Effect of dexmedetomidine on lung ischemia‑reperfusion injury

Jiang,Lili; Li,Li; Shen,Jinmei; Qi,Zeyou; Guo,Liang

doi:10.3892/mmr.2013.1867

Effect of dexmedetomidine on lung ischemia‑reperfusion injury

Authors:
- Lili Jiang
- Li Li
- Jinmei Shen
- Zeyou Qi
- Liang Guo
View Affiliations

Affiliations: Department of Anesthesiology, Second Xiang‑Ya Hospital, Xiang‑Ya Medical College, Central South University, Changsha, Hunan 410011, P.R. China
Published online on: December 17, 2013 https://doi.org/10.3892/mmr.2013.1867
Pages: 419-426
Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Dexmedetomidine, a specific selective α2‑adrenergic agonist, does not only have the characteristics of being a sedative and analgesic, but also exhibits a protective role in brain ischemia‑reperfusion injury and inhibits the inflammation in animals with sepsis. The objective of the present study was to investigate whether dexmedetomidine is capable of attenuating rat pulmonary damage induced by ischemia‑reperfusion injury, which is a type of acute sterile lung injury. Sprague‑Dawley rats were randomly assigned into six groups: The sham‑operated (sham) group, the lung ischemia‑reperfusion (I/R) group, intravenous injection of dexmedetomidine 2.5 µg/kg/h (Dex2.5) or 5 µg/kg/h (Dex5) for 1 h prior to ischemia, combination of α2‑adrenergic antagonist yohimbine prior to dexmedetomidine pre‑treatment (Dex+Yoh) and pre‑administration of yohimbine alone (Yoh) prior to ischemia. Lung injury was assessed by the histopathological changes, arterial blood gas, wet/dry (w/d) weight ratio and myeloperoxidase (MPO) activity of the lung. The concentration of tumor necrosis factor‑α (TNF‑α), interleukin‑6 (IL‑6) and monocyte chemoattractant protein‑1 (MCP‑1) in bronchoalveolar lavage fluid (BALF) was measured by an enzyme-linked immunosorbent assay. The expression of toll‑like receptor‑4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA in the lung were determined by quantitative PCR, and phosphorylated levels of c‑Jun N‑terminal kinase (JNK) and extracellular signal‑regulated kinase (ERK)1/2 were determined by western blotting. Pre‑treatment with dexmedetomidine significantly reduced the lung injury, w/d weight ratio and MPO activity, and decreased the concentration of TNF‑α, IL‑6 and MCP‑1 in BALF compared with the I/R group. The expression of TLR4 and MyD88 mRNA and the levels of phosphorylated JNK and ERK1/2 in the lung tissue were markedly downregulated by intravenous injection of dexmedetomidne for 1 h prior to lung I/R. The protective effects of dexmedetomidine on the lung were not completely reversed by the α2‑adrenergic antagonist, yohimbine. Pre‑treatment with dexmedetomidine is capable of reducing pulmonary damage and inhibiting sterile inflammation induced by lung I/R injury. TLR4/MyD88/mitogen-activated protein kinase (MAPK) signaling is involved in the protective mechanism of dexmedetomidine through α2‑adrenoceptor independence.

