PI3K Signaling and Aberrant Neutrophil Function in COPD; Implications for Disease Susceptibility, Prognosis and Therapeutic Targeting

慢性阻塞性肺疾病(COPD)是一个描述肺气肿和慢性支气管炎等疾病的术语，其特征是呼吸管(呼吸道)狭窄，并与肺组织破坏有关。它使人虚弱，影响着英国的300万人，是第五大死亡原因(英国每年有2.5万人死亡)。它是唯一一种死亡率上升的慢性病。英国慢性阻塞性肺病的费用估计为每年32亿GB。NHS每年的费用为9亿GB，其中50%是由于症状恶化而临时住院。更好的疾病管理将减少这种疾病的负担，但目前还没有治疗方法阻止疾病的发生或进展。COPD是一种慢性炎症性疾病，肺部持续存在过多的炎性蛋白和细胞会造成损害。吸烟是最重要的风险因素，但只有15%的吸烟者会患上COPD，而且这种疾病是家族遗传的，这表明存在易患COPD的遗传因素。即使在戒烟后，炎症和肺部破坏仍在继续。人们对此知之甚少，但我们认为COPD患者有异常的免疫反应，即使在有害刺激(香烟烟雾)消失后也会导致疾病。目前，我们不能预测谁会患上COPD，或者是否所有的疾病特征都是由相同的潜在免疫问题引起的。了解这一点是至关重要的，因为这将有助于指导新的治疗。中性粒细胞是对抗感染的关键白细胞。它们离开血液，准确地移动(迁移)到感染区域，在那里它们摄取细菌，用细胞内包含的大量蛋白质杀死它们。如果这些蛋白质在人体组织中释放，就会造成损害和炎症。中性粒细胞含有控制细胞表达的蛋白质的基因。这些蛋白质可能是酶，控制中性粒细胞内的化学反应，也可能是结构蛋白，控制它们的运动方式。中性粒细胞是慢性阻塞性肺疾病的中心。慢性阻塞性肺疾病患者肺部有大量中性粒细胞，中性粒细胞释放的化学物质可导致特征性肺损伤。我们的数据显示，COPD患者的中性粒细胞存在缺陷，迁移的准确性低于健康人或其他肺部疾病患者的细胞，在感染模型中摄取的细菌也较少。这一点很重要，因为不准确的迁移和细菌清除减少可能会导致感染期间更多的肺损伤和更差的结局；这两者都被认为是慢性阻塞性肺疾病的核心。我们已经证明，这种有害的细胞行为是由于一种名为磷脂酰肌醇-3激酶(PI3K)的蛋白质酶活性增加所致。PI3K信号异常可能是COPD中性粒细胞行为改变的原因，纠正这一点可能为COPD提供一种新的治疗方法。我们希望通过从COPD患者、有COPD风险的患者(COPD患者的家人)和健康志愿者的血液和肺分泌物中分离出中性粒细胞，来研究分子信号并确定COPD患者中性粒细胞损伤行为的相关性。这将决定有缺陷的中性粒细胞行为在COPD所有不同特征中的普遍程度，以及你是否可以通过评估他们的中性粒细胞来预测谁可能会患上这种疾病。然后，我们将通过研究COPD中性粒细胞内结构蛋白和酶(以及控制它们的基因)的活性，利用我们广泛的初步数据和细胞信号知识来确定中性粒细胞行为缺陷的原因，以集中我们的实验。确定中性粒细胞行为缺陷的具体原因将使我们能够形成针对COPD的新的有针对性的治疗方法，改善该疾病患者的健康。它还可以让我们预测谁是COPD风险最高的人，开发一种筛查工具，帮助告知人们他们的生活方式选择。

Chronic Obstructive Pulmonary Disease (COPD) is a term that describes conditions such as emphysema and chronic bronchitis which are characterised by narrowing of the breathing tubes (airways), and are associated with lung tissue destruction. It is debilitating, affects 3 million people in the UK, and is the 5th leading cause of death (25,000 deaths in the UK/year). It is the only chronic disease with a rising death rate. UK COPD costs are estimated at £3.2 billion per annum. Annual NHS costs are £900M, 50% of which are due to unscheduled hospital admissions due to deteriorating symptoms. Better disease management would reduce this disease burden, but currently no treatments prevent disease onset or halt progression. COPD is a chronic inflammatory condition, where the continued presence of excessive inflammatory proteins and cells in the lung cause damage. Smoking cigarettes is the most important risk factor, but only 15% of smokers develop COPD, and the disease runs in families, suggesting there are genetic factors that predispose towards COPD. Inflammation and lung destruction continue even after smoking cessation. This is poorly understood, but we believe that COPD patients have abnormal immune responses that drive disease even after noxious stimuli (cigarette smoke) have gone. Presently we cannot predict who will develop COPD or if all disease features are caused by the same underlying immune problem. It is vital to understand this, as it will help direct new treatments.Neutrophils are white blood cells crucial for fighting infection. They leave the blood, moving (migrating) accurately to areas of infection, where they ingest bacteria, killing them with an arsenal of proteins contained within the cell. These proteins cause damage and inflammation if they are released in the body's tissues. Neutrophils contain genes that control the cell by dictating what proteins are expressed. These proteins could be enzymes, controlling chemical reactions within the neutrophil, or structural proteins, controlling how they move. Neutrophils are central to COPD. COPD patients have many neutrophils in their lungs and the chemicals neutrophils release can cause the characteristic lung damage. Our data show that neutrophils from COPD patients are defective, migrating less accurately than cells from healthy subjects or people with other lung diseases and ingest less bacteria in models of infection. This is important, as inaccurate migration and reduced bacterial clearance could lead to more lung damage and poorer outcomes during infections; both of these are thought central in COPD. We have shown this harmful cell behaviour is due to increased activity of a protein enzyme called phophosinositide-3 kinase (PI3K). Abnormal PI3K signalling may be the cause of altered COPD neutrophil behaviour and correcting this may offer a new treatment in COPD.We wish to investigate the molecular signals and identify the relevance of injurious neutrophil behaviour in COPD, using neutrophils isolated from blood and lung secretions of COPD patients, those at risk of developing COPD (family members of COPD patients) and healthy volunteers. This will determine how prevalent the defective neutrophil behaviour is across all the differing features of COPD, and whether you can predict who might develop the disease by assessing their neutrophils. We will then identify the cause of the defective neutrophil behaviour, by studying the activity of structural proteins and enzymes (and the genes that control them) within COPD neutrophils, using our extensive preliminary data and knowledge of cell signaling to focus our experiments. Identifying the specific cause of defective neutrophil behaviour will allow us to form new targeted treatments for COPD, improving the health of patients with the disease. It may also allow us to predict who is most at risk of the COPD, developing a screening tool, helping to inform people about their lifestyle choices.