Abstract: Fulminant hepatic failure is a severe clinical condition associated with extremely poor outcomes and high mortality. A number of studies have demonstrated the ability of plasma transfusion to successfully treat fulminant hepatic failure, but the underlying mechanisms are not well understood. The aim of the present study is to define the mechanisms of plasma transfusion treatment in lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced mice. LPS/D-GalN treatment in mice causes significant hepatic failure, including increasing serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, histopathological changes in centrilobular necrosis and inflammatory cells, and the up-regulation of inflammation (tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)). When LPS/D-GaIN-induced mice were treated with plasma, these changes were halted. Results showed that plasma transfusion significantly reduced mortality, and decreased the levels of AST, ALT, and inflammation factors such as TNF-α and IL-6. The expression levels of cleaved Caspase-3, BAX, and p53 were down-regulated and Bcl-2 was up-regulated, suggesting that plasma can reduce LPS/D-GalN-induced apoptosis. The protective mechanism of plasma against LPS/D-GalN-induced fulminant hepatic failure is related to the inhibition of the inflammatory response and the reduction in apoptosis through the down-regulation of the p53-induced apoptotic pathway.

血浆输注通过抑制肝细胞凋亡对脂多糖/D-半乳糖诱导的小鼠急性肝损伤的保护作用

[1]Chen JJ, Huang JR, Yang Q, et al., 2016. Plasma exchange-centered artificial liver support system in hepatitis B virus-related acute-on-chronic liver failure: a nationwide prospective multicenter study in China. Hepatob Pancreat Dis Int, 2016:1-7.

[2]Fukuda T, Mogami A, Tanaka H, et al., 2006. Y-40138, a multiple cytokine production modulator, protects against D-galactosamine and lipopolysaccharide-induced hepatitis. Life Sci, 79(9):822-827.

[3]Galehdar Z, Swan P, Fuerth B, et al., 2010. Neuronal apoptosis induced by endoplasmic reticulum stress is regulated by ATF4–CHOP-mediated induction of the Bcl-2 homology 3-only member PUMA. J Neurosci, 30(50):16938-16948.

[4]Gu L, Deng W, Liu Y, et al., 2014. Ellagic acid protects lipopolysaccharide/D-galactosamine-induced acute hepatic injury in mice. Int Immunopharm, 22(2):341-345.

[5]Havens JM, Do WS, Kaafarani H, et al., 2016. Explaining the excess morbidity of emergency general surgery: packed red blood cell and fresh frozen plasma transfusion practices are associated with major complications in nonmassively transfused patients. Am J Surg, 211(4):656-663.

[6]Horie Y, 2012. Granulocytapheresis and plasma exchange for severe alcoholic hepatitis. J Gastroenterol Hepatol, 27(S2):99-103.

[7]Ikeda A, Sun X, Li Y, et al., 2000. p300/CBP-dependent and -independent transcriptional interference between NF-κB RelA and p53. Biochem Biophys Res Commun, 272(2):375-379.

[8]Iwai H, Nagaki M, Naito T, et al., 1998. Removal of endotoxin and cytokines by plasma exchange in patients with acute hepatic failure. Crit Care Med, 26(5):873-876.

[9]Jayne DRW, Gaskin G, Rasmussen N, et al., 2007. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol, 18(7):2180-2188.

[10]Jiang W, Gao M, Sun S, et al., 2012. Protective effect of L-theanine on carbon tetrachloride-induced acute liver injury in mice. Biochem Biophys Res Commun, 422(2):344-350.

[11]Kamimura K, Imai M, Sakamaki A, et al., 2014. Granulocytapheresis for the treatment of severe alcoholic hepatitis: a case series and literature review. Digest Dis Sci, 59(2):482-488.

[12]Kaplowitz N, 2000. Mechanisms of liver cell injury. J Hepatol, 32(Suppl 1):39-47.

[13]Kim SJ, Cho HI, Kim SJ, et al., 2014. Protective effect of linarin against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure. Eur J Pharm, 738:66-73.

[14]Liu B, Lei M, Hu T, et al., 2016. Inhibitory effects of SRT1720 on the apoptosis of rabbit chondrocytes by activating SIRT1 via p53/bax and NF-κB/PGC-1α pathways. J Huazhong Univ Sci Med, 36(3):350-355.

[15]Ma MM, Li Y, Liu XY, et al., 2015. Cyanidin-3-O-glucoside ameliorates lipopolysaccharide-induced injury both in vivo and in vitro suppression of NF-κB and MAPK pathways. Inflammation, 38(4):1669-1682.

[16]MacLennan S, 2016. Focus on fresh frozen plasma— facilitating optimal management of bleeding through collaboration between clinicians and transfusion specialists on component specifications. La Presse Med, 45(7-8):e299-e302.

[17]Mintz PD, Bass NM, Petz LD, et al., 2006. Photochemically treated fresh frozen plasma for transfusion of patients with acquired coagulopathy of liver disease. Blood, 107(9):3753-3760.

[18]Mu R, Lu N, Wang J, et al., 2010. An oxidative analogue of gambogic acid-induced apoptosis of human hepatocellular carcinoma cell line HepG2 is involved in its anticancer activity in vitro. Eur J Cancer Prev, 19(1):61-67.

[19]Nakamura T, Ushiyama C, Suzuki S, et al., 2000. Effect of plasma exchange on serum tissue inhibitor of metalloproteinase 1 and cytokine concentrations in patients with fulminant hepatitis. Blood Purificat, 18(1):50-54.

[20]Nakasone H, Sugama R, Sakugawa H, et al., 2001. Alcoholic liver cirrhosis complicated with torsade de pointes during plasma exchange and hemodiafiltration. J Gastroenterol, 36(8):564-568.

[21]Ramesh G, Reeves WB, 2002. TNF-α mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest, 110(6):835-842.

[22]Wang N, Fan YC, Xia HX, et al., 2016. Plasma interleukin-10 predicts short-term mortality of acute-on-chronic hepatitis B liver failure. Aliment Pharm Ther, 43(11):1208-1221.

[23]Xia X, Su C, Fu J, et al., 2014. Role of α-lipoic acid in LPS/D-GalN induced fulminant hepatic failure in mice: studies on oxidative stress, inflammation and apoptosis. Int Immunopharm, 22(2):293-302.

[24]Yan BZ, Yang BS, Li H, et al., 2016. The therapeutic effect of CORM-3 on acute liver failure induced by lipopolysaccharide/ D-galactosamine in mice. Hepatob Pancreat Dis Int, 15(1):73-80.

[25]Youssef WI, Salazar F, Dasarathy S, et al., 2003. Role of fresh frozen plasma infusion in correction of coagulopathy of chronic liver disease: a dual phase study. Am J Gastroenterol, 98(6):1391-1394.

[26]Zhang L, Ren F, Zhang X, et al., 2016. Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure. Dis Model Mech, 9(7):799-809. https://dx.doi.org/10.1242/dmm.023242

[27]Zhang Q, Ma S, Liu B, et al., 2016. Chrysin induces cell apoptosis via activation of the p53/Bcl-2/caspase-9 pathway in hepatocellular carcinoma cells. Exp Ther Med, 12(1):469-474.