二甲基精氨酸二甲氨基水解酶 1 通过抑制炎症和氧化应激来保护 PM 暴露诱导的小鼠肺损伤。
Dimethylarginine dimethylaminohydrolase 1 protects PM exposure-induced lung injury in mice by repressing inflammation and oxidative stress.
机构信息
College of Life Sciences, University of Chinese Academy of Sciences, 19A Yuquanlu, Beijing, 100049, China.
Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Sciences, Shanghai University, Shanghai, 200444, China.
出版信息
Part Fibre Toxicol. 2022 Oct 14;19(1):64. doi: 10.1186/s12989-022-00505-7.
BACKGROUND
Airborne fine particulate matter with aerodynamic diameter ≤ 2.5 μm (PM) pollution is associated with the prevalence of respiratory diseases, including asthma, bronchitis and chronic obstructive pulmonary disease. In patients with those diseases, circulating asymmetric dimethylarginine (ADMA) levels are increased, which contributes to airway nitric oxide deficiency, oxidative stress and inflammation. Overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme degrading ADMA, exerts protective effects in animal models. However, the impact of DDAH1/ADMA on PM-induced lung injury has not been investigated.
METHODS
Ddah1 and DDAH1-transgenic mice, as well as their respective wild-type (WT) littermates, were exposed to either filtered air or airborne PM (mean daily concentration ~ 50 µg/m) for 6 months through a whole-body exposure system. Mice were also acutely exposed to 10 mg/kg PM and/or exogenous ADMA (2 mg/kg) via intratracheal instillation every other day for 2 weeks. Inflammatory response, oxidative stress and related gene expressions in the lungs were examined. In addition, RAW264.7 cells were exposed to PM and/or ADMA and the changes in intracellular oxidative stress and inflammatory response were determined.
RESULTS
Ddah1 mice developed more severe lung injury than WT mice after long-term PM exposure, which was associated with greater induction of pulmonary oxidative stress and inflammation. In the lungs of PM-exposed mice, Ddah1 deficiency increased protein expression of p-p65, iNOS and Bax, and decreased protein expression of Bcl-2, SOD1 and peroxiredoxin 4. Conversely, DDAH1 overexpression significantly alleviated lung injury, attenuated pulmonary oxidative stress and inflammation, and exerted opposite effects on those proteins in PM-exposed mice. In addition, exogenous ADMA administration could mimic the effect of Ddah1 deficiency on PM-induced lung injury, oxidative stress and inflammation. In PM-exposed macrophages, ADMA aggravated the inflammatory response and oxidative stress in an iNOS-dependent manner.
CONCLUSION
Our data revealed that DDAH1 has a marked protective effect on long-term PM exposure-induced lung injury.
背景
空气动力学直径≤2.5μm 的细颗粒物（PM）污染与呼吸道疾病（包括哮喘、支气管炎和慢性阻塞性肺疾病）的流行有关。在这些疾病患者中，循环不对称二甲基精氨酸（ADMA）水平升高，导致气道一氧化氮缺乏、氧化应激和炎症。二甲基精氨酸二甲氨基水解酶 1（DDAH1）的过度表达可降解 ADMA，在动物模型中发挥保护作用。然而，DDAH1/ADMA 对 PM 诱导的肺损伤的影响尚未得到研究。
方法
通过全身暴露系统，将 Ddah1 和 DDAH1 转基因小鼠及其各自的野生型（WT）同窝仔鼠暴露于过滤空气或空气中的 PM（平均日浓度约为 50μg/m）6 个月。每隔一天通过气管内滴注 10mg/kg PM 和/或外源性 ADMA（2mg/kg）对小鼠进行急性暴露 2 周。检测肺部的炎症反应、氧化应激和相关基因表达。此外，将 RAW264.7 细胞暴露于 PM 和/或 ADMA，测定细胞内氧化应激和炎症反应的变化。
结果
与 WT 小鼠相比，长期 PM 暴露后 Ddah1 小鼠发生更严重的肺损伤，这与肺氧化应激和炎症的更大诱导有关。在 PM 暴露的小鼠肺部，Ddah1 缺乏增加了 p-p65、iNOS 和 Bax 的蛋白表达，降低了 Bcl-2、SOD1 和过氧化物酶 4 的蛋白表达。相反，DDAH1 过表达显著减轻了肺损伤，减轻了肺氧化应激和炎症，并对 PM 暴露小鼠的这些蛋白产生了相反的作用。此外，外源性 ADMA 给药可模拟 Ddah1 缺乏对 PM 诱导的肺损伤、氧化应激和炎症的作用。在 PM 暴露的巨噬细胞中，ADMA 以 iNOS 依赖的方式加重了炎症反应和氧化应激。
结论
我们的数据表明，DDAH1 对长期 PM 暴露引起的肺损伤具有显著的保护作用。
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