Protective Effect of Dexmedetomidine on Acute Lung Injury via the Upregulation of Tumour Necrosis Factor-α-Induced Protein-8-like 2 in Septic Mice
Qian Kong
Xiaojing Wu
Zhen Qiu
Qin Huang
Zhongyuan Xia
Xuemin Song
The aim of the present study was to investigate whether TIPE2 participates in the protective actions of dexmedetomidine (DEX) in a mouse model of sepsis-induced acute lung injury (ALI). We administered TIPE2 adeno-associated virus (AAV-TIPE2) intratracheally into the lungs of mice. Control mice were infected with an adeno-associated virus expressing no transgene. Three weeks later, an animal model of caecal ligation-perforation (CLP)-induced sepsis was established. DEX was administered intravenously 30 min after CLP. Twenty-four hours after sepsis, lung injury was assayed by lung histology, the ratio of polymorphonuclear leukocytes (PMNs) to total cells in the bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) activity, BALF protein content and the lung wet-to-dry (W/D) weight ratio. Proinflammatory factor levels in the BALF of mice were measured. The protein expression levels in lung tissues were analysed by Western blotting. The results showed that DEX treatment markedly mitigated sepsis-induced lung injury, which was characterized by the deterioration of histopathology, histologic scores, the W/D weight ratio and total protein levels in the BALF. Moreover, DEX markedly attenuated sepsis-induced lung inflammation, as evidenced by the decrease in the number of PMNs in the BALF, lung MPO activity and proinflammatory cytokines in the BALF. In addition, DEX dramatically prevented sepsis-induced pulmonary cell apoptosis in mice, as reflected by decreases in the number of TUNEL-positive cells, the protein expression of cleaved caspase-9 and cleaved caspase 3 and the Bax/Bcl-2 ratio. In addition, evaluation of protein expression showed that DEX blocked sepsis-activated JNK phosphorylation and NF-κB p65 nuclear translocation. Similar results were also observed in the TIPE2 overexpression group. Our study demonstrated that DEX inhibits acute inflammation and apoptosis in a murine model of sepsis-stimulated ALI via the upregulation of TIPE2 and the suppression of the activation of the NF-κB and JNK signalling pathways.
acute lung injury TIPE2 dexmedetomidine apoptosis inflammation
acute respiratory distress syndrome
caecal ligation-perforation
bronchoalveolar lavage fluid
myeloperoxidase
PMNs
polymorphonuclear neutrophils
deoxynucleotidyl transferase dUTP nick end labelling
wet-to-dry
TIPE2
tumour necrosis factor-α-induced protein 8-like 2
dexmedetomidine
Bcl-2-associated X
B cell lymphoma 2
Qian Kong and Xiaojing Wu contributed equally to this work.
This study was supported by the National Natural Science Foundation of China (no. 81571941 and no. 81671948).
Ethical approval was provided by the Medical Ethics Committee of Renmin Hospital of Wuhan University. All surgical procedures were performed in accordance with international and institutional guidelines for animal care.
The authors declare that they have no conflict of interests.
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Walkey, A.J., A.R. Kirkpatrick, and R.S. Summer. 2015. Systemic inflammatory response syndrome criteria for severe Sepsis. The New England Journal of Medicine 373 (9): 880.PubMedPubMedCentralGoogle Scholar
Khan, M.M., W.L. Yang, M. Brenner, A.C. Bolognese, and P. Wang. 2017. Cold- inducible RNA-binding protein (CIRP) causes sepsis-associated acute lung injury via induction of endoplasmic reticulum stress. Scientific Reports 7: 41363.PubMedPubMedCentralCrossRefGoogle Scholar
Li, C., D. Yang, X. Cao, F. Wang, H. Jiang, H. Guo, et al. 2016. LFG-500, a newly synthesized flavonoid, attenuates lipopolysaccharide-induced acute lung injury and inflammation in mice. Biochemical Pharmacology 113: 57–69.PubMedCrossRefPubMedCentralGoogle Scholar
