Dose-related effects of dexmedetomidine on sepsis-initiated lung injury in rats
Efeitos dose-dependentes de dexmedetomidina na lesão pulmonar induzida pela sepse em ratos
Gülsüm Karabulut, Nurdan Bedirli, Nalan Akyürek, Emin Ümit Bagrıacık
Abstract
Background
Sepsis is one of the leading causes of death in intensive care units. Dexmedetomidine is a sedative agent with anti-inflammatory properties. This study is designed to differentiate the impact of two different doses of dexmedetomidine on lung injury induced by sepsis.
Methods
Adult male Wistar rats were randomly divided into four groups: sham (n = 6), control (n = 12), 5DEX (n = 12), and 10DEX (n = 12). Cecal ligation puncture (CLP) was applied for sepsis initiation. The 5DEX group received 5 μg.kg-1.h-1 and the 10DEX group received 10 μg.kg-1.h-1 dexmedetomidine intravenous infusions for a 1-hour period. Six hours after CLP, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and intercellular adhesion molecule-1 (ICAM-1) levels were analyzed in blood samples. Twenty-four hours after CLP, lung samples from the remaining rats were collected for the measurement of myeloperoxidase (MPO) activity, histological examination, and TdT- (terminal deoxynucleotidyl transferase) mediated fluorescent-dUTP labeling staining for apoptosis detection.
Results
Serum cytokine release, MPO activity, and apoptosis in the lung were significantly increased in the CLP group compared with the sham and dexmedetomidine groups (p < 0.05). TNF-α, ICAM-1, and MPO were significantly lower in the 10DEX group compared with both 5DEX and control groups, while IL-1β, total injury score, and apoptotic cell count had significantly lower values in both 10DEX and 5DEX groups compared with the control group (p < 0.05).
Conclusion
Dexmedetomidine administration played a protective role against CLP-induced lung injury. High-dose dexmedetomidine was needed for suppressing the leukocyte-mediated lung injury and apoptosis of lung tissue.
Keywords
References
1 M. Singer, C.S. Deutschman, C.W. Seymour, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) JAMA, 315 (2016), pp. 801-810
2 G.D. Rubenfeld, E. Caldwell, E. Peabody, et al. Incidence and outcomes of acute lung injury N Engl J Med, 353 (2005), pp. 1685-1693
3 L.B. Ware, M.A. Matthay The acute respiratory distress syndrome N Engl J Med, 342 (2000), pp. 1334-1349
4 X.D. Zhang, J.F. Hou, X.J. Qin, et al. Pentoxifylline inhibits intercellular adhesion molecule-1 (ICAM-1) and lung injury in experimental phosgene-exposure rats Inhal Toxicol, 22 (2010), pp. 889-895
5 Y. Gong, H. Lan, Z. Yu, et al. Blockage of glycolysis by targeting PFKFB3 alleviates sepsis-related acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells Biochem Biophys Res Commun, 491 (2017), pp. 522-529
6 Y. Chen, L. Wang, Q. Kang, et al. Heat Shock Protein A12B Protects Vascular Endothelial Cells Against Sepsis-Induced Acute Lung Injury in Mice Cell Physiol Biochem, 42 (2017), pp. 156-168
7 J. Hill, T. Lindsay, C.R. Valeri, et al. A CD18 antibody prevents lung injury but not hypotension after intestinal ischemia-reperfusion J Appl Physiol, 74 (1993), pp. 659-664
8 B.C. Marcus, K.L. Hynes, B.L. Gewertz Loss of endothelial barrier function requires neutrophil adhesion Surgery, 122 (1997), pp. 420-427
9 E. Abraham Neutrophils and acute lung injury Crit Care Med, 31 (2003), pp. S195-9
10 X. Ma, D. Xu, Y. Ai, et al. Fas inhibition attenuates lipopolysaccharide-induced apoptosis and cytokine release of rat type II alveolar epithelial cells Mol Biol Rep, 37 (2010), pp. 3051-3056
11 C.Y. Chuang, T.L. Chen, Y.G. Cherng, et al. Lipopolysaccharide induces apoptotic insults to human alveolar epithelial A549 cells through reactive oxygen species-mediated activation of an intrinsic mitochondrion-dependent pathway Arch Toxicol, 85 (2011), pp. 209-218
