Hepatoprotective effects of erythropoietin on D‑galactosamine/lipopolysaccharide‑induced fulminant hepatic failure in mice

Yang,Xue‑Fei; He,Yi; Li,Hai‑Yuan; Liu,Xin; Chen,Huan; Liu,Jian‑Bang; Ji,Wen‑Jun; Wang,Bing; Chen,Li‑Na

doi:10.3892/mmr.2014.2164

Hepatoprotective effects of erythropoietin on D‑galactosamine/lipopolysaccharide‑induced fulminant hepatic failure in mice

Authors:
- Xue‑Fei Yang
- Yi He
- Hai‑Yuan Li
- Xin Liu
- Huan Chen
- Jian‑Bang Liu
- Wen‑Jun Ji
- Bing Wang
- Li‑Na Chen
View Affiliations

Affiliations: Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: April 24, 2014 https://doi.org/10.3892/mmr.2014.2164
Pages: 555-559

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

Fulminant hepatic failure is a severe clinical syndrome associated with a high rate of patient mortality. Recent studies have shown that in addition to its hematopoietic effect, erythropoietin (EPO) has multiple protective effects and exhibits antiapoptotic, antioxidant and anti‑inflammatory activities. The present study aimed to determine the hepatoprotective effect of EPO and to elucidate the underlying mechanisms using a D‑galactosamine (D‑GalN)/lipopolysaccharide (LPS)‑induced model of acute liver injury. Experimental groups of mice were administered with various doses of EPO (1,000, 3,000 or 10,000 U/kg, intraperitoneal) once per day for 3 days, prior to injection with D‑GalN (700 mg/kg)/LPS (10 µg/kg). Mice were sacrificed 8 h after treatment with D‑GalN/LPS. Liver function and histopathology, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH‑Px) activities and EPO receptor (EPOR) and phosphatidylinositol 3‑kinase (PI3K) mRNA expression were evaluated. D‑GalN/LPS administration markedly induced liver injury, as evidenced by elevated levels of serum aminotransferases, as well as histopathological changes. Compared with the D‑GalN/LPS group, pretreatment with EPO significantly decreased the levels of aspartate aminotransferase, alanine aminotransferase and MDA, and increased the activities of SOD and GSH‑Px. Furthermore, the protective effects of EPO were paralleled by an upregulation in the mRNA expression of EPOR and PI3K. These data suggest that EPO can ameliorate D‑GalN/LPS‑induced acute liver injury by reducing oxidative stress and upregulating the mRNA expression of EPOR and PI3K.

