Apoptosis and necrosis in the liver: A tale of two deaths?

Hepatology

Volumn 43, Issue 2 SUPPL. 1, 2006, Pages

  Malhi, Harmeet ^a   Gores, Gregory J ^a   Lemasters, John J ^b,c  

^a Mayo Clinic   (United States)

^b UNIVERSITY OF NORTH CAROLINA   (United States)

^c UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; CYTOCHROME C; DEATH RECEPTOR; FAS LIGAND; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; PARACETAMOL; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR RELATED APOPTOSIS INDUCING LIGAND;

APOPTOSIS; CELL DEATH; CELL PERMEABILIZATION; CHOLESTASIS; LIVER CELL DAMAGE; LIVER FAILURE; LIVER INJURY; LIVER ISCHEMIA; LIVER NECROSIS; LIVER TOXICITY; MITOCHONDRIAL MEMBRANE; NONHUMAN; PRIORITY JOURNAL; REPERFUSION INJURY; REVIEW; VIRUS HEPATITIS;

ACETAMINOPHEN; ANIMALS; ANTIGENS, CD95; APOPTOSIS; APOPTOSIS REGULATORY PROTEINS; CASPASES; CHOLESTASIS, INTRAHEPATIC; CYTOCHROMES C; HUMANS; HYDROGEN-ION CONCENTRATION; IMMUNITY, NATURAL; LIVER; MEMBRANE GLYCOPROTEINS; MITOCHONDRIA, LIVER; NECROSIS; NF-KAPPA B; RECEPTORS, TUMOR NECROSIS FACTOR; REPERFUSION INJURY; SIGNAL TRANSDUCTION; TNF-RELATED APOPTOSIS-INDUCING LIGAND; TUMOR NECROSIS FACTOR-ALPHA;

EID: 33644524120     PISSN: 02709139     EISSN: None     Source Type: Journal    
DOI: 10.1002/hep.21062     Document Type: Review

References (196)

