Divisione di Pneumologia e Laboratorio di Immunopatologia dell'Apparato Cardio Respiratorio, Istituti Clinici Scientifici Maugeri SpA, Societa Benefit, IRCCS, Veruno, Italy.
Divisione di Pneumologia, Istituti Clinici Scientifici Maugeri SpA, Societa Benefit, IRCCS, Telese, Italy.
Curr Med Chem. 2020;27(42):7149-7158. doi: 10.2174/0929867327666200604165451.
The imbalance between increased oxidative agents and antioxidant defence mechanisms is central in the pathogenesis of obstructive lung diseases such as asthma and COPD. In these patients, there are increased levels of reactive oxygen species. Superoxide anions (O -), Hydrogen Peroxide (HO) and hydroxyl radicals (•OH) are critical for the formation of further cytotoxic radicals in the bronchi and lung parenchyma. Chronic inflammation, partly induced by oxidative stress, can further increase the oxidant burden through activated phagocytic cells (neutrophils, eosinophils, macrophages), particularly in severer disease states. Antioxidants and anti-inflammatory genes are, in fact, frequently downregulated in diseased patients. Nrf2, which activates the Antioxidant Response Element (ARE) leading to upregulation of GPx, thiol metabolism-associated detoxifying enzymes (GSTs) and stressresponse genes (HO-1) are all downregulated in animal models and patients with asthma and COPD. An exaggerated production of Nitric Oxide (NO) in the presence of oxidative stress can promote the formation of oxidizing reactive nitrogen species, such as peroxynitrite (ONO -), leading to nitration and DNA damage, inhibition of mitochondrial respiration, protein dysfunction, and cell damage in the biological systems. Protein nitration also occurs by activation of myeloperoxidase and HO, promoting oxidation of nitrite (NO -). There is increased nitrotyrosine and myeloperoxidase in the bronchi of COPD patients, particularly in severe disease. The decreased peroxynitrite inhibitory activity found in induced sputum of COPD patients correlates with pulmonary function. Markers of protein nitration - 3- nitrotyrosine, 3-bromotyrosine, and 3-chlorotyrosine - are increased in the bronchoalveolar lavage of severe asthmatics. Targeting the oxidative, nitrosative stress and associated lung inflammation through the use of either denitration mechanisms or new drug delivery strategies for antioxidant administration could improve the treatment of these chronic disabling obstructive lung diseases.
在哮喘和 COPD 等阻塞性肺疾病的发病机制中，氧化应激物与抗氧化防御机制之间的失衡起着核心作用。在这些患者中，活性氧（ROS）的水平增加。超氧阴离子（O - ）、过氧化氢（HO ）和羟自由基（•OH）对于在支气管和肺实质中形成进一步的细胞毒性自由基至关重要。慢性炎症部分由氧化应激引起，通过激活吞噬细胞（中性粒细胞、嗜酸性粒细胞、巨噬细胞），特别是在更严重的疾病状态下，可以进一步增加氧化剂负担。抗氧化剂和抗炎基因实际上在患病患者中经常下调。Nrf2 激活抗氧化反应元件（ARE），导致谷胱甘肽过氧化物酶（GPx）、硫醇代谢相关解毒酶（GSTs）和应激反应基因（HO-1）上调，在哮喘和 COPD 的动物模型和患者中均下调。在氧化应激存在的情况下，一氧化氮（NO）的过度产生可以促进氧化性活性氮物种的形成，如过氧亚硝酸盐（ONO - ），导致硝化和 DNA 损伤、线粒体呼吸抑制、蛋白质功能障碍和生物系统中的细胞损伤。髓过氧化物酶和 HO 的激活也会导致蛋白质硝化，促进亚硝酸盐（NO - ）的氧化。COPD 患者的支气管中存在更多的硝基酪氨酸和髓过氧化物酶，尤其是在疾病严重的情况下。COPD 患者诱导痰中发现的过氧亚硝酸盐抑制活性降低与肺功能相关。严重哮喘患者支气管肺泡灌洗液中蛋白质硝化的标志物 - 3-硝基酪氨酸、3-溴酪氨酸和 3-氯酪氨酸 - 增加。通过使用脱硝机制或新的药物输送策略来靶向氧化应激、硝化应激和相关的肺炎症，可以改善这些慢性致残性阻塞性肺疾病的治疗。