View Figures

View References

1	Schiødt FV and Lee WM: Fulminant liver disease. Clin Liver Dis. 7:331–349. 2003.
2	Mukherjee S, Mahmoudi TM and Mukherjee U: Liver transplant for viral hepatitis and fulminant hepatic failure. Minerva Gastroenterol Dietol. 55:83–100. 2009.PubMed/NCBI
3	Xing WW, Zou MJ, Liu S, Xu T, Gao J, Wang JX and Xu DG: Hepatoprotective effects of IL-22 on fulminant hepatic failure induced by d-galactosamine and lipopolysaccharide in mice. Cytokine. 56:174–179. 2011. View Article : Google Scholar : PubMed/NCBI
4	Shin JW, Wang JH, Park HJ, Choi MK, Kim HG and Son CG: Herbal formula CGX ameliorates LPS/D-galactosamine-induced hepatitis. Food Chem Toxicol. 49:1329–1334. 2011. View Article : Google Scholar : PubMed/NCBI
5	Jeong YI, Jung ID, Lee CM, et al: The novel role of platelet-activating factor in protecting mice against lipopolysaccharide-induced endotoxic shock. PLoS One. 4:e65032009. View Article : Google Scholar : PubMed/NCBI
6	Thirunavukkarasu C, Uemura T, Wang LF, Watkins SC and Gandhi CR: Normal rat hepatic stellate cells respond to endotoxin in LBP-independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes. J Cell Physiol. 204:654–665. 2005. View Article : Google Scholar : PubMed/NCBI
7	Fisher JW: Erythropoietin: physiology and pharmacology update. Exp Biol Med (Maywood). 228:1–14. 2003.PubMed/NCBI
8	Coleman T and Brines M: Science review: recombinant human erythropoietin in critical illness: a role beyond anemia? Crit Care. 8:337–341. 2004. View Article : Google Scholar : PubMed/NCBI
9	Sepodes B, Maio R, Pinto R, et al: Recombinant human erythropoietin protects the liver from hepatic ischemia-reperfusion injury in the rat. Transpl Int. 19:919–926. 2006. View Article : Google Scholar : PubMed/NCBI
10	Lewis LD: Preclinical and clinical studies: a preview of potential future applications of erythropoietic agents. Semin Hematol. 41(4 Suppl 7): 17–25. 2004. View Article : Google Scholar : PubMed/NCBI
11	Kadota T, Shingo T, Yasuhara T, et al: Continuous intraventricular infusion of erythropoietin exerts neuroprotective/rescue effects upon Parkinson’s disease model of rats with enhanced neurogenesis. Brain Res. 1254:120–127. 2009.PubMed/NCBI
12	Mammis A, McIntosh TK and Maniker AH: Erythropoietin as a neuroprotective agent in traumatic brain injury Review. Surg Neurol. 71:527–531. 2009. View Article : Google Scholar : PubMed/NCBI
13	Lippi G, Franchini M and Banfi G: Biochemistry and physiology of anabolic androgenic steroids doping. Mini Rev Med Chem. 11:362–373. 2011. View Article : Google Scholar : PubMed/NCBI
14	Dimitrijevic ZM, Cvetkovic TP, Djordjevic VM, et al: How the duration period of erythropoietin treatment influences the oxidative status of hemodialysis patients. Int J Med Sci. 9:808–815. 2012. View Article : Google Scholar : PubMed/NCBI
15	Akisu M, Küllahçioğlu Girgin F, Baka M, Hüsseyinov A and Kültürsay N: The role of recombinant human erythropoietin in lipid peroxidation and platelet-activating factor generation in a rat model of necrotizing enterocolitis. Eur J Pediatr Surg. 11:167–172. 2001. View Article : Google Scholar : PubMed/NCBI
16	Nairz M, Sonnweber T, Schroll A, Theurl I and Weiss G: The pleiotropic effects of erythropoietin in infection and inflammation. Microbes Infect. 14:238–246. 2012. View Article : Google Scholar : PubMed/NCBI
17	Yang CW, Li C, Jung JY, et al: Preconditioning with erythropoietin protects against subsequent ischemia-reperfusion injury in rat kidney. FASEB J. 17:1754–1755. 2003.PubMed/NCBI
18	Chong ZZ, Kang JQ and Maiese K: Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades. J Cereb Blood Flow Metab. 22:503–514. 2002. View Article : Google Scholar
19	Kudo H, Takahara T, Yata Y, Kawai K, Zhang W and Sugiyama T: Lipopolysaccharide triggered TNF-alpha-induced hepatocyte apoptosis in a murine non-alcoholic steatohepatitis model. J Hepatol. 51:168–175. 2009. View Article : Google Scholar : PubMed/NCBI
20	Kuhla A, Eipel C, Abshagen K, Siebert N, Menger MD and Vollmar B: Role of the perforin/granzyme cell death pathway in D-Gal/LPS-induced inflammatory liver injury. Am J Physiol Gastrointest Liver Physiol. 296:G1069–G1076. 2009. View Article : Google Scholar : PubMed/NCBI
21	Ikeda T, Abe K, Kuroda N, et al: The inhibition of apoptosis by glycyrrhizin in hepatic injury induced by injection of lipopolysaccharide/D-galactosamine in mice. Arch Histol Cytol. 71:163–178. 2008. View Article : Google Scholar : PubMed/NCBI
22	Chen JC, Ng CJ, Chiu TF and Chen HM: Altered neutrophil apoptosis activity is reversed by melatonin in liver ischemia-reperfusion. J Pineal Res. 34:260–264. 2003. View Article : Google Scholar : PubMed/NCBI
23	Jaeschke H: Reactive oxygen and mechanisms of inflammatory liver injury: Present concepts. J Gastroenterol Hepatol. 26(Suppl 1): 173–179. 2011. View Article : Google Scholar : PubMed/NCBI
24	Han D, Hanawa N, Saberi B and Kaplowitz N: Hydrogen peroxide and redox modulation sensitize primary mouse hepatocytes to TNF-induced apoptosis. Free Radic Biol Med. 41:627–639. 2006. View Article : Google Scholar : PubMed/NCBI
25	Zou W, Roth RA, Younis HS, Burgoon LD and Ganey PE: Oxidative stress is important in the pathogenesis of liver injury induced by sulindac and lipopolysaccharide cotreatment. Toxicology. 272:32–38. 2010. View Article : Google Scholar : PubMed/NCBI
26	Fan X and van Bel F: Pharmacological neuroprotection after perinatal asphyxia. J Matern Fetal Neonatal Med. 23(Suppl 3): 17–19. 2010. View Article : Google Scholar
27	Shang Y, Li X, Prasad PV, et al: Erythropoietin attenuates lung injury in lipopolysaccharide treated rats. J Surg Res. 155:104–110. 2009. View Article : Google Scholar : PubMed/NCBI
28	Cetin H, Olgar S, Oktem F, Ciris M, Uz E, Aslan C and Ozguner F: Novel evidence suggesting an anti-oxidant property for erythropoietin on vancomycin-induced nephrotoxicity in a rat model. Clin Exp Pharmacol Physiol. 34:1181–1185. 2007.PubMed/NCBI
29	Guneli E, Cavdar Z, Islekel H, et al: Erythropoietin protects the intestine against ischemia/reperfusion injury in rats. Mol Med. 13:509–517. 2007. View Article : Google Scholar : PubMed/NCBI
30	Oztürk E, Demirbilek S, Köroğlu A, et al: Propofol and erythropoietin antioxidant properties in rat brain injured tissue. Prog in Neuropsychopharmacol Biol Psychiatry. 32:81–86. 2008.PubMed/NCBI
31	Brines M and Cerami A: Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci. 6:484–494. 2005. View Article : Google Scholar : PubMed/NCBI
32	Brines M, Grasso G, Fiordaliso F, et al: Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci USA. 101:14907–14912. 2004. View Article : Google Scholar : PubMed/NCBI
33	Datta SR, Brunet A and Greenberg ME: Cellular survival: a play in three Akts. Genes Dev. 13:2905–2927. 1999. View Article : Google Scholar : PubMed/NCBI
34	Meier R, Alessi DR, Cron P, Andjelković M and Hemmings BA: Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. J Biol Chem. 272:30491–30497. 1997. View Article : Google Scholar : PubMed/NCBI
35	Kim AH, Khursigara G, Sun X, Franke TF and Chao MV: Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 21:893–901. 2001. View Article : Google Scholar : PubMed/NCBI
36	Abdelrahman M, Sharples EJ, McDonald MC, Collin M, Patel NS, Yaqoob MM and Thiemermann C: Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia. Shock. 22:63–69. 2004. View Article : Google Scholar : PubMed/NCBI