Dexmedetomidine preconditioning protects against lung injury induced by ischemia-reperfusion through inhibition of autophagy

Zhang,Wei; Zhang,Jiaqiang

doi:10.3892/etm.2017.4623

Dexmedetomidine preconditioning protects against lung injury induced by ischemia-reperfusion through inhibition of autophagy

Authors:
- Wei Zhang
- Jiaqiang Zhang
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Affiliations: Department of Anesthesiology, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, P.R. China
Published online on: June 16, 2017 https://doi.org/10.3892/etm.2017.4623
Pages: 973-980
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to evaluate the role of autophagy in the protective effect of dexmedetomidine in lung injury caused by ischemia-reperfusion (IR) in rats. In total 48 adult male Sprague‑Dawley rats were randomly divided into 6 groups (n=8) as follows: i) Sham group; ii) the IR group; iii) IR + 1 µg/kg dexmedetomidine preconditioning group (pre‑LD); iv) IR + 10 µg/kg dexmedetomidine preconditioning group (pre‑HD); v) IR + 1 µg/kg dexmedetomidine postconditioning group (post‑LD); and vi) IR + 10 µg/kg dexmedetomidine postconditioning group (post‑HD). After the rats were anesthetized, the hilum of the left lung was occluded with a non‑invasive microvascular clip for 30 min to induce ischemia. The clip was then removed and the left lung was allowed to regain ventilation and blood for 2 h. The rats were then sacrificed, the left lung removed and the wet/dry (W/D) lung weight ratio was determined. Pathological changes to the lungs were evaluated by light and transmission electron microscopy. Furthermore, the rate of lung cell apoptosis was determined by the TUNEL assay. The expression of hypoxia‑inducible factor 1α (HIF‑1α), Bcl‑2/adenovirus E1B 19‑kDa interacting protein 3 (BNIP3), BNIP3 like (BNIP3 L) and microtubule‑associated protein 1A/1B light chain 3B (LC3II) was determined by western blotting. Compared with the sham group, a significant increase in the W/D lung weight ratio, and malondialdehyde (MDA), BNIP3, BNIP3 L and LC3II levels were observed in the IR group, and HIF‑1α levels and superoxide dismutase (SOD) activity were decreased. Furthermore, the W/D ratio was lower in the pre‑LD and pre‑HD groups than in the IR group. Additionally, SOD activity was significantly higher and MDA expression was significantly lower in the pre‑LD and pre‑HD groups compared with the IR group. BNIP3, BNIP3 L and LC3II protein levels were significantly lower in the pre‑LD and pre‑HD groups compared with the IR group, while HIF‑1α was notably upregulated in the pre‑LD and pre‑HD groups compared with the IR group. In conclusion, the results of the present study indicate that dexmedetomidine preconditioning protects against lung injury induced by IR through inhibition of autophagy and apoptosis.