View Figures

View References

1	Christie JD, Carby M, Bag R, Corris P, Hertz M and Weill D; ISHLT Working Group on Primary Lung Graft Dysfunction. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 24:1454–1459. 2005. View Article : Google Scholar : PubMed/NCBI
2	Ng CS, Wan S, Yim AP and Arifi AA: Pulmonary dysfunction after cardiac surgery. Chest. 121:1269–1277. 2002. View Article : Google Scholar : PubMed/NCBI
3	Shimamoto A, Pohlman TH, Shomura S, Tarukawa T, Takao M and Shimpo H: Toll-like receptor 4 mediates lung ischemia-reperfusion injury. Ann Thorac Surg. 82:2017–2023. 2006. View Article : Google Scholar : PubMed/NCBI
4	Ambrosio G and Tritto I: Reperfusion injury: experimental evidence and clinical implications. Am Heart J. 138:S69–S75. 1999. View Article : Google Scholar : PubMed/NCBI
5	Reino DC, Pisarenko V, Palange D, et al: Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice. PLoS One. 6:e148292011. View Article : Google Scholar : PubMed/NCBI
6	Zhao M, Fernandez LG, Doctor A, et al: Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol. 291:L1018–L1026. 2006. View Article : Google Scholar : PubMed/NCBI
7	Gu J, Chen J, Xia P, Tao G, Zhao H and Ma D: Dexmedetomidine attenuates remote lung injury induced by renal ischemia-reperfusion in mice. Acta Anaesthesiol Scand. 55:1272–1278. 2011. View Article : Google Scholar : PubMed/NCBI
8	Taniguchi T, Kidani Y, Kanakura H, Takemoto Y and Yamamoto K: Effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats. Crit Care Med. 32:1322–1326. 2004. View Article : Google Scholar : PubMed/NCBI
9	Memis̨ D, Hekimoğlu S, Vatan I, Yandim T, Yüksel M and Süt N: Effects of midazolam and dexmedetomidine on inflammatory responses and gastric intramucosal pH to sepsis, in critically ill patients. Br J Anaesth. 98:550–552. 2007.PubMed/NCBI
10	Yang CL, Tsai PS and Huang CJ: Effects of dexmedetomidine on regulating pulmonary inflammation in a rat model of ventilator-induced lung injury. Acta Anaesthesiol Taiwan. 46:151–159. 2008. View Article : Google Scholar : PubMed/NCBI
11	Arumugam TV, Okun E, Tang SC, Thundyil J, Taylor SM and Woodruff TM: Toll-like receptors in ischemia-reperfusion injury. Shock. 32:4–16. 2009. View Article : Google Scholar : PubMed/NCBI
12	Prakash A, Mesa KR, Wilhelmsen K, Xu F, Dodd-o JM and Hellman J: Alveolar macrophages and Toll-like receptor 4 mediate ventilated lung ischemia reperfusion injury in mice. Anesthesiology. 117:822–835. 2012. View Article : Google Scholar : PubMed/NCBI
13	Shi QQ, Wang H and Fang H: Dose-response and mechanism of protective functions of selective alpha-2 agonist dexmedetomidine on acute lung injury in rats. Saudi Med J. 33:375–381. 2012.PubMed/NCBI
14	Yang CL, Chen CH, Tsai PS, Wang TY and Huang CJ: Protective effects of dexmedetomidine-ketamine combination against ventilator-induced lung injury in endotoxemia rats. J Surg Res. 167:e273–e281. 2011. View Article : Google Scholar : PubMed/NCBI
15	Yang CH, Tsai PS, Wang TY and Huang CJ: Dexmedetomidine-ketamine combination mitigates acute lung injury in haemorrhagic shock rats. Resuscitation. 80:1204–1210. 2009. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001.
17	Emaminia A, Lapar DJ, Zhao Y, et al: Adenosine A₂A agonist improves lung function during ex vivo lung perfusion. Ann Thorac Surg. 92:1840–1846. 2011.
18	Guo W, Ge D, Wang Q, et al: Diazoxide decreases ischemia-reperfusion injury in a rat model of lung transplantation. Transplant Proc. 43:2510–2516. 2011. View Article : Google Scholar : PubMed/NCBI
19	Jan WC, Chen CH, Tsai PS and Huang CJ: Limb ischemic preconditioning mitigates lung injury induced by haemorrhagic shock/resuscitation in rats. Resuscitation. 82:760–766. 2011. View Article : Google Scholar : PubMed/NCBI
20	Xu B, Gao X, Xu J, et al: Ischemic postconditioning attenuates lung reperfusion injury and reduces systemic proinflammatory cytokine release via heme oxygenase 1. J Surg Res. 166:e157–e164. 2011. View Article : Google Scholar : PubMed/NCBI
21	Dahmani S, Rouelle D, Gressens P and Mantz J: Characterization of the postconditioning effect of dexmedetomidine in mouse organotypic hippocampal slice cultures exposed to oxygen and glucose deprivation. Anesthesiology. 112:373–383. 2010. View Article : Google Scholar : PubMed/NCBI
22	Hoffman WE, Kochs E, Werner C, Thomas C and Albrecht RF: Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole. Anesthesiology. 75:328–332. 1991. View Article : Google Scholar : PubMed/NCBI