1. Majno G, Joris I. Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 1995;146:3-15.
2. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972;26:239-257.
3. Searle J, Harmon BV, Bishop CJ, Kerr JFK. The significance of cell death by apoptosis in hepatobiliary disease. J Gastroenterol Hepatol 1987;2:77-96.
4. Lemasters JJ. V. Necrapoptosis and the mitochondrial permeability transition: shared pathways to necrosis and apoptosis. Am J Physiol 1999;276(1 Pt 1):G1-G6.
5. Lemasters JJ. Dying a thousand deaths: redundant pathways from different organelles to apoptosis and necrosis. Gastroenterology 2005;129:351-360.
6. Trump BF, Goldblatt PJ, Stowell RE. Studies of necrosis in vitro of mouse hepatic parenchymal cells. Ultrastructural alterations in endoplasmic reticulum, Golgi apparatus, plasma membrane, and lipid droplets. Lab Invest 1965;14:2000-2028.
7. Lemasters JJ, Ji S, Thurman RG. Centrilobular injury following hypoxia in isolated, perfused rat liver. Science 1981;213:661-663.
8. Lemasters JJ, Stemkowski CJ, Ji S, Thurman RG. Cell surface changes and enzyme release during hypoxia and reoxygenation in the isolated, perfused rat liver. J Cell Biol 1983;97:778-786.
9. Gores GJ, Herman B, Lemasters JJ. Plasma membrane bleb formation and rupture: a common feature of hepatocellular injury. HEPATOLOGY 1990;11:690-698.
10. Nishimura Y, Romer LH, Lemasters JJ. Mitochondrial dysfunction and cytoskeletal disruption during chemical hypoxia to cultured rat hepatic sinusoidal endothelial cells: the pH paradox and cytoprotection by glucose, acidotic pH, and glycine. HEPATOLOGY 1998;27:1039-1049.
11. Gores GJ, Nieminen A-L, Wray BE, Herman B, Lemasters JJ. Intracellular pH during 'chemical hypoxia' in cultured hepatocytes. J Clin Invest 1989;83:386-396.
12. Zahrebelski G, Nieminen AL, al Ghoul K, Qian T, Herman B, Lemasters JJ. Progression of subcellular changes during chemical hypoxia to cultured rat hepatocytes: a laser scanning confocal microscopic study. HEPATOLOGY 1995;21:1361-1372.
13. Herman B, Nieminen AL, Gores GJ, Lemasters JJ. Irreversible injury in anoxic hepatocytes precipirated by an abrupt increase in plasma membrane permeability. FASEB J 1988;2:146-151.
14. Nieminen AL, Gores GJ, Wray BE, Tanaka Y, Herman B, Lemasters JJ. Calcium dependence of bleb formation and cell death in hepatocytes. Cell Calcium 1988;9:237-246.
15. Dong Z, Patel Y, Saikumar P, Weinberg JM, Venkatachalam MA. Development of porous defects in plasma membranes of adenosine triphosphate-depleted Madin-Darby canine kidney cells and its inhibition by glycine. Lab Invest 1998;78:657-668.
16. Nishimura Y, Lemasters JJ. Glycine blocks opening of a death channel in cultured hepatic sinusoidal endothelial cells during chemical hypoxia. Cell Death Differ 2001;8:850-858.
17. Weinberg JM, Davis JA, Abarzua M, Rajan T. Cytoprotective effects of glycine and glutathione against hypoxic injury to renal tubules. J Clin Invest 1987;80:1446-1454.
18. Dickson RC, Bronk SF, Gores GJ. Glycine cytoprotection during lethal hepatocellular injury from adenosine triphosphate depletion. Gastroenterology 1992;102:2098-2107.
19. Marsh DC, Vreugdenhil PK, Mack VE, Belzer FO, Southard JH. Glycine protects hepatocytes from injury caused by anoxia, cold ischemia and mitochondrial inhibitors, but not injury caused by calcium ionophores or oxidative stress. HEPATOLOGY 1993;17:91-98.
20. Kerr JF, Cooksley WG, Searle J, Halliday JW, Halliday WJ, Holder L, et al. The nature of piecemeal necrosis in chronic active hepatitis. Ian 1979;2(8147):827-828.
21. Ding WX, Yin XM. Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. J Cell Mol Med 2004;8:445-454.
22. Bredesen DE. Apoptosis: overview and signal transduction pathways. J Neurotrauma 2000;17:801-810.
23. Green DR, Kroemer G. The pathophysiology of mitochondrial cell death. Science 2004;305:626-629.
24. Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu Rev Biochem 2004;73:87-106.
25. Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, et al. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 2001;292:727-730.
26. Shimizu S, Ide T, Yanagida T, Tsujimoto Y. Electrophysiological study of a novel large pore formed by Bax and the voltage-dependent anion channel that is permeable to cytochrome c. J Biol Chem 2000;275:12321-12325.
27. Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ, Schlesinger PH. Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release ot cytochrome c. Cell Death Differ 2000;7:1166-1173.
28. Marchetti P, Castedo M, Susin SA, Zamzami N, Hirsch T, Macho A, et al. Mitochondrial permeability transition is a central coordination event of apoptosis. J Exp Med 1996;184:1155-1160.
29. Bradham CA, Qian T, Streetz K, Traurwein C, Brenner DA, Lemasters JJ. The mitochondrial permeability transition is required tor tumor necrosis factor alpha-mediated apoptosis and cytochrome c release. Mol Cell Biol 1998;18:6353-6364.