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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, Doucet D, Bonitz RP, Lu Q, Colorado I, Sheth SU, Chandler B, Kannan KB, 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	Jiang L, Li L, Shen J, Qi Z and Guo L: Effect of dexmedetomidine on lung ischemia-reperfusion injury. Mol Med Rep. 9:419–426. 2014.PubMed/NCBI
7	Shen J and Fu G, Jiang L, Xu J, Li L and Fu G: Effect of dexmedetomidine pretreatment on lung injury following intestinal ischemia-reperfusion. Exp Ther Med. 6:1359–1364. 2013.PubMed/NCBI
8	Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, et al: Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 26:9220–9231. 2006. View Article : Google Scholar : PubMed/NCBI
9	Tra T, Gong L, Kao LP, Li XL, Grandela C, Devenish RJ, Wolvetang E and Prescott M: Autophagy in human embryonic stem cells. PLoS One. 6:e274852011. View Article : Google Scholar : PubMed/NCBI
10	Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, Ohsumi Y, Tokuhisa T and Mizushima N: The role of autophagy during the early neonatal starvation period. Nature. 432:1032–1036. 2004. View Article : Google Scholar : PubMed/NCBI
11	Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, Ezaki J, Mizushima N, Ohsumi Y, Uchiyama Y, et al: Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 169:425–434. 2005. View Article : Google Scholar : PubMed/NCBI
12	Suzuki C, Isaka Y, Takabatake Y, Tanaka H, Koike M, Shibata M, Uchiyama Y, Takahara S and Imai E: Participation of autophagy in renal ischemia/reperfusion injury. Biochem Biophys Res Commun. 368:100–106. 2008. View Article : Google Scholar : PubMed/NCBI
13	Jiang M, Liu K, Luo J and Dong Z: Autophagy is a renoprotective mechanism during in vitro hypoxia and in vivo ischemia-reperfusion injury. Am J Pathol. 176:1181–1192. 2010. View Article : Google Scholar : PubMed/NCBI
14	Gump JM, Staskiewicz L, Morgan MJ, Bamberg A, Riches DW and Thorburn A: Autophagy variation within a cell population determines cell fate through selective degradationof Fap-1. Nat Cell Biol. 16:47–54. 2014. View Article : Google Scholar : PubMed/NCBI
15	Zhang D, Li C, Zhou J, Song Y, Fang X, Ou J, Li J and Bai C: Autophagy protects against ischemia/reperfusion-induced lung injury through alleviating blood-air barrier damage. J Heart Lung Transplant. 34:746–755. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zhang J, Wang JS, Zheng ZK, Tang J, Fan K, Guo H and Wang JJ: Participation of autophagy in lung ischemia-reperfusion injury in vivo. J Surg Res. 182:e79–e87. 2013. View Article : Google Scholar : PubMed/NCBI
17	Luce JM: Acute lung injury and the acute respiratory distress syndrome. Crit Care Med. 26:369–376. 1998. View Article : Google Scholar : PubMed/NCBI
18	Zhang XY, Liu ZM, Wen SH, Li YS, Li Y, Yao X, Huang WQ and Liu KX: Dexmedetomidine administration before, but not after, ischemia attenuates intestinal injury induced by intestinal ischemia-reperfusion in rats. Anesthesiology. 116:1035–1046. 2012. View Article : Google Scholar : PubMed/NCBI
19	Lempiäinen J, Finchenberg P, Mervaala EE, Storvik M, Kaivola J, Lindstedt K, Levijoki J and Mervaala EM: Dexmedetomidine preconditioning ameliorates kidney ischemia-reperfusion injury. Pharmacol Res Perspect. 2:e000452014. View Article : Google Scholar : PubMed/NCBI
20	de Perrot M, Liu M, Waddell TK and Keshavjee S: Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med. 167:490–511. 2003. View Article : Google Scholar : PubMed/NCBI
21	Zimmerman BJ and Granger DN: Mechanisms of reperfusion injury. Am J Med Sci. 307:284–292. 1994. View Article : Google Scholar : PubMed/NCBI
22	De Greef KE, Ysebaert DK, Ghielli M, Vercauteren S, Nouwen EJ, Eyskens EJ and De Broe ME: Neutrophilsand acute ischemia-reperfusion injury. J Nephrol. 11:110–122. 1998.PubMed/NCBI
23	Oredsson S, Plate G and Qvarfordt P: Experimental evaluation of oxygen free radical scavengers in the prevention of reperfusion injury in skeletal muscle. Eur J Surg. 160:97–103. 1994.PubMed/NCBI
