Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse

BMC Gastroenterology

Christoph Eisenbach⁴  Wolfgang Stremmel⁴  Catharina Sandig⁴  Birgit Hoyler⁴  Spiros Vittas³  Carolin Mogler¹  Niels Steinebrunner² 

[1] Department of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 220/221, 69120 Heidelberg, Germany;Mailing address: Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany;Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany;Department of Gastroenterology, Hepatology, Intoxications and Infectious Diseases, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany

关键词: Cholinesterase inhibition;    Cholinergic anti-inflammatory pathway;    Acetaminophen;    Acute liver failure;   

Others  :  1121837
DOI  :  10.1186/1471-230X-14-148

 received in 2013-12-18, accepted in 2014-08-13,  发布年份 2014

【 摘 要 】

Background

Acetaminophen (APAP) is one of the most widely used analgesic and antipyretic pharmaceutical substances in the world and accounts for most cases of drug induced liver injury resulting in acute liver failure. Acute liver failure initiates a sterile inflammatory response with release of cytokines and innate immune cell infiltration in the liver. This study investigates, whether pharmacologic acetylcholinesterase inhibition with neostigmine diminishes liver damage in acute liver failure via the cholinergic anti-inflammatory pathway.

Methods

Acute liver failure was induced in BALB/c mice by a toxic dose of acetaminophen (APAP). Neostigmine and/or N-acetyl-cysteine (NAC) were applied therapeutically at set time points and the survival was investigated. Liver damage was assessed by serum parameters, histopathology and serum cytokine assays 12 h after initiation of acute liver failure.

Results

Serum parameters, histopathology and serum cytokine assays showed pronounced features of acute liver failure 12 h after application of acetaminophen (APAP). Neostigmine treatment led to significant reduction of serum liver enzymes (LDH (47,147 ± 12,726 IU/l vs. 15,822 ± 10,629 IU/l, p = 0.0014) and ALT (18,048 ± 4,287 IU/l vs. 7,585 ± 5,336 IU/l, p = 0.0013), APAP-alone-treated mice vs. APAP + neostigmine-treated mice), inflammatory cytokine levels (IL-1β (147 ± 19 vs. 110 ± 25, p = 0.0138) and TNF-α (184 ± 23 vs. 130 ± 33, p = 0.0086), APAP-alone-treated mice vs. APAP + neostigmine-treated mice) and histopathological signs of damage.

Animals treated with NAC in combination with the peripheral cholinesterase inhibitor neostigmine showed prolonged survival and improved outcome.

Conclusions

Neostigmine is an acetylcholinesterase inhibitor that ameliorates the effects of APAP-induced acute liver failure in the mouse and therefore may provide new treatment options for affected patients.

