Protective Effect of Quercetin in LPS-Induced Murine Acute Lung Injury Mediated by cAMP-Epac Pathway
- 75 Downloads
Quercetin (Que) as an abundant flavonol element possesses potent antioxidative properties and has protective effect in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the specific mechanism is still unclear, so we investigated the effect of Que from in vivo and in vitro studies and the related mechanism of cAMP-PKA/Epac pathway. The results in mice suggested that Que can inhibit the release of inflammatory cytokine, block neutrophil recruitment, and decrease the albumin leakage in dose-dependent manners. At the same time, Que can increase the cAMP content of lung tissue, and Epac content, except PKA. The results in epithelial cell (MLE-12) suggested that Que also can inhibit the inflammatory mediators keratinocyte-derived chemokines release after LPS stimulation; Epac inhibitor ESI-09 functionally antagonizes the inhibitory effect of Que; meanwhile, PKA inhibitor H89 functionally enhances the inhibitory effect of Que. Overexpression of Epac1 in MLE-12 suggested that Epac1 enhance the effect of Que. All those results suggested that the protective effect of quercetin in ALI is involved in cAMP-Epac pathway.
Key WordsQuercetin LPS acute lung injury cAMP Epac PKA
THF designed the study and wrote the manuscript. WXF and SSD prepared the LPS-induced lung injury model, harvested the lung samples, and completed the determination of WB, MPO, albumin, and cytokine. LYJ prepared the cell experiment and completed the determination of cytokine. HZQ prepared the plasmids of Epac1 and cultured the MHS cell. ZZW did the histology; YCG and LZG provided support of design and discussion. All authors approved the final version of the paper.
Compliance with Ethical Standards
Experimental protocols were approved by the Animal Care Committee of Zhejiang University in accordance with the international guidelines.
Conflict of Interest
The authors declare that they have no conflicts of interest.
- 8.Al-Rasheed, N.M., L. Fadda, H.A. Attia, I.A. Sharaf, A.M. Mohamed, and N.M. Al-Rasheed. 2017. Original research paper. Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats. Acta Pharmaceutica 67 (1): 125–135.CrossRefPubMedGoogle Scholar
- 9.Nakamura, T., M. Matsushima, Y. Hayashi, M. Shibasaki, K. Imaizumi, N. Hashimoto, K. Shimokata, Y. Hasegawa, and T. Kawabe. 2011. Attenuation of transforming growth factor-beta-stimulated collagen production in fibroblasts by quercetin-induced heme oxygenase-1. American Journal of Respiratory Cell and Molecular Biology 44 (5): 614–620.CrossRefPubMedGoogle Scholar
- 10.Impellizzeri, D., E. Talero, R. Siracusa, A. Alcaide, M. Cordaro, J. Maria Zubelia, G. Bruschetta, R. Crupi, E. Esposito, S. Cuzzocrea, and V. Motilva. 2015. Protective effect of polyphenols in an inflammatory process associated with experimental pulmonary fibrosis in mice. The British Journal of Nutrition 114 (6): 853–865.CrossRefPubMedGoogle Scholar
- 15.Hastie, A.T., M. Wu, G.C. Foster, G.A. Hawkins, V. Batra, K.A. Rybinski, et al. 2006. Alterations in vasodilator-stimulated phosphoprotein (VASP) phosphorylation: Associations with asthmatic phenotype, airway inflammation and beta2-agonist use. Respiratory Research 7: 25.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Meng L, Lv Z, Yu ZZ, Xu D, Yan X. 2016. Protective effect of quercetin on acute lung injury in rats with sepsis and its influence on ICAM-1 and MIP-2 expression. Genetics and Molecular Research 15 (3): gmr.15037265.Google Scholar
- 26.Kukongviriyapan, U., K. Sompamit, P. Pannangpetch, V. Kukongviriyapan, and W. Donpunha. 2012. Preventive and therapeutic effects of quercetin on lipopolysaccharide-induced oxidative stress and vascular dysfunction in mice. Canadian Journal of Physiology and Pharmacology 90 (10): 1345–1353.CrossRefPubMedGoogle Scholar
- 32.Kreckler, L.M., E. Gizewski, T.C. Wan, and J.A. Auchampach. 2009. Adenosine suppresses lipopolysaccharide-induced tumor necrosis factor-alpha production by murine macrophages through a protein kinase A- and exchange protein activated by cAMP-independent signaling pathway. The Journal of Pharmacology and Experimental Therapeutics 331 (3): 1051–1061.CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Gong, B., T. Shelite, F.C. Mei, T. Ha, Y. Hu, G. Xu, et al. 2013. Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses. Proceedings of the National Academy of Sciences of the United States of America 110 (48): 19615–19620.CrossRefPubMedPubMedCentralGoogle Scholar