Abstract
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.
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Matthay, M.A., L.B. Ware, and G.A. Zimmerman. 2012. The acute respiratory distress syndrome. The Journal of Clinical Investigation 122 (8): 2731–2740.
Huang, R., T. Zhong, and H. Wu. 2015. Quercetin protects against lipopolysaccharide-induced acute lung injury in rats through suppression of inflammation and oxidative stress. Archives of medical science: AMS 11 (2): 427–432.
Taslidere, E., M. Esrefoglu, H. Elbe, A. Cetin, and B. Ates. 2014. Protective effects of melatonin and quercetin on experimental lung injury induced by carbon tetrachloride in rats. Experimental Lung Research 40 (2): 59–65.
Takashima, K., M. Matsushima, K. Hashimoto, H. Nose, M. Sato, N. Hashimoto, et al. 2014. Protective effects of intratracheally administered quercetin on lipopolysaccharide-induced acute lung injury. Respiratory Research 15: 150.
Wang, L., J. Chen, B. Wang, D. Wu, H. Li, H. Lu, et al. 2014. Protective effect of quercetin on lipopolysaccharide-induced acute lung injury in mice by inhibiting inflammatory cell influx. Experimental Biology and Medicine 239 (12): 1653–1662.
Park, H.K., S.J. Kim, Y. Kwon do, J.H. Park, and Y.C. Kim. 2010. Protective effect of quercetin against paraquat-induced lung injury in rats. Life Sciences 87 (5–6): 181–186.
Yilmaz, M.Z., A. Guzel, A.C. Torun, A. Okuyucu, O. Salis, R. Karli, et al. 2014. The therapeutic effects of anti-oxidant and anti-inflammatory drug quercetin on aspiration-induced lung injury in rats. Journal of Molecular Histology 45 (2): 195–203.
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.
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.
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.
Wang, J., Y.Y. Zhang, J. Cheng, J.L. Zhang, and B.S. Li. 2015. Preventive and therapeutic effects of quercetin on experimental radiation induced lung injury in mice. Asian Pacific Journal of Cancer Prevention : APJCP 16 (7): 2909–2914.
Ng, J., T. Nardine, M. Harms, J. Tzu, A. Goldstein, Y. Sun, et al. 2002. Rac GTPases control axon growth, guidance and branching. Nature 416 (6879): 442–447.
Gerin, F., U. Sener, H. Erman, A. Yilmaz, B. Aydin, F. Armutcu, et al. 2016. The effects of quercetin on acute lung injury and biomarkers of inflammation and oxidative stress in the rat model of sepsis. Inflammation 39 (2): 700–705.
Chang, S.W., A. Sakai, and N.F. Voelkel. 1989. Dibutyryl-cAMP blocks endotoxin-induced lung injury in rats. The American Review of Respiratory Disease 140 (6): 1814–1817.
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.
Birukova, A.A., T. Zagranichnaya, E. Alekseeva, G.M. Bokoch, and K.G. Birukov. 2008. Epac/Rap and PKA are novel mechanisms of ANP-induced Rac-mediated pulmonary endothelial barrier protection. Journal of Cellular Physiology 215 (3): 715–724.
Birukova, A.A., D. Burdette, N. Moldobaeva, J. Xing, P. Fu, and K.G. Birukov. 2010. Rac GTPase is a hub for protein kinase A and Epac signaling in endothelial barrier protection by cAMP. Microvascular Research 79 (2): 128–138.
Pavan, B., A. Capuzzo, and G. Forlani. 2015. Quercetin and quercetin-3-O-glucoside interact with different components of the cAMP signaling cascade in human retinal pigment epithelial cells. Life Sciences 121: 166–173.
Beretz, A., A. Stierle, R. Anton, and J.P. Cazenave. 1982. Role of cyclic AMP in the inhibition of human platelet aggregation by quercetin, a flavonoid that potentiates the effect of prostacyclin. Biochemical Pharmacology 31 (22): 3597–3600.
Wu, S.N., H.T. Chiang, A.Y. Shen, and Y.K. Lo. 2003. Differential effects of quercetin, a natural polyphenolic flavonoid, on L-type calcium current in pituitary tumor (GH3) cells and neuronal NG108-15 cells. Journal of Cellular Physiology 195 (2): 298–308.