【 授权许可】

   
2014 Steinebrunner et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 1.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Merle U, Sieg O, Stremmel W, Encke J, Eisenbach C: Sensitivity and specificity of plasma disappearance rate of indocyanine green as a prognostic indicator in acute liver failure. BMC Gastroenterol 2009, 9:91.
• [2]Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiodt FV, Ostapowicz G, Shakil AO, Lee WM: Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005, 42(6):1364-1372.
• [3]Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM: Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002, 137(12):947-954.
• [4]Ju C: Damage-associated molecular patterns: their impact on the liver and beyond during acetaminophen overdose. Hepatology 2012, 56(5):1599-1601.
• [5]Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Giffin SL: 2008 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 26th Annual Report. Clin Toxicol (Phila) 2009, 47(10):911-1084.
• [6]Manthripragada AD, Zhou EH, Budnitz DS, Lovegrove MC, Willy ME: Characterization of acetaminophen overdose-related emergency department visits and hospitalizations in the United States. Pharmacoepidemiol Drug Saf 2011, 20(8):819-826.
• [7]Lee WM, Larson AM, Arenas J: Thinking through acetaminophen hepatotoxicity and liver transplantation: choosing worthy recipients. Liver Transpl 2009, 15(6):567-569.
• [8]Larson AM: Acetaminophen hepatotoxicity. Clin Liver Dis 2007, 11(3):525-548. vi
• [9]Kaplowitz N: Avoiding idiosyncratic DILI: Two is better than one. Hepatology 2013, 58(1):15-17.
• [10]Lee WM: Liver: determining prognosis in acute liver failure. Nat Rev Gastroenterol Hepatol 2012, 9(4):192-194.
• [11]Marques PE, Amaral SS, Pires DA, Nogueira LL, Soriani FM, Lima BH, Lopes GA, Russo RC, Avila TV, Melgaco JG, Oliveira AG, Pinto MA, Lima CX, De Paula AM, Cara DC, Leite MF, Teixeira MM, Menezes GB: Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure. Hepatology 2012, 56(5):1971-1982.
• [12]Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ: Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003, 421(6921):384-388.
• [13]Nathan C: Points of control in inflammation. Nature 2002, 420(6917):846-852.
• [14]Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ: The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med 2003, 9(5–8):125-134.
• [15]Tracey KJ: Physiology and immunology of the cholinergic antiinflammatory pathway. J Clin Invest 2007, 117(2):289-296.
• [16]Tracey KJ: The inflammatory reflex. Nature 2002, 420(6917):853-859.
• [17]Blazka ME, Wilmer JL, Holladay SD, Wilson RE, Luster MI: Role of proinflammatory cytokines in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 1995, 133(1):43-52.
• [18]Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ: Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000, 405(6785):458-462.
• [19]Hofer S, Eisenbach C, Lukic IK, Schneider L, Bode K, Brueckmann M, Mautner S, Wente MN, Encke J, Werner J, Dalpke AH, Stremmel W, Nawroth PP, Martin E, Krammer PH, Bierhaus A, Weigand MA: Pharmacologic cholinesterase inhibition improves survival in experimental sepsis. Crit Care Med 2008, 36(2):404-408.
• [20]Kox M, Pompe JC, Peters E, Vaneker M, van der Laak JW, van der Hoeven JG, Scheffer GJ, Hoedemaekers CW, Pickkers P: Alpha7 nicotinic acetylcholine receptor agonist GTS-21 attenuates ventilator-induced tumour necrosis factor-alpha production and lung injury. Br J Anaesth 2011, 107(4):559-566.
• [21]Rofe AM, Barry EF, Shelton TL, Philcox JC, Coyle P: Paracetamol hepatotoxicity in metallothionein-null mice. Toxicology 1998, 125(2–3):131-140.
• [22]Uzi D, Barda L, Scaiewicz V, Mills M, Mueller T, Gonzalez-Rodriguez A, Valverde AM, Iwawaki T, Nahmias Y, Xavier R, Chung RT, Tirosh B, Shibolet O: CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. J Hepatol 2013, 59(3):495-503.
• [23]Blazka ME, Elwell MR, Holladay SD, Wilson RE, Luster MI: Histopathology of acetaminophen-induced liver changes: role of interleukin 1 alpha and tumor necrosis factor alpha. Toxicol Pathol 1996, 24(2):181-189.
• [24]Dambach DM, Durham SK, Laskin JD, Laskin DL: Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inflammatory mediator production and hepatotoxicity. Toxicol Appl Pharmacol 2006, 211(2):157-165.
• [25]Carvalho NR, da Rosa EF, da Silva MH, Tassi CC, Dalla Corte CL, Carbajo-Pescador S, Mauriz JL, Gonzalez-Gallego J, Soares FA: New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure. PLoS One 2013, 8(12):e81961.
• [26]Chan K, Han XD, Kan YW: An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen. Proc Natl Acad Sci U S A 2001, 98(8):4611-4616.
• [27]Saito C, Zwingmann C, Jaeschke H: Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 2010, 51(1):246-254.
