Phenotypic characterisation of non-smoking COPD

非吸烟 COPD 的表型特征

• 批准号: MR/J000108/1
• 负责人: Peter Barnes
• 金额: $ 83.11万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ000108%2F1
• 关键词: Phenotypic; characterisation; non; smoking; COPD

Chronic obstructive pulmonary disease (COPD) is a severe, progressive, long-standing disorder of the lungs that affects over 300 million people worldwide. It is the 5th leading cause of death but by 2030 is predicted to rise to the 4th position. Death rates are increasing in Western countries, but to an even greater extent in developing countries. Although tobacco smoking is a well established risk factor for COPD, other causes, such as use of biomass fuel for cooking, outdoor air pollution, occupational exposures and poor socioeconomic status are also believed to be important causes, especially in the developing countries. Indeed, globally around 40% of COPD can be attributed to non-smoking causes. Despite this huge and growing burden, little is known about this non-smoking type of COPD. The first aim of our study is to compare the clinical features (symptoms, quality of life), lung function tests, lung scans and inflammatory profiles in sputum and lung lavage, systemic inflammation and comorbidities of non-smoking COPD patients compared to smoking-induced COPD in India and the UK. We will also document disease progression by measuring decline in lung function and health status over 3 years. The second aim to investigate whether the lower airways are colonised with bacteria and whether bacterial profiles measured by a new sensitive molecular technique differ from exposed and non-exposed controls and smoking COPD patients and whether this is linked to impaired uptake of bacteria by scavenger cells, as it is in smoking COPD patients. Thirdly, we will investigate underlying mechanisms in non-smoking compared to smoking COPD by measuring inflammatory regulators that are linked to increased inflammation and steroid resistance in smoking COPD. We will also study DNA methylation patterns in sputum samples of subjects with non-smoking and smoking COPD to understand the long-term mechanisms that may drive the underlying inflammatory process. We will measure the black carbon content in alveolar macrophages of healthy individuals, individuals with COPD due to exposure to biomass smoke and smoking COPD patients and to relate this to exposure to carbon particulates monitored in the air of homes using biomass fuels. Finally, we will determine the impact of replacing biomass fuel with a cleaner form of cooking (liquefied petroleum gas) on indoor air pollution levels, alveolar carbon content and on lung health using questionnaires, physiological measurements and sputum cellular and inflammatory mediator profiles. The proposed research study will help us better understand a common non-smoking phenotype of COPD, which is one of the leading causes of death in the world, especially in the developing countries, yet almost completely neglected by researchers and the pharmaceutical industry. We will also understand whether simple and relatively inexpensive environmental interventions, such as change in the fuel type, reduces levels of indoor air pollutants and has any impact on health outcomes. These pilot studies will inform future long-term controlled trials of cheap treatments, including low doses of oral and inhaled steroids and theophylline that may reverse steroid resistance, with measurement of important health outcomes, such as exacerbations, disease progression and mortality that are beyond the scope of the current proposal. The results of the study will help to generate new knowledge about non-smoking COPD in India and the UK, but will also have a direct impact on preventative and therapeutic strategies that will benefit policy makers and health care providers across the world. The study will help the exchange of knowledge between the British and Indian research teams and will build up research capacity. Our proposed study addresses a very important unmet clinical need and profits by the complementary strengths and approaches of the Indian and UK research teams.

