DDAH1 plays dual roles in PM2.5 induced cell death in A549 cells.

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an enzyme that can degrade asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor. Emerging evidence suggests that alterations in the ADMA-DDAH1 pathway are involved in environmental pollution induced airway inflammation. However, the role of DDAH1 in protection against cytotoxicity of ambient airborne particulate matter is unclear. We examined the influence of DDAH1 expression on oxidative stress and cell apoptosis in human type II alveolar epithelial A549 cells exposed to PM2.5 (particulate matter with an aerodynamic diameter less than 2.5μM). We found that PM2.5 exposure for 48h significantly decreased DDAH1 expression. However, knockdown of DDAH1 prior to PM2.5 exposure actually attenuated the cytotoxicity of PM2.5. Cytoprotection in DDAH1 deficient cells was due to increased reactive oxygen species, activation of PI3K-AKT and mitogen-activated protein kinase (MAPK) pathways, subsequent activation of nuclear factor erythroid-2-related factor 2 (Nrf2) and this caused a subsequent reduction in PM2.5 induced oxidative stress relative to control. DDAH1 depletion also repressed the induction of inducible NOS (iNOS) in PM2.5-exposed cells and knockdown of iNOS protected cells against PM2.5 induced cell death. Interestingly, overexpression of DDAH1 also exerted a protective effect against the cytotoxicity of PM2.5 and this was associated with a reduction in oxidative stress and upregulation of the anti-apoptotic protein Bcl-2. Our data indicate that DDAH1 plays dual roles in protection against cytotoxicity of PM2.5 exposure, apparently by limiting PM2.5 induced oxidative stress. Our findings reveal new insights into the role(s) of the DDAH1/ADMA in pulmonary protection against airborne pollutants. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.

Wang H ，Guo Y ，Liu L ，Guan L ，Wang T ，Zhang L ，Wang Y ，Cao J ，Ding W ，Zhang F ，Lu Z ... -  《-》

PM2.5 induces Nrf2-mediated defense mechanisms against oxidative stress by activating PIK3/AKT signaling pathway in human lung alveolar epithelial A549 cells.

Deng X ，Rui W ，Zhang F ，Ding W ... -  《-》

Dimethylarginine dimethylaminohydrolase 1 protects PM(2.5) exposure-induced lung injury in mice by repressing inflammation and oxidative stress.

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. 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. 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. Our data revealed that DDAH1 has a marked protective effect on long-term PM2.5 exposure-induced lung injury.

Gao J ，Lei T ，Wang H ，Luo K ，Wang Y ，Cui B ，Yu Z ，Hu X ，Zhang F ，Chen Y ，Ding W ，Lu Z ... -  《Particle and Fibre Toxicology》

Inflammatory cell signaling following exposures to particulate matter and ozone.

Particulate matter (PM) and ozone (O3) are two major ambient air pollutants. Epidemiological and toxicological studies have demonstrated exposure to these pollutants is associated with a variety of adverse health effects, including cardiovascular and respiratory disease, in which inflammation is believed to be a common and essential factor. This review mainly focuses on major inflammatory cell signaling pathways triggered by exposure to PM and O3. The receptors covered in this review include the EGF receptor, toll like receptor, and NOD-like receptor. Intracellular signaling protein kinases depicted in this review are phosphatidylinositol 3-kinase and mitogen-activated protein kinases. Activation of antioxidant and inflammatory transcription factors such as NrF2 and NFκB induced by PM and O3 is also discussed. Exposure to PM or O3 can activate cellular signaling networks including membrane receptors, intracellular kinases and phosphatases, and transcription factors that regulate inflammatory responses. While PM-induced cell signaling is associated with resultant ROS, O3-induced cell signaling implicates phosphates. Notably, the cellular signaling induced by PM and O3 exposure varies with cell type and physiochemical properties of these pollutants. Cellular signaling plays a critical role in the regulation of inflammatory pathogenesis. Elucidation of cellular signaling pathways initiated by PM or O3 cannot only help to uncover the mechanisms of air pollutant toxicity but also provide clues for development of interventional measures against air pollution-induced disorders. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.

Yan Z ，Jin Y ，An Z ，Liu Y ，Samet JM ，Wu W ... -  《-》

Direct effects of airborne PM2.5 exposure on macrophage polarizations.

Exposure of atmospheric particulate matter with an aerodynamic diameter less than 2.5μm (PM2.5) is epidemiologically associated with illnesses. Potential effects of air pollutants on innate immunity have raised concerns. As the first defense line, macrophages are able to induce inflammatory response. However, whether PM2.5 exposure affects macrophage polarizations remains unclear. We used freshly isolated macrophages as a model system to demonstrate effects of PM2.5 on macrophage polarizations. The expressions of cytokines and key molecular markers were detected by real-time PCR, and flow cytometry. The specific inhibitors and gene deletion technologies were used to address the molecular mechanisms. PM2.5 increased the expression of pro-inflammatory cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor alpha (TNFα). PM2.5 also enhanced the lipopolysaccharide (LPS)-induced M1 polarization even though there was no evidence in the change of cell viability. However, PM2.5 significantly decreased the number of mitochondria in a dose dependent manner. Pre-treatment with NAC, a scavenger of reactive oxygen species (ROS), prevented the increase of ROS and rescued the PM2.5-impacted M1 but not M2 response. However, mTOR deletion partially rescued the effects of PM2.5 to reduce M2 polarization. PM2.5 exposure significantly enhanced inflammatory M1 polarization through ROS pathway, whereas PM2.5 exposure inhibited anti-inflammatory M2 polarization through mTOR-dependent pathway. The present studies suggested that short-term exposure of PM2.5 acts on the balance of inflammatory M1 and anti-inflammatory M2 macrophage polarizations, which may be involved in air pollution-induced immune disorders and diseases. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.

Zhao Q ，Chen H ，Yang T ，Rui W ，Liu F ，Zhang F ，Zhao Y ，Ding W ... -  《-》