PM_2.5 is particulate matter with a diameter of 2.5 μm or less. Airway macrophages are the key players regulating PM_2.5-induced inflammation. High molecular weight hyaluronan (HMW-HA) has previously been shown to exert protective effects on PM_2.5-induced acute lung injury and inflammation. However, little is known about the detailed mechanism. In this study, we aimed to determine whether HMW-HA alleviates PM_2.5-induced pulmonary inflammation by modulating macrophage polarization. The levels of M1 biomarkers TNF-α, IL-1β, IL-6, CXCL1, CXCL2, NOS2 and CD86, as well as M2 biomarkers IL-10, MRC1, and Arg-1 produced by macrophages were measured by ELISA, qPCR, and flow cytometry. In addition, the amount of M1 macrophages in lung tissues was examined by immunofluorescence of CD68 and NOS2. We observed a decline in PM_2.5-induced M1 polarization both in macrophages and lung tissues when HMW-HA was administered simultaneously. Meanwhile, western blot analysis revealed that PM_2.5-induced JNK and p38 phosphorylation was suppressed by HMW-HA. Furthermore, in vitro and in vivo studies showed that co-stimulation with HMW-HA and PM_2.5 promoted the expression and release of IL-10, but exhibited limited effects on the transcription of MRC1 and ARG1. In conclusion, our results demonstrated that HMW-HA ameliorates PM_2.5-induced lung inflammation by repressing M1 polarization through JNK and p38 pathways and promoting the production of pro-resolving cytokine IL-10.

Arsenic is one of the most common environmental pollutants eliciting serious public health issues; however, it is also a well-recognized chemotherapeutic agent for acute promyelocytic leukemia. The association between arsenic exposure and lung diseases has been established, but underlying molecular mechanisms are poorly defined. Here we investigated the toxicology of arsenic in airway epithelium. Arsenic rapidly induced the activating transcription factor ATF3 expression through the JNK and p38 pathways. The ATF3-deficient BEAS-2B cells were relatively resistant to apoptosis upon arsenic exposure, indicating a facilitatory role of ATF3 in arsenic-induced apoptosis. We further showed that ATF3 oppositely regulated the transcription of death receptor (DR5) and Bcl2-like 1 (Bcl-xL) by directly binding to the promoter DR5 and Bcl-xL. Altogether, our findings establish ATF3 as a pro-apoptotic protein in arsenic-induced airway epithelial apoptosis through transcriptionally regulating DR5 and Bcl-xL, highlighting the potential of ATF3 as an early and sensitive biomarker for arsenic-caused lung injury.