Dexmedetomidine alleviates pulmonary edema by upregulating AQP1 and AQP5 expression in rats with acute lung injury induced by lipopolysaccharide

Abstract

This study aims to elucidate the mechanisms by which dexmedetomidine alleviates pulmonary edema in rats with acute lung injury induced by lipopolysaccharide (LPS). Male Wistar rats were randomly divided into five groups: normal saline control (NS) group, receiving intravenous 0.9% normal saline (5 mL/kg); LPS group, receiving intravenous LPS (10 mg/kg); small-dose dexmedetomidine (S) group, treated with a small dose of dexmedetomidine (0.5 μg·kg^-1·h^-1); medium-dose dexmedetomidine (M) group, treated with a medium dose of dexmedetomidine (2.5 μg·kg^-1·h^-1); high-dose dexmedetomidine (H) group, treated with a high dose of dexmedetomidine (5 μg·kg^-1·h^-1). The rats were sacrificed 6 h after intravenous injection of LPS or NS, and the lungs were removed for evaluating histological characteristics and determining the lung wet/dry weight ratio (W/D). The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) in the lung tissues were assessed by enzyme- linked immunosorbent assay (ELISA). The mRNA and protein expression levels of aquaporin-1 (AQP1) and aquaporin-5 (AQP5) were detected by RT-PCR, immunohistochemistry, and Western blotting. The lung tissues from the LPS groups were significantly damaged, which were less pronounced in the H group but not in the small-dose dexmedetomidine group or medium-dose dexmedetomidine group. The W/D and the concentrations of TNF-α and IL-1β in the pulmonary tissues were increased in the LPS group as compared with those in NS group, which were reduced in the H group but not in S group or M group (P<0.01). The expression of AQP1 and AQP5 was lower in the LPS group than in the NS group, and significantly increased in the H group but not in the S group or M group (P<0.01). Our findings suggest that dexmedetomidine may alleviate pulmonary edema by increasing the expression of AQP-1 and AQP-5.

Keywords

dexmedetomidine / acute lung injury / lung edema / aquaporin-1 / aquaporin-5

References

[1] DushianthanA, GrocottMP, PostleAD, et al. . Acute respiratory distress syndrome and acute lung injury. Postgrad Med J, 2011, 87(1031): 612-622 PMID: 21642654

[2] WareLB, MichelA, MatthaY. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med, 2001, 163(6): 1376-1383 PMID: 11371404

[3] WuXM, WangHY, LiGF, et al. . Dobutamine enhances alveolar fluid clearance in a rat model of acute lung injury. Lung, 2009, 187(4): 225-231 PMID: 19548031

[4] ZhangZQ, SongYL, ChenZH, et al. . Deletion of aquaporin 5 aggravates acute lung injury induced by Pseudomonas aeruginosa. J Trauma, 2011, 71(5): 1305-1311 PMID: 21502879

[5] JinLD, WangLR, WuLQ, et al. . Effects of COX-2 inhibitor on ventilator-induced lung injury in rats. Int Immunopharmacol, 2013, 16(2): 288-295 PMID: 23587488

[6] ZhaoS, LiXN. Expression of aquaporin-1 and aquaporin- 3 in lung tissue of rat model with ischemia-reperfusion injury. Chin Med J (Engl), 2010, 123(24): 3711-3713

[7] RubenfeldGD, CaldwellE, PeabodyE, et al. . Incidence and outcomes of acute lung injury. N Engl J Med, 2005, 353(16): 1685-1693 PMID: 16236739

[8] RikerRR, ShehabiY, BokeschPM, et al. . Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA, 2009, 301(5): 489-499 PMID: 19188334

[9] WunschH, KressJP. A new era for sedation in ICU patients. JAMA, 2009, 301(5): 542-544 PMID: 19188333

[10] PengM, WangYL, WangCY, et al. . Dexmedetomidine attenuates lipopoly-saccharide induced proinflammatory response in primary microglia. J Surg Res, 2013, 179(1): 219-225

[11] LaiYC, TsaiPS, HuangCJ. Effects of dexmedetomidine on regulating endotoxin-induced up-regulation of inflammatory molecules in murine macro-phages. J Surg Res, 2009, 154(2): 212-219 PMID: 19181340

[12] QiaoH, SandersRD, MaD, et al. . Sedation improves early outcome in severely septic Sprague Dawley rats. Crit Care, 2009, 13(4): R136 PMCID: 2750194 PMID: 19691839

[13] TaniguchiT, KidaniY, KanakuraH, et al. . Effects of dexmedetomidine on mortality rate and inflammatory responses to endotoxin-induced shock in rats. Crit Care Med, 2004, 32(6): 1322-1326 PMID: 15187514

[14] YangCL, TsaiPS, HuangCJ. Effects of dexmedetomidine on regulating pulmonary inflammation in a rat model of ventilator-induced lung injury. Acta Anaesthesiol Taiwan, 2008, 46(4): 151-159 PMID: 19097961

[15] ShiQQ, WangH, FangH, et al. . Dose-response and mechanism of protective functions of selective alpha-2 agonist dexmedetomidine on acute lung injury in rats. Saudi Med J, 2012, 33(4): 375-381 PMID: 22485231

[16] GuJ, ChenJ, XiaP, et al. . Dexmedetomidine attenuates remote lung injury induced by renal ischemia-reperfusion in mice. Acta Anaesthesiol Scand, 2011, 55(10): 1272-1278 PMID: 22092133

[17] MirzapoiazovaT, KolosovaIA, MorenoL, et al. . Suppression of endotoxin-induced inflammation by taxol. Eur Respir J, 2007, 30(3): 429-435 PMID: 17537765

[18] HanclV, YurdakanG, YurtluS, et al. . Protective effect of dexmedetomidine in a rat model of a-naphthylthiourea-induced acute lung injury. J Surg Res, 2012, 178(1): 424-430

[19] XingJ, BirukovaAA, et al. . ANP attenuates inflammatory signaling and Rho pathway of lung endothelial permeability induced by LPS and TNFa. Microvasc Res, 2010, 79(1): 56-62 PMCID: 2813389 PMID: 19931545

[20] GanterMT, RouxJ, MiyazawaB, et al. . Interleukin-1ß causes acute lung injury via avß5 and avß6 integrin-dependent mechanisms. Circ Res, 2008, 102(7): 804-812 PMCID: 2739091 PMID: 18276918

[21] TaniguchiT, KuritaA, KobayashiK, et al. . Dose-and time-related effects of dexmedetomidine on mortality and inflammatory responses to endotoxin-induced shock in rats. J Anesth, 2008, 22(3): 221-228 PMID: 18685927

[22] LiZ, GaoC, WangY, et al. . Reducing pulmonary injury by hyperbaric oxygen preconditioning during simulated high altitude exposure in rats. J Trauma, 2011, 71(3): 673-679 PMID: 21248653

[23] TowneJE, KraneCM, BachurskiCJ, et al. . Tumor necrosis factor-alpha inhibits aquaporin expression in mouse lung epithelial cells. J Biol Chem, 2001, 276(22): 18657-18664 PMID: 11279049

[24] CherCD, ArmugamA, LachumananR, et al. . Pulmonary inflammation and edema induced by phospholipase A2: global gene analysis and effects on aquaporins and Na⁺/K⁺ATPase. J Biol Chem, 2003, 278(33): 31352-31360 PMID: 12746451