mucociliary transport (MCT) and ciliary beat frequency (CBF) in primary cultures of human bronchial epithelium (HBE); (ii) to determine the effects of zinc on ENaC activity in a heterologous expression system; and (iii) to identify the molecular mechanism by which zinc activates ENaC. Our proposed studies regarding the effects of extracellular zinc on ENaC activity in primary cultures of airway epithelium and in heterologous expression systems will provide fundamental biophysical and molecular information towards our understanding of the pulmonary response to inhaled particulate matter. Our proposed study will examine the link between excess zinc, a suspected major player in human lung injury due to inhaled particulates, and the activity of lung sodium channels that are critical regulators of mucus clearance, the primary lung defense mechanism. This study will enhance our understanding of mechanisms by which atmospheric dusts result in lung damage, and will provide basic information that may lead to the development of intervention measures.

描述（由申请人提供）：锌是颗粒物质的主要可溶成分，可能是暴露于大气灰尘的心肺病理生理影响中的关键有毒药物。尽管如此，肺内锌毒性构成的分子靶标仍然未知。我们最近报道说，细胞外锌（1-100？m）增加了异源表达的鼠上皮Na+通道（ENAC）亚基的阿米洛利敏感性钠电流。由于a）跨气道上皮的ENAC依赖性钠重吸收在调节气道表面液体的体积（以及粘膜纤毛运输）中具有重要作用； b）ENAC的激活对于诸如囊性纤维化等慢性气道疾病的发病机理至关重要，我们假设锌通过锌激活ENAC是吸入颗粒物毒性毒性的重要分子决定因素。因此，该提案的具体目的是（i）确定锌对ENAC活性及其对周围液体（PCL）高度，粘膜纤维转运（MCT）和纤毛搏动频率（CBF）对人支气管上皮（HBE）原发性培养的影响； （ii）确定锌对异源表达系统中ENAC活性的影响； （iii）确定锌激活ENAC的分子机制。我们提出的关于细胞外锌对气道上皮原发性培养物和异源表达系统中ENAC活性的影响的研究将提供基本的生物物理和分子信息，以了解我们对吸入颗粒物的肺反应的理解。我们提出的研究将检查过量锌之间的联系，锌是由于吸入的颗粒物而导致的人类肺损伤的主要参与者，以及肺钠通道的活性，这是粘液清除的关键调节剂，这是主要的肺防御机制。这项研究将增强我们对大气灰尘导致肺损害的机制的理解，并提供可能导致干预措施发展的基本信息。