12 Y.W. Hsu, L.I. Cortinez, K.M. Robertson, et al. Dexmedetomidine pharmacodynamics: part I: crossover comparison of the respiratory effects of dexmedetomidine and remifentanil in healthy volunteers Anesthesiology, 101 (2004), pp. 1066-1076
13 Y. Zhang, K. Ran, S.B. Zhang, et al. Dexmedetomidine may upregulate the expression of caveolin-1 in lung tissues of rats with sepsis and improve the short-term outcome Mol Med Rep, 15 (2017), pp. 635-642
14 P.P. Pandharipande, R.D. Sanders, T.D. Girard, et al. Effect of dexmedetomidine versus lorazepam on outcome in patients with sepsis: an a priori-designed analysis of the MENDS randomized controlled trial Crit Care, 14 (2010), p. R38
15 L.F. Poli-de-Figueiredo, A.G. Garrido, N. Nakagawa, et al. Experimental models of sepsis and their clinical relevance Shock, 30 (2008), pp. 53-59
16 S. Ebong, D. Call, J. Nemzek, et al. Immunopathologic alterations in murine models of sepsis of increasing severity Infect Immun, 67 (1999), pp. 6603-6610
17 D. Torre, G. Minoja, D. Maraggia, et al. Effect of recombinant IL-1 beta and recombinant gamma interferon on septic acute lung injury in mice Chest, 105 (1994), pp. 1241-1245
18 Y. Wu, Y. Liu, H. Huang, et al. Dexmedetomidine inhibits inflammatory reaction in lung tissues of septic rats by suppressing TLR4/NF-kappaB pathway Mediators Inflamm, 2013 (2013), Article 562154
19 C. Ma, L. Zhu, J. Wang, et al. Anti-inflammatory effects of water extract of Taraxacum mongolicum hand.-Mazz on lipopolysaccharide-induced inflammation in acute lung injury by suppressing PI3K/Akt/mTOR signaling pathway J Ethnopharmacol, 168 (2015), pp. 349-355
20 X. Wang, B. Zhao, X. Li Dexmedetomidine attenuates isoflurane-induced cognitive impairment through antioxidant, anti-inflammatory and anti-apoptosis in aging rat Int J Clin Exp Med, 8 (2015), pp. 17281-17288
21 Z. Liu, Y. Wang, Y. Wang, et al. Dexmedetomidine attenuates inflammatory reaction in the lung tissues of septic mice by activating cholinergic anti-inflammatory pathway Int Immunopharmacol, 35 (2016), pp. 210-216
22 Y. Ma, X.Y. Yu, Y. Wang Dose-related effects of dexmedetomidine on immunomodulation and mortality to septic shock in rats World J Emerg Med, 9 (2018), pp. 56-63
23 O.V. Hein, K. Misterek, J.P. Tessmann, et al. Time course of endothelial damage in septic shock: prediction of outcome Crit Care, 9 (2005), p. R323
24 W. Jing, M. Chunhua, W. Shumin Effects of acteoside on lipopolysaccharide-induced inflammation in acute lung injury via regulation of NF-kappaB pathway in vivo and in vitro Toxicol Appl Pharmacol, 285 (2015), pp. 128-135
25 T. Chen, Y. Mou, J. Tan, et al. The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice Int Immunopharmacol, 25 (2015), pp. 55-64
26 T. Chen, R. Wang, W. Jiang, et al. Protective Effect of Astragaloside IV Against Paraquat-Induced Lung Injury in Mice by Suppressing Rho Signaling Inflammation, 39 (2016), pp. 483-492
27 X. Huang, Y. Liu, Y. Lu, et al. Anti-inflammatory effects of eugenol on lipopolysaccharide-induced inflammatory reaction in acute lung injury via regulating inflammation and redox status Int Immunopharmacol, 26 (2015), pp. 265-271
28 X. Zhou, Q. Dai, X. Huang Neutrophils in acute lung injury Front Biosci, 17 (2012), pp. 2278-2283
29 A.J. McCabe, M. Dowhy, B.A. Holm, et al. Myeloperoxidase activity as a lung injury marker in the lamb model of congenital diaphragmatic hernia J Pediatr Surg, 36 (2001), pp. 334-337
30 R.H. Bardales, S.S. Xie, R.F. Schaefer, et al. Apoptosis is a major pathway responsible for the resolution of type II pneumocytes in acute lung injury Am J Pathol, 149 (1996), pp. 845-852
Facebook
Google+
Twitter
LinkedIn
Mendeley
StumbleUpon
CiteULike
Reddit
Email