• [28]Scheiermann P, Bachmann M, Goren I, Zwissler B, Pfeilschifter J, Muhl H: Application of interleukin-22 mediates protection in experimental acetaminophen-induced acute liver injury. Am J Pathol 2013, 182(4):1107-1113.
• [29]Gelotte CK, Auiler JF, Lynch JM, Temple AR, Slattery JT: Disposition of acetaminophen at 4, 6, and 8 g/day for 3 days in healthy young adults. Clin Pharmacol Ther 2007, 81(6):840-848.
• [30]Hodgman MJ, Garrard AR: A review of acetaminophen poisoning. Crit Care Clin 2012, 28(4):499-516.
• [31]Scaffidi P, Misteli T, Bianchi ME: Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002, 418(6894):191-195.
• [32]Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, Knippers R: DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 2001, 61(4):1659-1665.
• [33]Jones DP, Lemasters JJ, Han D, Boelsterli UA, Kaplowitz N: Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol Interv 2010, 10(2):98-111.
• [34]Kaplowitz N, Shinohara M, Liu ZX, Han D: How to protect against acetaminophen: don’t ask for JUNK. Gastroenterology 2008, 135(4):1047-1051.
• [35]Schwabe RF, Seki E, Brenner DA: Toll-like receptor signaling in the liver. Gastroenterology 2006, 130(6):1886-1900.
• [36]Martin-Murphy BV, Holt MP, Ju C: The role of damage associated molecular pattern molecules in acetaminophen-induced liver injury in mice. Toxicol Lett 2010, 192(3):387-394.
• [37]Blazka ME, Germolec DR, Simeonova P, Bruccoleri A, Pennypacker KR, Luster MI: Acetaminophen-induced hepatotoxicity is associated with early changes in NF-kB and NF-IL6 DNA binding activity. J Inflamm 1995, 47(3):138-150.
• [38]Olofsson PS, Rosas-Ballina M, Levine YA, Tracey KJ: Rethinking inflammation: neural circuits in the regulation of immunity. Immunol Rev 2012, 248(1):188-204.
• [39]Ishida Y, Kondo T, Tsuneyama K, Lu P, Takayasu T, Mukaida N: The pathogenic roles of tumor necrosis factor receptor p55 in acetaminophen-induced liver injury in mice. J Leukoc Biol 2004, 75(1):59-67.
• [40]Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL: Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med 2007, 13(7):851-856.
• [41]Shayiq RM, Roberts DW, Rothstein K, Snawder JE, Benson W, Ma X, Black M: Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: an explanation for high acetaminophen dosage in humans without hepatic injury. Hepatology 1999, 29(2):451-463.
• [42]Kubes P, Mehal WZ: Sterile inflammation in the liver. Gastroenterology 2012, 143(5):1158-1172.
• [43]McDonald B, Kubes P: Neutrophils and intravascular immunity in the liver during infection and sterile inflammation. Toxicol Pathol 2012, 40(2):157-165.
• [44]van Westerloo DJ, Giebelen IA, Meijers JC, Daalhuisen J, de Vos AF, Levi M, van der Poll T: Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats. J Thromb Haemost 2006, 4(9):1997-2002.
• [45]van Westerloo DJ, Giebelen IA, Florquin S, Bruno MJ, Larosa GJ, Ulloa L, Tracey KJ, van der Poll T: The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 2006, 130(6):1822-1830.
• [46]Crockett ET, Galligan JJ, Uhal BD, Harkema J, Roth R, Pandya K: Protection of early phase hepatic ischemia-reperfusion injury by cholinergic agonists. BMC Clin Pathol 2006, 6:3.
• [47]Chatterjee PK, Al-Abed Y, Sherry B, Metz CN: Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation. Am J Physiol Cell Physiol 2009, 297(5):C1294-C1306.
• [48]Antoine DJ, Williams DP, Kipar A, Jenkins RE, Regan SL, Sathish JG, Kitteringham NR, Park BK: High-mobility group box-1 protein and keratin-18, circulating serum proteins informative of acetaminophen-induced necrosis and apoptosis in vivo. Toxicol Sci 2009, 112(2):521-531.
• [49]Bechmann LP, Jochum C, Kocabayoglu P, Sowa JP, Kassalik M, Gieseler RK, Saner F, Paul A, Trautwein C, Gerken G, Canbay A: Cytokeratin 18-based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. J Hepatol 2010, 53(4):639-647.
• [50]Yin H, Cheng L, Holt M, Hail N Jr, Maclaren R, Ju C: Lactoferrin protects against acetaminophen-induced liver injury in mice. Hepatology 2010, 51(3):1007-1016.
• [51]Bourdi M, Davies JS, Pohl LR: Mispairing C57BL/6 substrains of genetically engineered mice and wild-type controls can lead to confounding results as it did in studies of JNK2 in acetaminophen and concanavalin A liver injury. Chem Res Toxicol 2011, 24(6):794-796.
• [52]McGill MR, Li F, Sharpe MR, Williams CD, Curry SC, Ma X, Jaeschke H: Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans. Arch Toxicol 2014, 88(2):391-401.
• [53]Bechmann LP, Marquitan G, Jochum C, Saner F, Gerken G, Canbay A: Apoptosis versus necrosis rate as a predictor in acute liver failure following acetaminophen intoxication compared with acute-on-chronic liver failure. Liver Int 2008, 28(5):713-716.
• [54]Krammer PH: CD95′s deadly mission in the immune system. Nature 2000, 407(6805):789-795.
• [55]Lien CA: Neostigmine: how much is necessary for patients who receive a nondepolarizing neuromuscular blocking agent? Anesthesiology 2010, 112(1):16-18.