Advances in Clinical and Experimental Medicine
2020, vol. 29, nr 7, July, p. 813–817
Publication type: original article
Ketamine alleviates HMGB1-induced acute lung injury through TLR4 signaling pathway
1 Department of Anesthesiology, Jinan Central Hospital Affiliated to Shandong University, China
2 Department of Intensive Care Unit, Jinan Central Hospital Affiliated to Shandong University, China
3 Department of Anesthesiology, Binzhou People’s Hospital, China
Background. Acute lung injury (ALI) is a common critical respiratory disease that seriously threatens human health. Ketamine has good anti-inflammatory and immune-regulating properties that can delay the lung injury process.
Objectives. High mobility group box protein 1 (HMGB1) plays an important role in the occurrence, development and treatment of ALI. Toll-like receptor 4 (TLR4) is the receptor for HMGB1. The aim of this study was to determine the role of the HMGB1 TLR4 signaling pathway in the treatment of ALI using ketamine.
Material and Methods. A total of 30 healthy, male, 8-week-old Sprague-Dawley rats were randomly, equally divided into a control group, an lipopolysaccharide (LPS) group and a ketamine group. In order to establish a rat ALI model, 15 mg/kg of LPS was injected into the femoral veins. Ketamine was intravenously injected (10 mg/kg) into the experimental group rats. The rats were euthanized 24 h after modeling and lung tissue samples were collected. Western blot was used to test TLR4, MyD88, TRAF-6, LOX-1, and HMGB1 protein expression in the lung tissue. Real-time polymerase chain reaction (RT-PCR) was performed to detect TLR4, MyD88, TRAF-6, LOX-1, and HMGB1 mRNA levels.
Results. Compared with the controls, the LPS group had significantly higher TLR4, MyD88, TRAF-6, LOX-1, and HMGB1 mRNA and protein levels (p < 0.05). These levels were significantly lower after ketamine intervention in comparison with the LPS group (p < 0.05). A positive correlation was found between TLR4 and HMGB1 expression in the LPS and ketamine groups (r = 0.952, p < 0.001; r = 0.941, p < 0.001).
Conclusion. Ketamine attenuates HMGB1-induced ALI, possibly by regulating the TLR4 signaling pathway.
ketamine, acute lung injury, TLR4, HMGB1
- Kao RL, Xu X, Xenocostas A, et al. Induction of acute lung inflammation in mice with hemorrhagic shock and resuscitation: Role of HMGB1. J Inflamm (Lond). 2014;11(1):30.
- Luh SP, Chiang CH. Acute lung injury/acute respiratory distress syndrome (ALI/ARDS): The mechanism, present strategies and future perspectives of therapies. J Zhejiang Univ Sci B. 2007;8(1):60–69.
- Villar J, Sulemanji D, Kacmarek RM. The acute respiratory distress syndrome: Incidence and mortality, has it changed? Curr Opin Crit Care. 2014;20(1):3–9.
- Berger MM, Pitzer B, Zugel S, et al. Alveolar but not intravenous S-ketamine inhibits alveolar sodium transport and lung fluid clearance in rats. Anesth Analg. 2010;111(1):164–170.
- Yang CL, Chen CH, Tsai PS, Wang TY, Huang CJ. Protective effects of dexmedetomidine-ketamine combination against ventilator-induced lung injury in endotoxemia rats. J Surg Res. 2011;167(2):e273–e281.
- Yang CH, Tsai PS, Wang TY, Huang CJ. Dexmedetomidine-ketamine combination mitigates acute lung injury in haemorrhagic shock rats. Resuscitation. 2009;80(10):1204–1210.
- Shen H, Jin L, Zhuang X, Zhou Y. A single small dose of ketamine prevents lung injury following hepatic ischemia-reperfusion in rabbits. J Chin Med Assoc. 2011;74(8):350–356.
- Erdem MK, Yurdakan G, Yilmaz-Sipahi E. The effects of ketamine, midazolam and ketamine/xylazine on acute lung injury induced by alpha-naphthylthiourea in rats. Adv Clin Exp Med. 2014;23(3):343–351.
