Phenotypic characterisation of non-smoking COPD

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，影响着全世界3亿多人。它是第五大死因，但预计到2030年将升至第四位。西方国家的死亡率正在上升，但发展中国家的死亡率上升幅度更大。虽然吸烟是COPD的一个公认的风险因素，但其他原因，如使用生物质燃料做饭、室外空气污染、职业暴露和社会经济地位低下，也被认为是重要原因，特别是在发展中国家。事实上，在全球范围内，约40%的慢性阻塞性肺病可归因于非吸烟原因。尽管这种巨大且不断增加的负担，但人们对这种非吸烟类型的慢性阻塞性肺病知之甚少。本研究的第一个目的是比较印度和英国非吸烟COPD患者与吸烟诱导COPD患者的临床特征（症状、生活质量）、肺功能检查、肺部扫描和痰液和肺灌洗中的炎症谱、全身性炎症和合并症。我们还将通过测量3年内肺功能和健康状况的下降来记录疾病进展。第二个目的是调查下气道是否有细菌定植，以及通过一种新的敏感分子技术测量的细菌谱是否与暴露和非暴露对照以及吸烟COPD患者不同，以及这是否与清除细胞对细菌的吸收受损有关，就像吸烟COPD患者一样。第三，我们将通过测量与吸烟COPD中炎症和类固醇抵抗增加相关的炎症调节因子，来研究非吸烟与吸烟COPD的潜在机制。我们还将研究非吸烟和吸烟COPD受试者痰样本中的DNA甲基化模式，以了解可能驱动潜在炎症过程的长期机制。我们将测量健康个体、因暴露于生物质烟雾而患有COPD的个体和吸烟的COPD患者肺泡巨噬细胞中的黑碳含量，并将其与使用生物质燃料的家庭空气中监测的碳颗粒暴露量联系起来。最后，我们将通过问卷调查、生理测量和痰细胞和炎症介质谱来确定用更清洁的烹饪形式（液化石油气）取代生物质燃料对室内空气污染水平、肺泡碳含量和肺部健康的影响。拟议的研究将帮助我们更好地了解慢性阻塞性肺病的一种常见的非吸烟表型，这是世界上主要的死亡原因之一，特别是在发展中国家，但几乎完全被研究人员和制药行业所忽视。我们还将了解简单和相对廉价的环境干预措施，如改变燃料类型，是否能降低室内空气污染物水平并对健康结果产生任何影响。这些试点研究将为未来廉价治疗的长期对照试验提供信息，包括可能逆转类固醇耐药性的低剂量口服和吸入类固醇和茶碱，并测量超出当前建议范围的重要健康结果，如恶化、疾病进展和死亡率。这项研究的结果将有助于在印度和英国产生关于非吸烟慢性阻塞性肺病的新知识，但也将对预防和治疗策略产生直接影响，这将使全世界的政策制定者和卫生保健提供者受益。这项研究将有助于英国和印度研究团队之间的知识交流，并将建立研究能力。我们提议的研究通过印度和英国研究团队的互补优势和方法解决了一个非常重要的未满足的临床需求和利润。

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.