MICA: Senolytic therapies for chronic obstructive pulmonary disease

慢性阻塞性肺疾病（简称COPD），影响45岁以上的10人中约有1人，现在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。慢性阻塞性肺病会在运动时引起进行性呼吸短促，这是由于小气管狭窄（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COPD的症状，但没有针对COPD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时间恶化或阻止人们死于COPD。这是因为我们仍然不了解COPD的基础疾病过程。慢性阻塞性肺病是一种主要发生在老年人身上的疾病，越来越多的证据表明，这可能是由于长期暴露于香烟烟雾或其他刺激物（如空气污染物）导致肺部加速或过早老化。存在被称为衰老细胞的衰老细胞的积累，有时被称为“僵尸”细胞，其处于假死状态并且不能像往常一样修复肺损伤，而是释放有害细胞产物的整个混合物，这种混合物被称为衰老相关分泌表型。（或简称SASP），并导致肺部炎症、小气管瘢痕化、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，并显着减轻小鼠中的几种与年龄相关的疾病模型。已经发现几种类型的药物选择性消除衰老细胞，称为衰老清除疗法。在COPD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-小气道的衬里细胞，导致小气道瘢痕形成的细胞，以及最终修复肺损伤的细胞。我们将研究三种不同类型的衰老清除疗法，并研究它们对人肺细胞（从常规手术中取出的肺中获得）的影响。这些都是阿斯利康正在开发的新疗法，我们已经与他们合作了一段时间。我们将观察这些衰老清除疗法是否能够选择性地杀死来自COPD肺部的衰老细胞，而不是来自可能吸烟或不吸烟但肺部正常的人的细胞。我们已经证明，这些方法似乎在组织培养实验和培养皿中的肺切片中选择性地对COPD细胞起作用。我们还表明，这种方法在COPD小鼠模型中有效。当一种新的衰老药物被吹入小鼠的肺部时，它会阻止这些动物长期接触香烟引起的肺部衰老和炎症，并允许肺部重新生长。这表明这种治疗方法可能会减少疾病进展，甚至有可能逆转疾病。衰老清除疗法已经被用于一些患有与年龄有关的疾病的人，并显示出良好的耐受性。我们的研究可能为COPD患者最有效的衰老清除疗法提供证据，并为将来开展衰老清除疗法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.