Zhao, Z., X. Tang, X. Zhao, M. Zhang, W. Zhang, S. Hou, et al. 2014. Tylvalosin exhibits anti-inflammatory property and attenuates acute lung injury in different models possibly through suppression of NF-kappaB activation. Biochemical Pharmacology 90 (1): 73–87.PubMedCrossRefPubMedCentralGoogle Scholar
Matthay, M.A., and G.A. Zimmerman. 2005. Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis and rational management. American Journal of Respiratory Cell and Molecular Biology 33 (4): 319–327.PubMedPubMedCentralCrossRefGoogle Scholar
Singh, G., G. Gladdy, T.T. Chandy, and N. Sen. 2014. Incidence and outcome of acute lung injury and acute respiratory distress syndrome in the surgical intensive care unit. Indian J Crit Care Med 18 (10): 659–665.PubMedPubMedCentralCrossRefGoogle Scholar
Z'graggen, B.R., J. Tornic, B. Müller-Edenborn, L. Reyes, C. Booy, and B. Beck-Schimmer. 2010. Acute lung injury: Apoptosis in effector and target cells of the upper and lower airway compartment. Clinical and Experimental Immunology 161 (2): 324–331.PubMedPubMedCentralGoogle Scholar
Hotchkiss, R.S., P.E. Swanson, B.D. Freeman, K.W. Tinsley, J.P. Cobb, G.M. Matuschak, et al. 1999. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Critical Care Medicine 27 (7): 1230–1251.PubMedCrossRefPubMedCentralGoogle Scholar
Davis, R.J. 2000. Signal transduction by the JNK group of MAP kinases. Cell 103 (2): 239–252.PubMedPubMedCentralCrossRefGoogle Scholar
Lin, A. 2003. Activation of the JNK signaling pathway: Breaking the brake on apoptosis. Bioessays 25 (1): 17–24.PubMedCrossRefGoogle Scholar
Cho, J.S., J.K. Shim, S. Soh, M.K. Kim, and Y.L. Kwak. 2016. Perioperative dexmedetomidine reduces the incidence and severity of acute kidney injury following valvular heart surgery. Kidney International 89 (3): 693–700.PubMedCrossRefGoogle Scholar
Taniguchi, T., Y. Kidani, H. Kanakura, Y. Takemoto, and K. Yamamoto. 2004. Effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats. Critical Care Medicine 32 (6): 1322–1326.PubMedCrossRefGoogle Scholar
Sanders, R.D., P. Sun, S. Patel, M. Li, M. Maze, and D. Ma. 2010. Dexmedetomidine provides cortical neuroprotection: Impact on anaesthetic-induced neuroapoptosis in the rat developing brain. Acta Anaesthesiologica Scandinavica 54 (6): 710–716.PubMedCrossRefGoogle Scholar
Zhang, Q., D. Wu, Y. Yang, T. Liu, and H. Liu. 2017. Dexmedetomidine alleviates Hyperoxia-induced acute lung injury via inhibiting NLRP3 Inflammasome activation. Cellular Physiology and Biochemistry 42 (5): 1907–1919.PubMedCrossRefGoogle Scholar
Zhang, Y., S. Jia, T. Gao, R. Zhang, Z. Liu, and Y. Wang. 2018. Dexmedetomidine mitigate acute lung injury by inhibiting IL-17-induced inflammatory reaction. Immunobiology 223 (1): 32–37.PubMedCrossRefGoogle Scholar
Géloën, A., C. Pichot, S. Leroy, C. Julien, M. Ghignone, C.N. May, et al. 2015. Pressor response to noradrenaline in the setting of septic shock: Anything new under the Sun-Dexmedetomidine, clonidine? A Minireview. BioMed Research International 2015: 863715.PubMedPubMedCentralCrossRefGoogle Scholar
Kumar, D., P. Gokhale, C. Broustas, D. Chakravarty, I. Ahmad, and U. Kasid. 2004. Expression of SCC-S2, an antiapoptotic molecule, correlates with enhanced proliferation and tumorigenicity of MDA-MB 435 cells. Oncogene 23 (2): 612–616.PubMedCrossRefGoogle Scholar
Sun, H., S. Gong, R.J. Carmody, A. Hilliard, L. Li, J. Sun, et al. 2008. TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell 133 (3): 415–426.PubMedPubMedCentralCrossRefGoogle Scholar
Siempos, I.I., H.C. Lam, Y. Ding, M.E. Choi, A.M. Choi, and S.W. Ryter. 2014. Cecal ligation and puncture-induced sepsis as a model to study autophagy in mice. Journal of Visualized Experiments 84: e51066.Google Scholar
