DOES MITOCHONDRIA-TARGETED HYDROGEN SULFIDE PREVENT AND/OR REVERSE CIGARETTE SMOKE-INDUCED LUNG INJURY? IMPLICATIONS FOR COPD.

慢性阻塞性肺疾病（COPD）是一种影响肺部的长期疾病，随着时间的推移而恶化（即它是一种“进行性疾病”），并且是不可逆的。没有有效的治疗方法可以阻止COPD的进展或逆转疾病。COPD的特征在于导致肺部和肺部内的气道中的广泛炎症，并导致长期呼吸问题，例如由于肺部内和周围的不良气流导致的持续呼吸短促，以及气道中粘液的积聚。2015年，COPD导致全球约317万人死亡（占当年全球死亡人数的5%）。在英国，近120万人（约占人口的2%; 40岁以上的所有人的4.5%）患有COPD，使其成为仅次于哮喘的第二大常见肺部疾病（见影响摘要）。2014年，仅NHS的肺部疾病直接成本就为99亿英镑，如果包括休息日，护理成本，专科护理成本，这一数字上升到1542亿英镑，其中466亿英镑（29%）归因于COPD。这给家庭和社会带来了巨大的成本，例如，随着疾病的进展而请假、残疾津贴和个人护理（医疗保健服务和家庭）。由于慢性阻塞性肺病的持续炎症性质，患者患肺癌的机会也增加了6倍，大大增加了患者及其家人和护理人员的压力和焦虑。在西方国家，这种疾病发展的主要风险因素是主流或二手烟（CS），约80%的COPD死亡与此原因有关。CS暴露不仅会引起炎症，还会损害肺中可以调节炎症过程的细胞（例如巨噬细胞）。具体来说，CS损害这些细胞的特定部分（线粒体），控制“能量生产”（以ATP的形式）。正常情况下，细胞中的能量生产是严格控制和高效的，但当线粒体受损时，代谢燃料（例如来自食物）被浪费，线粒体变得泄漏并导致高毒性“自由基”的积聚，这加剧了炎症，需要从体内清除（或防止形成）。我们还发现，CS消耗了巨噬细胞和线粒体中的一种新发现的抗炎分子，这种分子通常存在于我们的身体中，并在细胞受到压力时被线粒体用作“紧急燃料”来源。这种分子被称为硫化氢（H2S）。因此，我们制造了新的化合物（称为mtH 2SD），专门针对细胞内的线粒体并提供微量的H2S。我们的初步研究表明这些化合物可以拯救线粒体（和巨噬细胞）从CS诱导的损伤中分离细胞，预防CS诱导的炎症、肺损伤，改善小鼠肺功能（例如，mtH 2SD阻止了CS诱导的COPD），关键的是，防止了CS诱导的肺部微小气囊的破坏使用一系列新的mtH 2SD，我们已经进行了分离的细胞实验和使用独特的实验性COPD小鼠模型的实验，我们将研究mtH 2 SD如何（a）预防和（B）拯救COPD患者的肺免受CS暴露的有害影响。我们还将确定将化合物输送到肺部的最佳途径。我们希望我们项目的数据将为一种严重且使人衰弱的疾病带来新的有效治疗方法，这种疾病在全球的重要性正在迅速增长（即由CS暴露引起的COPD，但也由日益工业化和污染的星球上的空气污染引起）。

Chronic obstructive pulmonary disease (COPD) is a long term disease affecting the lungs that gets worse over time (i.e. it is a 'progressive disease') and it is irreversible. There are no effective treatments that halt the progression of COPD or reverse the disease. COPD is characterised by extensive inflammation in the airways leading to, and within the lungs and results in long term breathing problems such as persistent shortness of breath due to poor airflow in and around the lungs, and the build-up of mucus in the airways. In 2015 COPD was responsible for ~ 3.17 million deaths worldwide (5% of all deaths globally that year). In the UK, almost 1.2 million people (~2% of the population; 4.5% of all people >40 yrs old) are living with COPD making it the second most common lung disease, after asthma (see Impact Summary). In 2014, the direct costs of lung diseases to the NHS alone was £9.9 billion and when days off work, nursing costs, specialist care costs are included, this figure rises to £154.2 billion of which £46.6 billion (29%) is due to attributed to COPD. This represents a significant cost to family and society e.g. time off work as the disease progresses, disability allowances, and care for individuals (healthcare services and family). Due to the persistent inflammatory nature of COPD, patients also have a 6 fold greater chance of developing lung cancer, greatly adding to stress and anxiety to the patient and their families and carers. The major risk factor in the development of this disease in Western countries is mainstream or second hand cigarette smoke (CS) with ~ 80% of all COPD deaths linked to this cause. CS exposure not only causes inflammation, it damages cells in the lung that can regulate inflammatory processes (e.g. macrophages). Specifically, CS damages a specific part of these cells (the mitochondria) that control 'energy production' (in the form of ATP). Normally energy production in cells is tightly controlled and highly efficient but when mitochondria are damaged, metabolic fuel (e.g. from food) is wasted and mitochondria become leaky and cause a build up of highly toxic "free radicals" which exacerbate inflammation and need to be removed from the body (or prevented from forming). We have also found that CS depletes macrophages and mitochondria of a newly identified anti-inflammatory molecule usually found in our body and used by mitochondria as an "emergency fuel" source when cells become stressed. This molecule is called hydrogen sulfide (H2S). We have therefore made novel compounds (called mtH2SD) which specifically target mitochondria within cells and deliver tiny doses of H2S. Our preliminary studies have shown these compounds can rescue mitochondria (and macrophages) from CS-induced damage in isolated cells and prevent CS-induced inflammation, lung damage and improve lung function in mice (e.g. mtH2SD stopped CS-induced COPD) and critically, prevented CS-induced destruction of the tiny air sacs in our lungs (mtH2SD prevented emphysema).Using a series of novel mtH2SD we have made, isolated cell experiments and experiments using unique mouse models of experimental COPD, we will look at how mtH2SD (a) prevent and (b) rescue the lung from the detrimental effects of CS exposure in COPD. We will also determine the best route to get the compounds to the lungs. We hope data from our project will lead to new and effective treatments for a serious and debilitating disease of rapidly growing global importance (i.e. COPD induced by CS exposure but also caused by air pollution in an increasingly industrialised and polluted planet).