Abstract
Valproic acid (VPA) has been shown to exert anti-inflammatory and antioxidant effects in a range of diseases including septic shock. However, the effects of VPA on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains not well understood. We found that VPA pretreatment attenuated the LPS-induced ALI, as evidenced by the reduced histological scores, myeloperoxidase activity, and wet-to-dry weight ratio in the lung tissues. This was accompanied by the downregulated nuclear factor kappa B (NF-κB) p65, nitric oxide, and inducible nitric oxide synthase in the lung tissues and the decreased levels of tumor necrosis factor alpha and interleukin-1β in the bronchoalveolar lavage fluid. Furthermore, VPA reduced the nuclear histone deacetylase (HDAC)3 expression whereas increased the cytoplasmic HDAC3 expression. Our results suggested that VPA attenuates the LPS-induced ALI via inhibiting the NF-κB activation probably through a mechanism depending on HDAC3 redistribution.
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REFERENCES
Rubenfeld, G.D., E. Caldwell, E. Peabody, J. Weaver, D.P. Martin, M. Neff, E.J. Stern, and L.D. Hudson. 2005. Incidence and outcomes of acute lung injury. The New England Journal of Medicine 353(16): 1685–1693.
Ji, M.H., X.L. Zhu, F.F. Liu, G.M. Li, M. Tian, J. Wu, Y.X. Fan, N. Li, and J.J. Yang. 2012. Alpha 2A-adrenoreceptor blockade improves sepsis-induced acute lung injury accompanied with depressed high mobility group box-1 levels in rats. Cytokine 60(3): 639–645.
Ji, M., R. Li, G.M. Li, Y. Fan, L. Dong, J. Yang, Y.G. Peng, and J. Wu. 2012. Effects of combined levosimendan and vasopressin on pulmonary function in porcine septic shock. Inflammation 35(3): 871–880.
Li, Y., B. Liu, X. Gu, A.R. Kochanek, E.Y. Fukudome, Z. Liu, T. Zhao, W. Chong, Y. Zhao, D. Zhang, T.A. Libermann, and H.B. Alam. 2012. Creating a “pro-survival” phenotype through epigenetic modulation. Surgery 152(3): 455–464.
Halili, M.A., M.R. Andrews, L.I. Labzin, K. Schroder, G. Matthias, C. Cao, E. Lovelace, R.C. Reid, G.T. Le, D.A. Hume, K.M. Irvine, P. Matthias, D.P. Fairlie, and M.J. Sweet. 2010. Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the Toll-like receptor 4 agonist LPS. Journal of Leukocyte Biology 87(6): 1103–1114.
Grabiec, A.M., S. Krausz, W. de Jager, T. Burakowski, D. Groot, M.E. Sanders, B.J. Prakken, W. Maslinski, E. Eldering, P.P. Tak, and K.A. Reedquist. 2010. Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. Journal of Immunology 184(5): 2718–2728.
Wu, C., A. Li, Y. Leng, Y. Li, and J. Kang. 2012. Histone deacetylase inhibition by sodium valproate regulates polarization of macrophage subsets. DNA and Cell Biology 31(4): 592–599.
Liu, Z., Y. Li, B. Liu, D.K. Deperalta, T. Zhao, W. Chong, X. Duan, P. Zhou, G.C. Velmahos, and H.B. Alam. 2013. Synergistic effects of hypertonic saline and valproic acid in a lethal rat two-hit model. Journal of Trauma and Acute Care Surgery 74(4): 991–997.
Kim, K., Y. Li, G. Jin, W. Chong, B. Liu, J. Lu, K. Lee, M. Demoya, G.C. Velmahos, and H.B. Alam. 2012. Effect of valproic acid on acute lung injury in a rodent model of intestinal ischemia reperfusion. Resuscitation 83(2): 243–248.
Bai, G.Z., H.T. Yu, Y.F. Ni, X.F. Li, Z.P. Zhang, K. Su, J. Lei, B.Y. Liu, C.K. Ke, D.X. Zhong, Y.J. Wang, and J.B. Zhao. 2012. Shikonin attenuates lipopolysaccharide-induced acute lung injury in mice. Journal of Surgical Research 182(2): 303–311. doi:10.1016/j.jss.2012.10.039.