- Wang WF, Liu S, Xu B. A study of the protective effect and mechanism of ketamine on acute lung injury induced by mechanical ventilation. Eur Rev Med Pharmacol Sci. 2017;21(6):1362–1367.
- Dange RB, Agarwal D, Teruyama R, Francis J. Toll-like receptor 4 inhibition within the paraventricular nucleus attenuates blood pressure and inflammatory response in a genetic model of hypertension. J Neuroinflammation. 2015;12:31.
- Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285(5425):248–251.
- Zhou M, Zhang Y, Chen X, et al. PTEN-Foxo1 signaling triggers HMGB1-mediated innate immune responses in acute lung injury. Immunol Res. 2015;62(1):95–105.
- Entezari M, Javdan M, Antoine DJ, et al. Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury. Redox Biol. 2014;2:314–322.
- Haitsma JJ, Lachmann B, Papadakos PJ. Additives in intravenous anesthesia modulate pulmonary inflammation in a model of LPS-induced respiratory distress. Acta Anaesthesiol Scand. 2009;53(2):176–182.
- Liu XX, Yu DD, Chen MJ, et al. Hesperidin ameliorates lipopolysaccharide-induced acute lung injury in mice by inhibiting HMGB1 release. Int Immunopharmacol. 2015;25(2):370–376.
- Chen Y, Huang XJ, Yu N, et al. HMGB1 contributes to the expression of P-glycoprotein in mouse epileptic brain through toll-like receptor 4 and receptor for advanced glycation end products. PLoS One. 2015;10(10):e0140918.
- Li G, Wu X, Yang L, et al. TLR4-mediated NF-kappaB signaling pathway mediates HMGB1-induced pancreatic injury in mice with severe acute pancreatitis. Int J Mol Med. 2016;37(1):99–107.
- Lai CH, Wang KC, Lee FT, et al. Toll-like receptor 4 is essential in the development of abdominal aortic aneurysm. PLoS One. 2016;11(1):e0146565.
- Gokcinar D, Ergin V, Cumaoglu A, Menevse A, Aricioglu A. Effects of ketamine, propofol, and ketofol on pro-inflammatory cytokines and markers of oxidative stress in a rat model of endotoxemia-induced acute lung injury. Acta Biochim Pol. 2013;60(3):451–456.
- Lange M, Broking K, van Aken H, Hucklenbruch C, Bone HG, Westphal M. Role of ketamine in sepsis and systemic inflammatory response syndrome [in German]. Anaesthesist. 2006;55(8):883–891.
- Wu Y, Li W, Zhou C, et al. Ketamine inhibits lipopolysaccharide-induced astrocytes activation by suppressing TLR4/NF-kB pathway. Cell Physiol Biochem. 2012;30(3):609–617.
- Yu M, Shao D, Yang R, Feng X, Zhu S, Xu J. Effects of ketamine on pulmonary inflammatory responses and survival in rats exposed to polymicrobial sepsis. J Pharm Pharm Sci. 2007;10(4):434–442.
- Tianzhu Z, Shumin W. Esculin inhibits the inflammation of LPS-induced acute lung injury in mice via regulation of TLR/NF-kappaB pathways. Inflammation. 2015;38(4):1529–1536.
- Wang SY, Li ZJ, Wang X, Li WF, Lin ZF. Effect of ulinastatin on HMGB1 expression in rats with acute lung injury induced by sepsis. Genet Mol Res. 2015;14(2):4344–4353.
- Abdelmageed ME, El-Awady MS, Suddek GM. Apocynin ameliorates endotoxin-induced acute lung injury in rats. Int Immunopharmacol. 2016;30:163–170.
- Qin MZ, Gu QH, Tao J, et al. Ketamine effect on HMGB1 and TLR4 expression in rats with acute lung injury. Int J Clin Exp Pathol. 2015;8(10):12943–12948.