Cazzola Mario, Calzetta Luigino, Facciolo Francesco, Rogliani Paola, Matera Maria Gabriella
Department of Systems Medicine, Chair of Respiratory Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
Regina Elena National Cancer Institute, Thoracic Surgery Unit, Rome, Italy.
Respir Res. 2017 Jan 24;18(1):26. doi: 10.1186/s12931-016-0500-y.
Oxidative stress is recognized to be one of predisposing factor in the pathogenesis of COPD. The oxidant/antioxidant imbalance is significantly pronounced in patients with COPD exacerbation. N-acetylcysteine (NAC) seems to be able to reduce COPD exacerbations by modulating the oxidative stress in addition to its well-known mucolytic activity, but there are discordant findings on the actual anti-oxidant activity of NAC.
The anti-oxidant effect of NAC and its impact on the inflammatory response have been pharmacologically characterized on a human ex vivo model of COPD exacerbation induced by lipopolysaccharide (LPS).
NAC prevented the desensitization induced by LPS incubation on the contractile tone in linear concentration-response manner. Concentrations of NAC ≥1 μM reduced the pro-oxidant response (peroxidase activity, hydrogen peroxide, malondialdehyde, nitric oxide), and improved the anti-oxidant response (total anti-oxidant capacity, glutathione, superoxide dismutase) induced by LPS. Lower concentrations of NAC (<1 μM) did not modulate the bronchial oxidative imbalance. Concentrations of NAC ≥300 μM inhibited the inflammatory response (release of IL-1β, IL-8, and TNF-α) of human airways induced by the overnight stimulation with LPS, whereas lower concentrations of NAC (≥1 μM) were sufficient to reduce the release of IL-6 elicited by LPS. Both the anti-oxidant effect and the anti-inflammatory effect of NAC were inversely correlated with the release of NKA.
The findings of this study suggest that NAC may have a role in modulating the detrimental effect induced by LPS in course of COPD exacerbation. It may elicit both anti-oxidant and anti-inflammatory effects when administered at high concentrations.
氧化应激被认为是慢性阻塞性肺疾病（COPD）发病机制中的诱发因素之一。在COPD急性加重期患者中，氧化剂/抗氧化剂失衡明显加剧。N-乙酰半胱氨酸（NAC）除了具有众所周知的黏液溶解活性外，似乎还能够通过调节氧化应激来减少COPD急性加重，但关于NAC实际的抗氧化活性存在不一致的研究结果。
在脂多糖（LPS）诱导的COPD急性加重的人体离体模型上，对NAC的抗氧化作用及其对炎症反应的影响进行了药理学特征研究。
NAC以线性浓度-反应方式阻止了LPS孵育诱导的收缩张力脱敏。≥1 μM的NAC浓度降低了LPS诱导的促氧化反应（过氧化物酶活性、过氧化氢、丙二醛、一氧化氮），并改善了抗氧化反应（总抗氧化能力、谷胱甘肽、超氧化物歧化酶）。较低浓度的NAC（<1 μM）未调节支气管氧化失衡。≥300 μM的NAC浓度抑制了LPS过夜刺激诱导的人气道炎症反应（IL-1β、IL-8和TNF-α的释放），而较低浓度的NAC（≥1 μM）足以减少LPS诱导的IL-6释放。NAC的抗氧化作用和抗炎作用均与NKA的释放呈负相关。
本研究结果表明，NAC可能在调节COPD急性加重过程中LPS诱导的有害作用方面发挥作用。高浓度给药时，它可能会产生抗氧化和抗炎作用。
