MICA: Senolytic therapies for chronic obstructive pulmonary disease

慢性阻塞性肺疾病（简称COPD）影响了大约十分之一的45岁以上人群，目前是英国第三大最常见的死亡原因，也是人们在冬季住院的主要原因。慢性阻塞性肺病导致运动时进行性呼吸短促，其原因是小气管变窄（小气道疾病）和肺组织损失（称为肺气肿）。虽然我们有很好的吸入器来改善慢性阻塞性肺病的症状，但没有针对慢性阻塞性肺病潜在疾病过程的治疗方法，因此目前的治疗方法无法防止疾病随着时间的推移恶化或阻止人们死于慢性阻塞性肺病。这是因为我们仍然不了解慢性阻塞性肺病的潜在疾病过程。慢性阻塞性肺病主要是老年人的疾病，越来越多的证据表明，慢性阻塞性肺病可能是由于长期接触香烟烟雾或空气污染物等其他刺激物而导致肺部加速或过早老化所致。衰老细胞的积累被称为衰老细胞，有时被称为“僵尸”细胞，它们处于假死状态，不能像往常一样修复肺损伤，而是释放出一种有害细胞产物的混合物，这种混合物被称为衰老相关分泌表型（或简称SASP），导致肺部炎症，小气管受到威胁，肺部破坏并将衰老扩散到其他细胞，导致疾病进展。通过选择性地去除这些衰老细胞，有可能延长小鼠的寿命，并显着减轻小鼠的几种与年龄相关的疾病模型。已经发现有几种类型的药物可以选择性地消除衰老细胞，这些药物被称为抗衰老疗法。在慢性阻塞性肺病中应用这些治疗是合乎逻辑的。然而，不同类型的细胞对这些疗法的反应可能不同。我们建议研究三种类型的肺细胞，它们在COPD的潜在疾病过程中发挥关键作用——小气道的内衬细胞、导致小气道瘢痕形成的细胞和最终修复肺损伤的细胞。我们将研究三种不同类型的抗衰老疗法，并研究它们对人体肺细胞（从常规手术切除的肺中获得）的影响。这些都是阿斯利康正在开发的新疗法，我们与阿斯利康合作了一段时间。我们将看看这些抗衰老疗法是否能够选择性地杀死COPD肺中的衰老细胞，而不是那些可能吸烟或不吸烟但肺正常的人的细胞。我们已经在组织培养实验和培养皿中的肺切片中表明，这些方法似乎对COPD细胞有选择性地起作用。我们也证明了这种方法在COPD小鼠模型中有效。当一种新型的抗衰老药物被吹入老鼠的肺部时，它会阻止这些动物因长期吸烟而引起的肺部衰老和炎症，并使肺部重新生长。这表明，这种治疗方法可能会减少疾病的进展，甚至有可能逆转疾病。抗衰老疗法已经被用于治疗一些与年龄有关的疾病，并显示出良好的耐受性。我们的研究可能为COPD患者最有效的抗衰老治疗方法提供证据，并为将来开展抗衰老治疗的临床试验提供基础。

Chronic obstructive pulmonary disease (COPD for short), affects about 1 in 10 people over 45 years of age and is now the 3rd commonest cause of death in the UK as well as the main reason people are admitted to hospital in the winter. COPD causes progressive shortness of breath on exercise and is due to narrowing of small air tubes (small airway disease) and a loss of lung tissue (known as emphysema). Although we have good inhalers to improve symptoms of COPD, there are no treatments that target the underlying disease process in COPD so that current therapies fail to prevent the disease worsening over time or stop people dying from COPD. This is because we still do not understand the underling disease process in COPD. COPD is a disease mainly of the elderly and there is increasing evidence that it may be due to accelerated or premature ageing of the lungs, as a result of long-term exposure to cigarette smoke or other irritants like air pollutants. There is an accumulation of aged cells known as senescent cells, sometimes called "zombie" cells, which are in a state of suspended animation and fail to repair lung damage as usual, but release a whole mixture of harmful cell products, This mixture is termed the senescence-associated secretory phenotype (or SASP for short), and lead to lung inflammation, scaring of the small air tubes, lung destruction and spreads senescence to other cells, resulting in disease progression. By selectively removing these senescence cells it has been possible to prolong the lifespan of mice and to markedly alleviate several age-related disease models in mice. Several types of drug have been found to selectivity eliminate senescent cells and are called senolytic therapies. It is logical to apply these treatments in COPD. Different types of cell may respond differently to these therapies, however. We propose to study three types of lung cell that play a key role in the in the underlying disease process of COPD - the lining cells of small airways, the cells that cause scarring of small airways and finally cells that repair lung injury. We will look at three different types of senolytic therapy and study their effects in human lung cells (obtained from lung removed at routine surgery). These are novel therapies that are being developed by AstraZeneca, with whom we have worked collaboratively for some time.We will see if these senolytic therapies are able to selective kill off senescent cells from COPD lungs compared to cells from people who may or may not smoke but have normal lungs. We have shown that these approaches appear to work selectively on COPD cells in tissue culture experiments and in slices of lung in a dish. We have also shown that this approach works in a mouse model of COPD. When a novel senolytic drug is blown into the lungs of mice it stops the senescence and inflammation in the lung that are caused by long term cigarette exposure in these animals and allows the lung to grow back. This suggests that this therapeutic approach may reduce disease progression and could even have the potential to reverse the disease. Senolytic therapies have already been given to a few humans with age-related diseases and shown to be well tolerated. Our studies may provide evidence for which is the most effective senolytic therapy for COPD patients and provide the basis for developing a clinical trial of senolytic therapy in the future.