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/m(3)) 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12989-022-00505-7.