Chronic pulmonary conditions now account for 1 in 15 deaths in the US and mortality is increasing. Chronic obstructive pulmonary disease (COPD) is due to become the 3rd largest cause of mortality by 2030 and mortality from other respiratory conditions such as asthma, idiopathic pulmonary fibrosis and cystic fibrosis are not reducing. There is an urgent need for novel therapies to address this problem as many of the current strategies targeting inflammation are not sufficient. The innate immune system of the lung is an important defence against invading pathogens, but in many chronic pulmonary diseases, this system mounts an inappropriate response. In COPD, macrophages are increased in number, but fail to clear pathogens correctly and become highly activated. This leads to increased damage and remodelling of the airways. In idiopathic fibrosis, there is a switch of macrophage phenotype to a cell that promotes abnormal repair. Neutrophils also display dysfunction in COPD where aberrant migratory profiles may lead to increased damage to lung tissue and emphysema; while in cystic fibrosis the proteolytic lung environment damages neutrophil receptors leading to ineffective phagocytosis and migration. Targeting the innate immune system to restore 'normal function' could have enormous benefits. Improving phagocytosis of pathogens could reduce exacerbations and hence the associated decline in lung function, and novel therapeutics such as sulforaphane appear to do this in vitro. Other natural products such as resveratrol and derivatives also have anti-inflammatory properties. Statins have traditionally been used to manage cholesterol levels in hypercholesterolaemia, however these molecules also have beneficial effects on the innate immune cells. Statins have been shown to be anti-inflammatory and restore aberrant neutrophil chemotaxis in aged cells. Other possible agents that may be efficacious are senolytics. These compounds include natural products such as quercetin which have anti-inflammatory properties but can also suppress viral replication. As viruses have been shown to suppress phagocytosis of macrophages, it is possible that these compounds could have benefit during viral exacerbations to protect this innate response. These compounds demonstrate that it is possible to address defective innate responses in the lung but a better understanding of the mechanisms driving defective innate immunity in pulmonary disease may lead to improved therapeutics.

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针对有缺陷的肺先天免疫-一种新的治疗选择？

在美国，慢性肺病现在占15例死亡中的1例，并且死亡率正在增加。到2030年，慢性阻塞性肺疾病（COPD）将成为第三大死亡原因，而其他呼吸道疾病（例如哮喘，特发性肺纤维化和囊性纤维化）的死亡率也不会降低。由于许多针对炎症的当前策略还不够，因此迫切需要新颖的疗法来解决该问题。肺的先天免疫系统是抵御病原体入侵的重要防御手段，但在许多慢性肺部疾病中，这种系统会产生不适当的反应。在COPD中，巨噬细胞数量增加，但是不能正确清除病原体并被高度活化。这导致气道的损坏和重塑增加。在特发性纤维化中 巨噬细胞表型转换为促进异常修复的细胞。中性粒细胞在COPD中也显示功能障碍，其中异常的迁徙特征可能导致对肺组织和肺气肿的损害增加；而在囊性纤维化中，蛋白水解性肺环境损害中性粒细胞受体，导致吞噬作用和迁移无效。靶向先天免疫系统以恢复“正常功能”可能具有巨大的好处。改善病原体的吞噬作用可以减少病情加重，从而减少相关的肺功能下降，而新型药物如萝卜硫烷似乎可以在体外进行。其他天然产物，如白藜芦醇和衍生物也具有抗炎特性。传统上，他汀类药物可用于控制高胆固醇血症中的胆固醇水平，然而，这些分子对先天免疫细胞也有有益作用。他汀类药物已被证明具有抗炎作用，并能在衰老细胞中恢复异常的嗜中性粒细胞趋化性。可能有效的其他可能的试剂是senolytics。这些化合物包括天然产物，例如槲皮素，具有抗炎特性，但也可以抑制病毒复制。由于已显示病毒抑制巨噬细胞的吞噬作用，因此这些化合物在病毒恶化期间可能有益于保护这种先天应答。这些化合物证明有可能解决肺中先天性应答的缺陷，但是对驱动肺部疾病中先天性免疫缺陷的机制的更好理解可能会导致治疗方法的改善。