Metals in exhaled breath condensate as COPD biomarkers

呼出气体冷凝物中的金属作为 COPD 生物标志物

• 批准号: 6666787
• 负责人: ANTONIO MUTTI
• 金额: $ 36.95万
• 依托单位: UNIVERSITA DEGLI STUDI DI PARMA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6666787
• 关键词: Italy; United States; aldehydes; aluminum; asthma; atomic absorption spectrometry; biomarker; breath composition; cadmium; chromium; chronic obstructive pulmonary disease; clinical research; disease /disorder proneness /risk; human subject; lead; liquid chromatography mass spectrometry; mass spectrometry; metalloproteins; metals; nickel; oxidative stress; pathologic process; patient oriented research; peroxidation; smoking; tobacco abuse; toxicology; trace elements

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide and is increasing with a high prevalence, high morbidity and high cost. COPD is an important medical area for which biomarkers are needed for the study of the pathogenesis, the diagnosis and the clinical management. Exhaled breath condensate (EBC) can be collected with non-invasive methods and is a promising medium to develop biomarkers of COPD. The present research project is aimed at applying the most sensitive, selective and specific reference analytical techniques to the study of the composition of EBC in COPD patients. EBC levels of toxic metals and essential trace elements will be measured in COPD patients by electro-thermal atomic absorption spectroscopy (ETAAS) and inductively coupled plasma - mass spectrometry (ICP-MS). Such a novel approach (never done before) will be applied to identify and validate biomarkers of exposure and susceptibility to toxic metals, known to be contained in tobacco smoke, and probably playing a fundamental etiologic role in the pathogenetic path leading to COPD. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) will be used as a complementary approach to develop biomarkers of effect (aldehydes from lipid peroxidation) suitable for the long-term monitoring of COPD patients. This novel approach represents a significant advance over the analysis of alternative media (BALF, blood, serum, urine, hair), which are not as reliable (owing to interfering substances in the complex matrix) and reflect systemic rather than lung (target tissue) levels of both toxic metals and essential trace elements. Tobacco smoke and polluted environments substantially increase the lung burden of pneumotoxic chemicals, particularly heavy metals. Biomarkers of exposure (EBC levels of AI, Cd, Cr, Ni, Pb) should provide a quantitative estimate of the target tissue dose, thus distinguishing exposed from non-exposed controls. The lung response to inhaled pneumotoxic substances shows a high inter-individual variability as a function of different detoxifying capacity. Biomarkers of susceptibility will be developed relying on the consideration that some trace elements (Mn, Cu, Zn, Se, and Mo) are components of metalloproteins (superoxide dismutase, glutathione peroxidase, xanthine oxidase) known to modulate the response to toxic substances, possibly accounting for the limited proportion (15-20%) of smokers developing COPD. Biomarkers of susceptibility could be useful to identify and counsel people who are at increased risk of disease when exposed to tobacco smoke or environmental pollutants. Biomarkers of effect will be developed starting from aldehydes released into the EBC after lipid peroxidation in cell membranes. The pattern of aldehydes could distinguish membrane damage due to either oxidative stress or other mechanisms, such as a direct attack by free radicals. In summary, we propose a novel approach to the development of COPD biomarkers, relying on (i) noninvasive collection procedures to obtain (ii) a simple, interference-free matrix (EBC is practically water) to be analyzed by (iii) reference analytical methods, which are highly selective and specific (mainly, if not entirely, based on mass spectrometry), to determine (iv) stable analytes (heavy metals and trace elements). Through EBC biomarkers we sought to address two specific aims: a) to determine the validity of metals and aldehydes levels in EBC as biomarkers of exposure, of susceptibility and of effect in patients with COPD; b) to determine the clinical utility of EBC biomarkers as prognostic tools to predict the natural history of COPD. Establishing heavy and toxic metal levels in EBC as novel biomarkers of exposure, effect and susceptibility in patients with COPD could assist health care providers in devising new primary and secondary interventions, including drugs, to improve the quality of life and outcome of patients with COPD worldwide.

描述（由申请人提供）： 慢性阻塞性肺疾病（COPD）是全球一个主要的健康问题，并且随着高流行，高发病率和高成本而增加。 COPD是一个重要的医疗领域，需要生物标志物来研究发病机理，诊断和临床管理。呼出的呼吸冷凝物（EBC）可以通过非侵入性方法收集，并且是开发COPD生物标志物的有前途的培养基。本研究项目旨在将最敏感，最选择和特定的参考分析技术应用于COPD患者的EBC组成的研究。 EBC的有毒金属水平和必不可少的痕量元素将在COPD患者中通过电 - 心理吸收光谱（ETAA）和电感偶联等离子体 - 质谱法（ICP-MS）测量。 这种新颖的方法（以前从未做过）将用于识别和验证暴露和易感性的有毒金属的生物标志物（已知包含在烟草烟中，并可能在通往COPD的致病道路中起基本的病因学作用。液相色谱串联质谱法（LC-MS/MS）将用作一种互补方法，用于开发适合长期监测COPD患者的效应生物标志物（脂质过氧化产生的醛）。这种新颖的方法代表了对替代介质（BALF，血液，血清，尿液，头发）的分析的重大进步，这些介质不那么可靠（由于复杂矩阵中的干扰物质），反映了有毒金属和基本痕量元素的全身性而不是肺（靶组织）水平。烟草烟雾和污染的环境大大增加了气毒性化学物质的肺部负担，尤其是重金属。暴露的生物标志物（AI，CD，CR，NI，PB的EBC水平应提供对靶组织剂量的定量估计，从而将暴露与非暴露对照区分开。对吸入的肺毒性物质的肺反应显示出很高的个体间变异性，这是不同排毒能力的函数。易感性的生物标志物将依赖于这样的考虑，即某些微量元素（Mn，Cu，Zn，Se和Mo）是金属蛋白蛋白（超氧化物歧化酶，谷胱甘肽过氧化物酶，黄嘌呤氧化酶）的成分，已知可以调节对有毒物质的反应，可能对有限的coptifect（15--20）进行copt（15--20％）的反应（可能会考虑到有限的（15--20％））。易感性的生物标志物可能对识别和咨询患有烟草烟雾或环境污染物的疾病风险增加的人有用。效应的生物标志物将从细胞膜中脂质过氧化后释放到EBC的醛开始发展。醛的模式可以区分由于氧化应激或其他机制，例如自由基的直接攻击。 In summary, we propose a novel approach to the development of COPD biomarkers, relying on (i) noninvasive collection procedures to obtain (ii) a simple, interference-free matrix (EBC is practically water) to be analyzed by (iii) reference analytical methods, which are highly selective and specific (mainly, if not entirely, based on mass spectrometry), to determine (iv) stable analytes (heavy metals and trace元素）。 通过EBC生物标志物，我们试图解决两个具体的目标：a）确定EBC中金属和醛水平的有效性，作为暴露，易感性和对COPD患者的影响的生物标志物； b）确定EBC生物标志物作为预测COPD自然历史的预后工具的临床实用性。 在EBC中建立大量和有毒的金属水平，作为COPD患者暴露，效果和敏感性的新型生物标志物，可以帮助医疗保健提供者设计新的原发性和继发性干预措施，包括药物，以改善全球COPD患者的生活质量和结果。