24	Deby C and Goutier R: New perspectives on the biochemistry of superoxide anion and the efficiency of superoxide dismutases. Biochem Pharmacol. 39:399–405. 1990. View Article : Google Scholar : PubMed/NCBI
25	Feinman R, Deitch EA, Watkins AC, Abungu B, Colorado I, Kannan KB, Sheth SU, Caputo FJ, Lu Q, Ramanathan M, et al: HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 299:G833–G843. 2010. View Article : Google Scholar : PubMed/NCBI
26	Zhao X, Jin Y, Li H, Wang Z, Zhang W and Feng C: Hypoxia-inducible factor 1 alpha contributes to pulmonary vascular dysfunction in lung ischemia-reperfusion injury. Int J Clin Exp Pathol. 7:3081–3088. 2014.PubMed/NCBI
27	Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L and Elazar Z: Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBOJ. 26:1749–1760. 2007. View Article : Google Scholar
28	Høyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, Bianchi K, Fehrenbacher N, Elling F, Rizzuto R, et al: Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell. 25:193–205. 2007. View Article : Google Scholar : PubMed/NCBI
29	Zhang J, Wang JS, Zheng ZK, Tang J, Fan K, Guo H and Wang JJ: Participation of autophagy in lung ischemia-reperfusion injury in vivo. J Surg Res. 182:e79–e87. 2013. View Article : Google Scholar : PubMed/NCBI
30	Matsui Y, Kyoi S, Takagi H, Hsu CP, Hariharan N, Ago T, Vatner SF and Sadoshima J: Molecular mechanisms and physiological significance of autophagy during myocardial ischemia and reperfusion. Autophagy. 4:409–415. 2008. View Article : Google Scholar : PubMed/NCBI
31	Zhang D, Li C, Zhou J, Song Y, Fang X, Ou J, Li J and Bai C: Autophagy protects against ischemia/reperfusion-induced lung injury through alleviating blood-air barrier damage. J Heart Lung Transplant. 34:746–755. 2015. View Article : Google Scholar : PubMed/NCBI
32	Maiuri MC, Zalckvar E, Kimchi A and Kroemer G: Selfeating and self-killing: Crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 8:741–752. 2007. View Article : Google Scholar : PubMed/NCBI
33	Eisenberg-Lerner A, Bialik S, Simon HU and Kimchi A: Life and death partners: Apoptosis, autophagy and the cross-talk between them. Cell Death Differ. 16:966–975. 2009. View Article : Google Scholar : PubMed/NCBI
34	Feng Z, Zhang H, Levine AJ and Jin S: The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA. 102:pp. 8204–8209. 2005; View Article : Google Scholar : PubMed/NCBI
35	Kim SY, Song X, Zhang L, Bartlett DL and Lee YJ: Role of Bcl-xL/Beclin-1 in interplay between apoptosis and autophagy in oxaliplatin and bortezomib-induced cell death. Biochem Pharmacol. 88:178–188. 2014. View Article : Google Scholar : PubMed/NCBI
36	Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, Gottlieb RA and Gustafsson AB: Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ. 14:146–157. 2007. View Article : Google Scholar : PubMed/NCBI
37	Tracy K, Dibling BC, Spike BT, Knabb JR, Schumacker P and Macleod KF: BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy. Mol Cell Biol. 27:6229–6242. 2007. View Article : Google Scholar : PubMed/NCBI
38	Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward E, Israels SJ and Gibson SB: Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy. 4:195–204. 2008. View Article : Google Scholar : PubMed/NCBI
39	Zhang H, Bosch-Marcc M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ and Semenza GL: Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem. 283:10892–10903. 2008. View Article : Google Scholar : PubMed/NCBI
40	Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, Rogov V, Löhr F, Popovic D, Occhipinti A, et al: Nix is selective autophagy receptor for mitochondrial clearance. EMBO Rep. 11:45–51. 2010. View Article : Google Scholar : PubMed/NCBI
41	Band M, Joel A, Hernandez A and Avivi A: Hypoxia-induced BNIP3 expression and mitophagy: In vivo comparision of the rat and the hypoxia-tolerant mole, Spalax ehrenbergi. FASEB J. 23:2327–2335. 2009. View Article : Google Scholar : PubMed/NCBI
42	Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J and Mazure NM: Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 29:2570–2581. 2009. View Article : Google Scholar : PubMed/NCBI