MICA: Senolytic therapies for chronic obstructive pulmonary disease

慢性阻塞性肺疾病(简称COPD)，每10名45岁以上的人中就有1人受到影响，现在是英国第三大最常见的死亡原因，也是人们在冬季入院的主要原因。慢性阻塞性肺疾病会导致运动时进行性呼吸短促，原因是小气管变窄(小气道疾病)和肺组织丢失(称为肺气肿)。尽管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着时间的推移恶化或阻止人们死于COPD。这是因为我们仍然不了解COPD的潜在疾病过程。慢性阻塞性肺病主要是一种老年人的疾病，越来越多的证据表明，它可能是由于长期暴露在香烟烟雾或其他刺激物(如空气污染物)中而导致肺部加速或过早老化。有一种被称为衰老细胞的老化细胞的积累，有时被称为僵尸细胞，它们处于悬浮状态，无法像往常一样修复肺损伤，但释放出整个混合物的有害细胞产物，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，小气管受惊，肺破坏，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，已经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。已发现几种类型的药物可以选择性地消除衰老细胞，并被称为衰老疗法。在COPD中应用这些治疗方法是合乎逻辑的。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，导致小气道瘢痕的细胞，最后是修复肺损伤的细胞。我们将观察三种不同类型的感觉神经溶解疗法，并研究它们对人类肺细胞(从常规手术中取出的肺细胞中获得)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。我们将看看与可能吸烟或可能不吸烟但肺部正常的人的细胞相比，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。我们已经证明，在组织培养实验中，这些方法似乎对COPD细胞和培养皿中的肺切片具有选择性的作用。我们还证明了这种方法在COPD的小鼠模型上有效。当一种新的抗衰老药物被吹入小鼠的肺部时，它可以阻止这些动物因长期吸烟而导致的肺部衰老和炎症，并允许肺重新生长。这表明这种治疗方法可能会减缓疾病的进展，甚至有可能逆转疾病。一些患有年龄相关疾病的人已经接受了抗衰老疗法，并被证明耐受性良好。我们的研究可能会为哪种疗法对COPD患者最有效提供证据，并为未来开展感觉剂治疗的临床试验提供依据。

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.