LincRNA-p21 promotes classical macrophage activation in acute respiratory distress syndrome by activating NF-κB.

Background: Previous studies have revealed the important role of alveolar macrophages (AMs) in the pathogenesis of acute respiratory distress syndrome (ARDS) and potential anti-inflammatory properties of lincRNA-p21. This study aims to study the association between lincRNA-p21 and active AMs to understand the molecular mechanisms of AMs-mediated inflammatory responses in ARDS. Methods: This study was mainly investigated in mice with the intratracheal instillation of lipopolysaccharide (LPS) or LPS-treated AMs. The expression of lincRNA-p21 and classical macrophage markers, IL-12 beta and iNOS, was detected by quantitative RT-PCR, while NF-kappa B p65 translocation was measured by western blotting analysis. And, NF-kappa B activity was analyzed through luciferase report assays. Gain- and loss-of-function studies were also performed for further investigations. Results: Elevated lincRNA-p21 levels were observed in both LPS-induced ARDS mice and LPS-treated AMs, with upregulated expression of IL-12 beta and iNOS, namely M1 activation, and p65 nuclear translocation. Further in vitro studies showed that LPS-induced M1 activation could be counteracted by both lincRNA-p21 inhibition and inhibited NF-kappa B activation. Moreover, both p65 nuclear translocation and NF-kappa B activity were promoted by lincRNA-p21 overexpression, while lincRNA-p21 inhibition showed a negative effect on LPS-induced p65 nuclear translocation and increase of NF-kappa B activity. Additionally, LPS-induced lung injuries could be attenuated by lincRNA-p21 inhibition in vivo. Conclusion: This study revealed elevated lincRNA-p21 levels in LPS-induced ARDS and investigated the potential role of lincRNA-p21 in LPS-induced pro-inflammatory response via NF-kappa B/p65 mediated pathways, suggesting the potential application of lincRNA-p21 for ADRS therapy.