二甲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PM2.5暴露引起的小鼠肺损伤。

IF 7.2 1区医学 Q1 TOXICOLOGY

Particle and Fibre Toxicology Pub Date : 2022-10-14 DOI:10.1186/s12989-022-00505-7

Junling Gao, Tong Lei, Hongyun Wang, Kai Luo, Yuanli Wang, Bingqing Cui, Zhuoran Yu, Xiaoqi Hu, Fang Zhang, Yingjie Chen, Wenjun Ding, Zhongbing Lu

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引用次数: 7

摘要

研究背景:空气中空气动力学直径≤2.5 μm的细颗粒物(PM2.5)污染与哮喘、支气管炎、慢性阻塞性肺疾病等呼吸系统疾病的患病率有关。在患有这些疾病的患者中，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)是一种降解ADMA的酶，在动物模型中过表达具有保护作用。然而，DDAH1/ADMA对pm2.5诱导的肺损伤的影响尚未被研究。方法:将Ddah1-/-和Ddah1转基因小鼠及其野生型(WT)仔鼠通过全身暴露系统暴露于过滤空气或空气中PM2.5(平均日浓度~ 50µg/m3) 6个月。小鼠也急性暴露于10 mg/kg PM2.5和/或每隔一天气管内灌注外源性ADMA (2 mg/kg)，持续2周。检测肺组织炎症反应、氧化应激及相关基因表达。此外，将RAW264.7细胞暴露于PM2.5和/或ADMA中，测定细胞内氧化应激和炎症反应的变化。结果:长期暴露于PM2.5后，Ddah1-/-小鼠比WT小鼠发生更严重的肺损伤，肺氧化应激和炎症的诱导程度更高。在pm2.5暴露小鼠的肺中，Ddah1缺乏增加了p-p65、iNOS和Bax的蛋白表达，降低了Bcl-2、SOD1和过氧化物还蛋白4的蛋白表达。相反，在pm2.5暴露小鼠中，DDAH1过表达可显著减轻肺损伤，减轻肺氧化应激和炎症，而对这些蛋白的作用则相反。此外，外源性ADMA可以模拟Ddah1缺乏对pm2.5诱导的肺损伤、氧化应激和炎症的影响。在pm2.5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:我们的数据显示，DDAH1对长期暴露于PM2.5引起的肺损伤具有显著的保护作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress.

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Dimethylarginine dimethylaminohydrolase 1 protects PM_2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress.

Background: Airborne fine particulate matter with aerodynamic diameter ≤ 2.5 μm (PM_2.5) 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_2.5-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_2.5 (mean daily concentration ~ 50 µg/m³) for 6 months through a whole-body exposure system. Mice were also acutely exposed to 10 mg/kg PM_2.5 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_2.5 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_2.5 exposure, which was associated with greater induction of pulmonary oxidative stress and inflammation. In the lungs of PM_2.5-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_2.5-exposed mice. In addition, exogenous ADMA administration could mimic the effect of Ddah1 deficiency on PM_2.5-induced lung injury, oxidative stress and inflammation. In PM_2.5-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_2.5 exposure-induced lung injury.

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来源期刊

Particle and Fibre Toxicology TOXICOLOGY-

CiteScore

15.90

自引率

4.00%

发文量

审稿时长

6 months

期刊介绍： Particle and Fibre Toxicology is an online journal that is open access and peer-reviewed. It covers a range of disciplines such as material science, biomaterials, and nanomedicine, focusing on the toxicological effects of particles and fibres. The journal serves as a platform for scientific debate and communication among toxicologists and scientists from different fields who work with particle and fibre materials. The main objective of the journal is to deepen our understanding of the physico-chemical properties of particles, their potential for human exposure, and the resulting biological effects. It also addresses regulatory issues related to particle exposure in workplaces and the general environment. Moreover, the journal recognizes that there are various situations where particles can pose a toxicological threat, such as the use of old materials in new applications or the introduction of new materials altogether. By encompassing all these disciplines, Particle and Fibre Toxicology provides a comprehensive source for research in this field.