23	Eser O, Fidan H, Sahin O, et al: The influence of dexmedetomidine on ischemic rat hippocampus. Brain Res. 1218:250–256. 2008. View Article : Google Scholar : PubMed/NCBI
24	Cosar M, Eser O, Fidan H, et al: The neuroprotective effect of dexmedetomidine in the hippocampus of rabbits after subarachnoid hemorrhage. Surg Neurol. 71:54–59. 2009. View Article : Google Scholar
25	Nishina K, Akamatsu H, Mikawa K, et al: The effects of clonidine and dexmedetomidine on human neutrophil functions. Anesth Analg. 88:452–458. 1999.
26	Tasdogan M, Memis D, Sut N and Yuksel M: Results of a pilot study on the effects of propofol and dexmedetomidine on inflammatory responses and intraabdominal pressure in severe sepsis. J Clin Anesth. 21:394–400. 2009. View Article : Google Scholar : PubMed/NCBI
27	Taniguchi T, Kurita A, Kobayashi K, Yamamoto K and Inaba H: Dose- and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxin-induced shock in rats. J Anesth. 22:221–228. 2008. View Article : Google Scholar : PubMed/NCBI
28	Sezer A, Memis̨ D, Usta U and Süt N: The effect of dexmedetomidine on liver histopathology in a rat sepsis model: an experimental pilot study. Ulus Travma Acil Cerrahi Derg. 16:108–112. 2010.PubMed/NCBI
29	Qiao H, Sanders RD, Ma D, Wu X and Maze M: Sedation improves early outcome in severely septic Sprague Dawley rats. Crit Care. 13:R1362009. View Article : Google Scholar : PubMed/NCBI
30	Arslan F, Keogh B, McGuirk P and Parker AE: TLR2 and TLR4 in ischemia reperfusion injury. Mediators Inflamm. 2010:7042022010. View Article : Google Scholar : PubMed/NCBI
31	Li Y, Xiang M, Yuan Y, et al: Hemorrhagic shock augments lung endothelial cell activation: role of temporal alterations of TLR4 and TLR2. Am J Physiol Regul Integr Comp Physiol. 297:R1670–R1680. 2009. View Article : Google Scholar : PubMed/NCBI
32	Fan J, Li Y, Vodovotz Y, Billiar TR and Wilson MA: Hemorrhagic shock-activated neutrophils augment TLR4 signaling-induced TLR2 upregulation in alveolar macrophages: role in hemorrhage-primed lung inflammation. Am J Physiol Lung Cell Mol Physiol. 290:L738–L746. 2006. View Article : Google Scholar : PubMed/NCBI
33	Gao Y, Fang X, Sun H, et al: Toll-like receptor 4-mediated myeloid differentiation factor 88-dependent signaling pathway is activated by cerebral ischemia-reperfusion in hippocampal CA1 region in mice. Biol Pharm Bull. 32:1665–1671. 2009. View Article : Google Scholar : PubMed/NCBI
34	Feng Y, Zhao H, Xu X, et al: Innate immune adaptor MyD88 mediates neutrophil recruitment and myocardial injury after ischemia-reperfusion in mice. Am J Physiol Heart Circ Physiol. 295:H1311–H1318. 2008. View Article : Google Scholar : PubMed/NCBI
35	Hua F, Ha T, Ma J, et al: Blocking the MyD88-dependent pathway protects the myocardium from ischemia/reperfusion injury in rat hearts. Biochem Biophys Res Commun. 338:1118–1125. 2005. View Article : Google Scholar : PubMed/NCBI
36	Wang S, Schmaderer C, Kiss E, et al: Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling. Dis Model Mech. 3:92–103. 2010. View Article : Google Scholar : PubMed/NCBI
37	Wu H, Chen G, Wyburn KR, et al: TLR4 activation mediates kidney ischemia/reperfusion injury. J Clin Invest. 117:2847–2859. 2007. View Article : Google Scholar : PubMed/NCBI
38	Ben DF, Yu XY, Ji GY, et al: TLR4 mediates lung injury and inflammation in intestinal ischemia-reperfusion. J Surg Res. 174:326–333. 2012. View Article : Google Scholar : PubMed/NCBI
39	Zanotti G, Casiraghi M, Abano JB, et al: Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema. Am J Physiol Lung Cell Mol Physiol. 297:L52–L63. 2009. View Article : Google Scholar : PubMed/NCBI
40	Dahmani S, Paris A, Jannier V, et al: Dexmedetomidine increases hippocampal phosphorylated extracellular signal-regulated protein kinase 1 and 2 content by an alpha 2-adrenoceptor-independent mechanism: evidence for the involvement of imidazoline I1 receptors. Anesthesiology. 108:457–466. 2008. View Article : Google Scholar
41	Zhang F, Ding T, Yu L, Zhong Y, Dai H and Yan M: Dexmedetomidine protects against oxygen-glucose deprivation-induced injury through the I2 imidazoline receptor-PI3K/AKT pathway in rat C6 glioma cells. J Pharm Pharmacol. 64:120–127. 2012. View Article : Google Scholar
42	Afonso J and Reis F: Dexmedetomidine: current role in anesthesia and intensive care. Rev Bras Anestesiol. 62:118–133. 2012. View Article : Google Scholar : PubMed/NCBI