Jeremias, I.C., V.J. Victorino, H.V. Barbeiro, S.A. Kubo, C.M. Prado, T.M. Lima, et al. 2016. The role of acetylcholine in the inflammatory response in animals surviving Sepsis induced by Cecal ligation and puncture. Molecular Neurobiology 53 (10): 6635–6643.PubMedCrossRefPubMedCentralGoogle Scholar
Su, X., L. Wang, Y. Song, and C. Bai. 2004. Inhibition of inflammatory responses by ambroxol, a mucolytic agent, in a murine model of acute lung injury induced by lipopolysaccharide. Intensive Care Medicine 30 (1): 133–140.PubMedCrossRefPubMedCentralGoogle Scholar
Johnson, E.R., and M.A. Matthay. 2010. Acute lung injury: Epidemiology, pathogenesis, and treatment. Journal of Aerosol Medicine and Pulmonary Drug Delivery 23 (4): 243–252.PubMedPubMedCentralCrossRefGoogle Scholar
Pandharipande, P.P., R.D. Sanders, T.D. Girard, S. McGrane, J.L. Thompson, A.K. Shintani, et al. 2010. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: An a priori-designed analysis of the MENDS randomized controlled trial. Critical Care 14 (2): R38.PubMedPubMedCentralCrossRefGoogle Scholar
Hu, H., D. Shi, C. Hu, X. Yuan, J. Zhang, and H. Sun. 2017. Dexmedetomidine mitigates CLP-stimulated acute lung injury via restraining the RAGE pathway. American Journal of Translational Research 9 (12): 5245–5258.PubMedPubMedCentralGoogle Scholar
Freundt, E.C., N. Bidere, and M.J. Lenardo. 2008. A different TIPE of immune homeostasis. Cell 133 (3): 401–402.PubMedPubMedCentralCrossRefGoogle Scholar
Xi, W., Y. Hu, Y. Liu, J. Zhang, L. Wang, Y. Lou, et al. 2011. Roles of TIPE2 in hepatitis B virus-induced hepatic inflammation in humans and mice. Molecular Immunology 48 (9–10): 1203–1208.PubMedCrossRefPubMedCentralGoogle Scholar
Li, D., L. Song, Y. Fan, X. Li, Y. Li, J. Chen, et al. 2009. Down-regulation of TIPE2 mRNA expression in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Clinical Immunology 133 (3): 422–427.PubMedCrossRefGoogle Scholar
Kumar, D., T.L. Whiteside, and U. Kasid. 2000. Identification of a novel tumor necrosis factor-alpha-inducible gene, SCC-S2, containing the consensus sequence of a death effector domain of fas-associated death domain-like interleukin- 1beta-converting enzyme-inhibitory protein. The Journal of Biological Chemistry 275 (4): 2973–2978.PubMedCrossRefGoogle Scholar
Yan, X., X. Cheng, L. Zhou, X. He, W. Zheng, and H. Chen. 2017. Dexmedetomidine alleviates lipopolysaccharide-induced lung injury in Wistar rats. Oncotarget 8 (27): 44410–44417.PubMedPubMedCentralCrossRefGoogle Scholar
Buras, J.A., B. Holzmann, and M. Sitkovsky. 2005. Animal models of sepsis: Setting the stage. Nature Reviews. Drug Discovery 4 (10): 854–865.PubMedCrossRefPubMedCentralGoogle Scholar
Hubbard, W.J., M. Choudhry, M.G. Schwacha, J.D. Kerby, L.W. Rue, K.I. Bland, et al. 2005. Cecal ligation and puncture. Shock 24 (Suppl 1): 52–57.PubMedCrossRefPubMedCentralGoogle Scholar
Abraham, E., and M. Singer. 2007. Mechanisms of sepsis-induced organ dysfunction. Critical Care Medicine 35 (10): 2408–2416.PubMedCrossRefPubMedCentralGoogle Scholar
Matthay, M.A., and R.L. Zemans. 2011. The acute respiratory distress syndrome: Pathogenesis and treatment. Annual Review of Pathology 6: 147–163.PubMedPubMedCentralCrossRefGoogle Scholar
Brown, K.A., S.D. Brain, J.D. Pearson, J.D. Edgeworth, S.M. Lewis, and D.F. Treacher. 2006. Neutrophils in development of multiple organ failure in sepsis. Lancet 368 (9530): 157–169.PubMedCrossRefPubMedCentralGoogle Scholar
Yang, K.Y., J.J. Arcaroli, and E. Abraham. 2003. Early alterations in neutrophil activation are associated with outcome in acute lung injury. American Journal of Respiratory and Critical Care Medicine 167 (11): 1567–1574.PubMedCrossRefPubMedCentralGoogle Scholar