慢性阻塞性肺疾病（COPD）是一种严重的，进行性的，长期存在的肺部疾病，影响了全球超过3亿人。这是死亡的第五个主要原因，但预计到2030年将上升到第四位。西方国家的死亡率正在增加，但在发展中国家的死亡率更大。尽管吸烟是COPD的良好危险因素，但其他原因，例如将生物质燃料用于烹饪，户外空气污染，职业暴露和社会经济地位差也是重要的原因，尤其是在发展中国家。实际上，全球约40％的COPD可以归因于非吸烟原因。尽管负担巨大，但对这种非吸烟类型的COPD知之甚少。我们研究的第一个目的是比较与印度和英国吸烟诱导的COPD相比，痰液和肺灌洗，全身性炎症和合并症的临床特征，肺功能测试，肺部扫描和炎症特征，全身性炎症和合并症。我们还将通过衡量3年内肺功能和健康状况的下降来记录疾病进展。第二个目的是研究下呼吸道是否用细菌定居，以及通过新的敏感分子技术测量的细菌谱是否与暴露和非暴露的对照和吸烟COPD患者不同，以及这是否与通过吸烟COPD患者在清除剂细胞中摄取细菌的摄取受损。第三，与吸烟COPD相比，我们将通过测量与吸烟COPD中的炎症和类固醇耐药性有关的炎症调节剂来研究非吸烟的潜在机制。我们还将研究具有非吸烟和吸烟COPD的受试者的痰液样本中的DNA甲基化模式，以了解可能驱动潜在炎症过程的长期机制。由于暴露于生物质烟雾和吸烟COPD患者，我们将测量健康个体的肺泡巨噬细胞中的黑碳含量，并将其与使用生物质燃料在房屋空气中监测的碳颗粒相关。最后，我们将确定使用一种清洁形式的烹饪形式（液化石油气）对室内空气污染水平，肺泡碳含量以及使用问卷调查，生理测量以及痰液细胞和炎症介体配置文件来替换生物质燃料的影响。拟议的研究将帮助我们更好地理解COPD的常见非吸烟表型，COPD是世界上主要的死亡原因之一，尤其是在发展中国家，但几乎完全被研究人员和制药行业所忽视。我们还将了解简单且相对廉价的环境干预措施（例如燃料类型的变化）是否会降低室内空气污染物的水平，并对健康结果产生任何影响。这些试点研究将为廉价治疗的未来长期对照试验提供信息，包括低剂量的口服类固醇和茶碱，可能会逆转类固醇的耐药性，并测量重要的健康结果，例如加剧，疾病进展和死亡率，这些结果超出了当前建议的范围。该研究的结果将有助于在印度和英国产生有关非吸烟COPD的新知识，但也将对预防和治疗策略产生直接影响，这将使全球政策制定者和医疗保健提供者受益。这项研究将有助于英国研究团队之间的知识交流，并将建立研究能力。我们提出的研究通过印度和英国研究团队的补充优势和方法解决了非常重要的未满足临床需求和利润。

项目成果

ERS/ATS workshop report on respiratory health effects of household air pollution.

• DOI: 10.1183/13993003.00698-2017
• 发表时间: 2018-01
• 期刊: The European respiratory journal
• 作者: Sood A;Assad NA;Barnes PJ;Churg A;Gordon SB;Harrod KS;Irshad H;Kurmi OP;Martin WJ 2nd;Meek P;Mortimer K;Noonan CW;Perez-Padilla R;Smith KR;Tesfaigzi Y;Ward T;Balmes J
• 通讯作者: Balmes J

COPD immunopathology.

• DOI: 10.1007/s00281-016-0561-5
• 发表时间: 2016-07
• 期刊: Seminars in immunopathology
• 影响因子: 9
• 作者: Caramori G;Casolari P;Barczyk A;Durham AL;Di Stefano A;Adcock I
• 通讯作者: Adcock I

Reduced Clearance of Fungal Spores by Chronic Obstructive Pulmonary Disease GM-CSF- and M-CSF-derived Macrophages.

慢性阻塞性肺病 GM-CSF 和 M-CSF 衍生巨噬细胞对真菌孢子的清除率降低。

• DOI: 10.1165/rcmb.2017-0351le
• 发表时间: 2018
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Wrench C

Interaction of Pattern Recognition Receptors with Mycobacterium Tuberculosis.

• DOI: 10.1007/s10875-014-0103-7
• 发表时间: 2015-01
• 期刊: JOURNAL OF CLINICAL IMMUNOLOGY
• 影响因子: 9.1
• 作者: Mortaz, Esmaeil;Adcock, Ian M.;Tabarsi, Payam;Masjedi, Mohammad Reza;Mansouri, Davood;Velayati, Ali Akbar;Casanova, Jean-Laurent;Barnes, Peter J.
• 通讯作者: Barnes, Peter J.