Li, G.M., M.H. Ji, X.J. Sun, Q.T. Zeng, M. Tian, Y.X. Fan, W.Y. Li, N. Li, and J.J. Yang. 2012. Effects of hydrogen-rich saline treatment on polymicrobial sepsis. Journal of Surgical Research 181(2): 279–286.
Zhang, H., P. Neuhöfer, L. Song, B. Rabe, M. Lesina, M.U. Kurkowski, M. Treiber, T. Wartmann, S. Regnér, H. Thorlacius, D. Saur, G. Weirich, A. Yoshimura, W. Halangk, J.P. Mizgerd, R.M. Schmid, S. Rose-John, and H. Algül. 2013. IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. The Journal of Clinical Investigation 123(3): 1019–1031.
Park, W.Y., R.B. Goodman, K.P. Steinberg, J.T. Ruzinski, F. Radella 2nd, D.R. Park, J. Pugin, S.J. Skerrett, L.D. Hudson, and T.R. Martin. 2001. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 164(10 Pt 1): 1896–1903.
Li, Y., and H.B. Alam. 2012. Creating a pro-survival and anti-inflammatory phenotype by modulation of acetylation in models of hemorrhagic and septic shock. Advances in Experimental Medicine and Biology 710: 107–133.
Chen, X., I. Barozzi, A. Termanini, E. Prosperini, A. Recchiuti, J. Dalli, F. Mietton, G. Matteoli, S. Hiebert, and G. Natoli. 2012. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proceedings of the National Academy of Sciences of the United States of America 109(42): E2865–E2874.
Mullican, S.E., C.A. Gaddis, T. Alenghat, M.G. Nair, P.R. Giacomin, L.J. Everett, D. Feng, D.J. Steger, J. Schug, D. Artis, and M.A. Lazar. 2011. Histone deacetylase 3 is an epigenomic brake in macrophage alternative activation. Genes & Development 25(23): 2480–2488.
Yan, Q., R.J. Carmody, Z. Qu, Q. Ruan, J. Jager, S.E. Mullican, M.A. Lazar, and Y.H. Chen. 2012. Nuclear factor-κB binding motifs specify Toll-like receptor-induced gene repression through an inducible repressosome. Proceedings of the National Academy of Sciences of the United States of America 109(35): 14140–14145.
Zhu, T., D.X. Wang, W. Zhang, X.Q. Liao, X. Guan, H. Bo, J.Y. Sun, N.W. Huang, J. He, Y.K. Zhang, J. Tong, and C.Y. Li. 2013. Andrographolide protects against LPS-induced acute lung injury by inactivation of NF-κB. PLoS One 8(2): e56407.
Chen, Lf., W. Fischle, E. Verdin, and W.C. Greene. 2001. Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293(5535): 1653–1657.
Winkler, A.R., K.N. Nocka, and C.M. Williams. 2012. Smoke exposure of human macrophages reduces HDAC3 activity, resulting in enhanced inflammatory cytokine production. Pulmonary Pharmacology & Therapeutics 25(4): 286–292.
Ziesché, E., D. Kettner-Buhrow, A. Weber, T. Wittwer, L. Jurida, J. Soelch, H. Müller, D. Newel, P. Kronich, H. Schneider, O. Dittrich-Breiholz, S. Bhaskara, S.W. Hiebert, M.O. Hottiger, H. Li, E. Burstein, M.L. Schmitz, and M. Kracht. 2013. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB. Nucleic Acids Research 41(1): 90–109.
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This work was supported by the Natural Science Foundation of Jiangsu Province (BK2012778).
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The authors have no potential conflicts of interest to disclose.
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Mu-huo Ji and Guo-min Li contributed equally to this work.
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Ji, Mh., Li, Gm., Jia, M. et al. Valproic Acid Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice. Inflammation 36, 1453–1459 (2013). https://doi.org/10.1007/s10753-013-9686-z
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DOI: https://doi.org/10.1007/s10753-013-9686-z