Zhang, H.X., S.J. Liu, X.L. Tang, G.L. Duan, X. Ni, X.Y. Zhu, et al. 2016. H2S attenuates LPS-induced acute lung injury by reducing oxidative/Nitrative stress and inflammation. Cellular Physiology and Biochemistry 40 (6): 1603–1612.PubMedCrossRefPubMedCentralGoogle Scholar
Grommes, J., and O. Soehnlein. 2011. Contribution of neutrophils to acute lung injury. Molecular Medicine 17 (3–4): 293–307.PubMedCrossRefPubMedCentralGoogle Scholar
Hirano, Y., M. Aziz, W.L. Yang, Z. Wang, M. Zhou, M. Ochani, et al. 2015. Neutralization of osteopontin attenuates neutrophil migration in sepsis-induced acute lung injury. Critical Care 19: 53.PubMedPubMedCentralCrossRefGoogle Scholar
Liu, S.F., and A.B. Malik. 2006. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. American Journal of Physiology. Lung Cellular and Molecular Physiology 290 (4): L622–L645.PubMedCrossRefPubMedCentralGoogle Scholar
Wang, H., L. Wang, N.L. Li, J.T. Li, F. Yu, Y.L. Zhao, et al. 2014. Subanesthetic isoflurane reduces zymosan-induced inflammation in murine Kupffer cells by inhibiting ROS-activated p38 MAPK/NF-kappaB signaling. Oxidative Medicine and Cellular Longevity 2014: 851692.PubMedPubMedCentralGoogle Scholar
Blackwell, T.S., T.R. Blackwell, E.P. Holden, B.W. Christman, and J.W. 1996. Christman. In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation. Journal of Immunology 157 (4): 1630–1637.Google Scholar
Galani, V., E. Tatsaki, M. Bai, P. Kitsoulis, M. Lekka, G. Nakos, et al. 2010. The role of apoptosis in the pathophysiology of acute respiratory distress syndrome (ARDS): An up-to-date cell-specific review. Pathology, Research and Practice 206 (3): 145–150.PubMedCrossRefPubMedCentralGoogle Scholar
Chopra, M., J.S. Reuben, and A.C. Sharma. 2009. Acute lung injury:Apoptosis and signaling mechanisms. Experimental Biology and Medicine (Maywood, N.J.) 234 (4): 361–371.CrossRefGoogle Scholar
Perl, M., C.S. Chung, U. Perl, R. Thakkar, J. Lomas-Neira, and A. Ayala. 2010. Therapeutic accessibility of caspase-mediated cell death as a key pathomechanism in indirect acute lung injury. Critical Care Medicine 38 (4): 1179–1186.PubMedPubMedCentralCrossRefGoogle Scholar
Porter, A.G., and R.U. Janicke. 1999. Emerging roles of caspase-3 in apoptosis. Cell Death and Differentiation 6 (2): 99–104.PubMedCrossRefPubMedCentralGoogle Scholar
Lee, I.T., and C.M. Yang. 2013. Inflammatory signalings involved in airway and pulmonary diseases. Mediators of Inflammation 2013: 791231.PubMedPubMedCentralGoogle Scholar
Kyriakis, J.M., P. Banerjee, E. Nikolakaki, T. Dai, E.A. Rubie, M.F. Ahmad, et al. 1994. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369 (6476): 156–160.PubMedCrossRefPubMedCentralGoogle Scholar
Sui, X., N. Kong, L. Ye, W. Han, J. Zhou, Q. Zhang, et al. 2014. p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Letters 344 (2): 174–179.PubMedCrossRefPubMedCentralGoogle Scholar
Kluck, R.M., E. Bossy-Wetzel, D.R. Green, and D.D. Newmeyer. 1997. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science 275 (5303): 1132–1136.PubMedCrossRefPubMedCentralGoogle Scholar
Li, B., M. Zeng, W. He, X. Huang, L. Luo, H. Zhang, et al. 2015. Ghrelin protects alveolar macrophages against lipopolysaccharide-induced apoptosis through growth hormone secretagogue receptor 1a-dependent c-Jun N-terminal kinase and Wnt/beta-catenin signaling and suppresses lung inflammation. Endocrinology 156 (1): 203–217.PubMedCrossRefGoogle Scholar
© Springer Science+Business Media, LLC, part of Springer Nature 2020
1.Department of AnesthesiologyRenmin Hospital of Wuhan UniversityWuhanChina
2.Department of Anesthesiology and Critical Care MedicineZhongnan Hospital of Wuhan UniversityWuhanChina
Kong, Q., Wu, X., Qiu, Z. et al. Inflammation (2020). https://doi.org/10.1007/s10753-019-01169-w
DOI https://doi.org/10.1007/s10753-019-01169-w
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