Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress
Abstract Background Airborne fine particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5) pollution is associated with the prevalence of respiratory diseases, including asthma, bronchitis and chronic obstructive pulmonary disease. In patients with those diseases, circulating asymmetric dimethy...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | Particle and Fibre Toxicology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12989-022-00505-7 |
| _version_ | 1811238900767653888 |
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| author | Junling Gao Tong Lei Hongyun Wang Kai Luo Yuanli Wang Bingqing Cui Zhuoran Yu Xiaoqi Hu Fang Zhang Yingjie Chen Wenjun Ding Zhongbing Lu |
| author_facet | Junling Gao Tong Lei Hongyun Wang Kai Luo Yuanli Wang Bingqing Cui Zhuoran Yu Xiaoqi Hu Fang Zhang Yingjie Chen Wenjun Ding Zhongbing Lu |
| author_sort | Junling Gao |
| collection | DOAJ |
| description | Abstract Background Airborne fine particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5) 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 PM2.5-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 PM2.5 (mean daily concentration ~ 50 µg/m3) for 6 months through a whole-body exposure system. Mice were also acutely exposed to 10 mg/kg PM2.5 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 PM2.5 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 PM2.5 exposure, which was associated with greater induction of pulmonary oxidative stress and inflammation. In the lungs of PM2.5-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 PM2.5-exposed mice. In addition, exogenous ADMA administration could mimic the effect of Ddah1 deficiency on PM2.5-induced lung injury, oxidative stress and inflammation. In PM2.5-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 PM2.5 exposure-induced lung injury. |
| first_indexed | 2024-04-12T12:50:24Z |
| format | Article |
| id | doaj.art-38ded9a599bf4e0ead6c78a643f27934 |
| institution | Directory Open Access Journal |
| issn | 1743-8977 |
| language | English |
| last_indexed | 2024-04-12T12:50:24Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Particle and Fibre Toxicology |
| spelling | doaj.art-38ded9a599bf4e0ead6c78a643f279342022-12-22T03:32:30ZengBMCParticle and Fibre Toxicology1743-89772022-10-0119111710.1186/s12989-022-00505-7Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stressJunling Gao0Tong Lei1Hongyun Wang2Kai Luo3Yuanli Wang4Bingqing Cui5Zhuoran Yu6Xiaoqi Hu7Fang Zhang8Yingjie Chen9Wenjun Ding10Zhongbing Lu11College of Life Sciences, University of Chinese Academy of SciencesCollege of Life Sciences, University of Chinese Academy of SciencesCollege of Life Sciences, University of Chinese Academy of SciencesCollege of Life Sciences, University of Chinese Academy of SciencesCollege of Life Sciences, University of Chinese Academy of SciencesCollege of Life Sciences, University of Chinese Academy of SciencesCollege of Life Sciences, University of Chinese Academy of SciencesCollege of Life Sciences, University of Chinese Academy of SciencesCollege of Life Sciences, University of Chinese Academy of SciencesDepartment of Physiology and Biophysics, University of Mississippi Medical CenterCollege of Life Sciences, University of Chinese Academy of SciencesCollege of Life Sciences, University of Chinese Academy of SciencesAbstract Background Airborne fine particulate matter with aerodynamic diameter ≤ 2.5 μm (PM2.5) 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 PM2.5-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 PM2.5 (mean daily concentration ~ 50 µg/m3) for 6 months through a whole-body exposure system. Mice were also acutely exposed to 10 mg/kg PM2.5 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 PM2.5 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 PM2.5 exposure, which was associated with greater induction of pulmonary oxidative stress and inflammation. In the lungs of PM2.5-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 PM2.5-exposed mice. In addition, exogenous ADMA administration could mimic the effect of Ddah1 deficiency on PM2.5-induced lung injury, oxidative stress and inflammation. In PM2.5-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 PM2.5 exposure-induced lung injury.https://doi.org/10.1186/s12989-022-00505-7DDAH1PM2.5Lung injuryInflammationOxidative stress |
| spellingShingle | Junling Gao Tong Lei Hongyun Wang Kai Luo Yuanli Wang Bingqing Cui Zhuoran Yu Xiaoqi Hu Fang Zhang Yingjie Chen Wenjun Ding Zhongbing Lu Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress Particle and Fibre Toxicology DDAH1 PM2.5 Lung injury Inflammation Oxidative stress |
| title | Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress |
| title_full | Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress |
| title_fullStr | Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress |
| title_full_unstemmed | Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress |
| title_short | Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress |
| title_sort | dimethylarginine dimethylaminohydrolase 1 protects pm2 5 exposure induced lung injury in mice by repressing inflammation and oxidative stress |
| topic | DDAH1 PM2.5 Lung injury Inflammation Oxidative stress |
| url | https://doi.org/10.1186/s12989-022-00505-7 |
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