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 (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.