Ko, W.C., C.M. Shih, Y.H. Lai, J.H. Chen, and H.L. Huang. 2004. Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships. Biochemical Pharmacology 68 (10): 2087–2094.
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.
Bradley, P.P., D.A. Priebat, R.D. Christensen, and G. Rothstein. 1982. Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker. The Journal of Investigative Dermatology 78 (3): 206–209.
Chen, H., C. Bai, and X. Wang. 2010. The value of the lipopolysaccharide-induced acute lung injury model in respiratory medicine. Expert Review of Respiratory Medicine 4 (6): 773–783.
Poppe, H., S.D. Rybalkin, H. Rehmann, T.R. Hinds, X.B. Tang, A.E. Christensen, et al. 2008. Cyclic nucleotide analogs as probes of signaling pathways. Nature Methods 5 (4): 277–278.
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.
Wadsworth, T.L., and D.R. Koop. 2001. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced release of nitric oxide. Chemico-Biological Interactions 137 (1): 43–58.
Sun, G.Y., Z. Chen, K.J. Jasmer, D.Y. Chuang, Z. Gu, M. Hannink, et al. 2015. Quercetin attenuates inflammatory responses in BV-2 microglial cells: Role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS One 10 (10): e0141509.
Lee, S., H.S. Park, Y. Notsu, H.S. Ban, Y.P. Kim, K. Ishihara, et al. 2008. Effects of hyperin, isoquercitrin and quercetin on lipopolysaccharide-induced nitrite production in rat peritoneal macrophages. Phytotherapy research: PTR 22 (11): 1552–1556.
Haag, S., M. Warnken, U.R. Juergens, and K. Racke. 2008. Role of Epac1 in mediating anti-proliferative effects of prostanoid EP(2) receptors and cAMP in human lung fibroblasts. Naunyn-Schmiedeberg's Archives of Pharmacology 378 (6): 617–630.
Moon, E.Y., J.H. Lee, J.W. Lee, J.H. Song, and S. Pyo. 2011. ROS/Epac1-mediated Rap1/NF-kappaB activation is required for the expression of BAFF in Raw264.7 murine macrophages. Cellular Signalling 23 (9): 1479–1488.
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.
Rehmann, H. 2013. Epac-inhibitors: Facts and artefacts. Scientific Reports 3: 3032.
Zhu, Y., H. Chen, S. Boulton, F. Mei, N. Ye, G. Melacini, et al. 2015. Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: Defining the ESI-09 “therapeutic window”. Scientific Reports 5: 9344.
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.
Iozzi, D., R. Schubert, V.U. Kalenchuk, A. Neri, G. Sgaragli, F. Fusi, et al. 2013. Quercetin relaxes rat tail main artery partly via a PKG-mediated stimulation of KCa 1.1 channels. Acta Physiologica 208 (4): 329–339.
Gao, W., Y. Zan, Z.J. Wang, X.Y. Hu, and F. Huang. 2016. Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCepsilon-dependent activation of TRPV1. Acta Pharmacologica Sinica 37 (9): 1166–1177.
Wang, Y., W. Zhang, Q. Lv, J. Zhang, and D. Zhu. 2016. The critical role of quercetin in autophagy and apoptosis in HeLa cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 37 (1): 925–929.
Kim, Y.H., D.H. Lee, J.H. Jeong, Z.S. Guo, and Y.J. Lee. 2008. Quercetin augments TRAIL-induced apoptotic death: Involvement of the ERK signal transduction pathway. Biochemical Pharmacology 75 (10): 1946–1958.
Liu, J., X. Zhao, J. Cao, Q. Xue, X. Feng, X. Liu, et al. 2011. Differential roles of PKA and Epac on the production of cytokines in the endotoxin-stimulated primary cultured microglia. Journal of molecular neuroscience: MN 45 (2): 186–193.
Funding
These researches were supported by the National Natural Science Foundation of China (81202980, 30800497, 81100051, 31400751 and 81570056).
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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.
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Experimental protocols were approved by the Animal Care Committee of Zhejiang University in accordance with the international guidelines.
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Wang, Xf., Song, Sd., Li, Yj. et al. Protective Effect of Quercetin in LPS-Induced Murine Acute Lung Injury Mediated by cAMP-Epac Pathway. Inflammation 41, 1093–1103 (2018). https://doi.org/10.1007/s10753-018-0761-3
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DOI: https://doi.org/10.1007/s10753-018-0761-3