30. Hatano E, Bradham CA, Stark A, Iimuro Y, Lemasters JJ, Brenner DA. The mitochondrial permeability transition augments Fas-induced apoptosis in mouse hepatocytes. J Biol Chem 2000;275:11814-11823.
31. Crompton M, Virji S, Ward JM. Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. Eur J Biochem 1998;258:729-735.
32. Halestrap AP, Davidson AM. Inhibition of Ca2(+)-induced large-amplitude swelling of liver and heart mitochondria by cyclosporin is probably caused by the inhibitor binding to mitochondnal-matrix peptidyl-prolyl cis-trans isomerase and preventing it interacting with the adenine nucleotide translocase. Biochem J 1990;268:153-160.
33. Connern CP, Halestrap AP. Recruitment ot mitochondrial cyclophilin to the mitochondrial inner membrane under conditions ot oxidative stress that enhance the opening of a calcium-sensitive non-specific channel. Biochem J 1994;302(Pt 2):321-324.
34. Crompton M, Ellinger H, Costi A. Inhibition by cyclosporin A of a Ca2+-dependent pore in heart mitochondria activated by inorganic phosphate and oxidative stress. Biochem J 1988;255:357-360.
35. Waldmeier PC, Zimmermann K, Qian T, Tintelnot-Blomley M, Lemasters JJ. Cyclophilin D as a drug target. Curr Med Chem 2003;10:1485-1506.
36. Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, et al. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 2004;427:461-465.
37. He L, Lemasters JJ. Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett 2002;512:1-7.
38. Gunter TE, Pfeiffer DR. Mechanisms by which mitochondria transport calcium. Am J Physiol 1990;258:C755-C786.
39. Qian T, Herman B, Lemasters JJ. The mitochondrial permeability transition mediates both necrotic and apoptotic death of hepatocytes exposed to Br-A23187. Toxicol Appl Pharmacol 1999;154:117-125.
40. Kim JS, Qian T, Lemasters JJ. Mitochondrial permeability transition in the switch from necrotic to apoptotic cell death in ischemic rat hepatocytes. Gastroentcrology 2003;124:494-503.
41. Jaeschke H, Lemasters JJ. Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology 2003;125:1246-1257.
42. Bradford BU, Marotto M, Lemasters JJ, Thurman RG. New, simple models to evaluate zone-specific damage due to hypoxia in the perfused rat liver: time course and effect of nutritional state. J Pharmacol Exp Ther 1986;236:263-268.
43. de la Monte SM, Arcidi JM, Moore GW, Hutchins GM. Midzonal necrosis as a pattern of hepatocellular injury after shock. Gastroenterology 1984;86:627-631.
44. Jaeschke H. Molecular mechanisms of hepatic ischemia-repcrfusion injury and preconditioning. Am J Physiol Gastrointest Liver Physiol 2003;284:G15-G26.
45. Anundi I, King J, Owen DA, Schneider H, Lemasters JJ, Thurman RG. Fructose prevents hypoxic cell death in liver. Am J Physiol 1987;253(3 Pt 1):G390-G396.
46. Gores GJ, Nieminen AL, Fleishman KE, Dawson TL, Herman B, Lemasters JJ. Extracellular acidosis delays onset of cell death in ATP-depleted hepatocytes. Am J Physiol 1988:255(3 Pt 1):C315-C322.
47. Harper IS, Bond JM, Chacon E, Reece JM, Herman B, Lemasters JJ. Inhibition of Na+/H+ exchange preserves viability, restores mechanical function, and prevents the pH paradox in reperfusion injury to rat neonatal myocytes. Basic Res Cardiol 1993;88:430-442.
48. Bond JM, Chacon E, Herman B, Lemasters LJ. Intracellular pH and Ca2+ homeostasis in rhe pH paradox of reperfusion injury to neonatal rat cardiac myocytes. Am J Physiol 1993:265(1 Pt 1):C129-C137.
49. Caldwell-Kenkel JC, Currin RT, Tanaka Y, Thurman RG, Lemasters JJ. Kupffer cell activation and endothelial cell damage after storage of rat livers: effects of reperfusion. HEPATOLOGY 1991;13:83-95.
50. Qian T, Niemmen AL, Herman B, Lemasters JJ. Mitochondrial permeability transition in pH-dependent reperfusion injury to rat hepatocytes. Am J Physiol 1997;273(6 Pt 1):C1783-C1792.
51. Gujral JS, Bucci TJ, Farhood A, Jaeschke H. Mechanism of cell death during warm hepatic ischemia-reperfusion in rats: apoptosis or necrosis? HEPATOLOGY 2001;33:397-405.
52. Jaeschke H, Farhood A. Neutrophil and Kupffer cell-induced oxidant srressand ischemia-reperfusion injury in rat liver. Am J Physiol 1991;260: G355-G362.
53. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci 2002;65:166-176.
54. Zwacka RM, Zhang Y, Halldorson J, Schlossberg H, Dudus L, Engelhardt JF. CD4(+) T-lymphocytes mediate ischemia/reperfusion-induced inflammatory responses in mouse liver. J Clin Invest 1997;100:279-289.
55. Caldwell CC, Okaya T, Martignoni A, Husted T, Schuster R, Lentsch AB. Divergent functions of CD4+ T lymphocytes in acute liver inflammation and injury after ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 2005;289:G969-G976.
56. Caldwell-Kenkel JC, Currin RT, Tanaka Y, Thurman RG, Lemasters JJ. Reperfusion injury to endothelial cells following cold ischemic storage of rat livers. HEPATOLOGY 1989;10:292-299.
57. Huet PM, Nagaoka MR, Desbiens G, Tarrah E, Brault A, Bralet MP, et al. Sinusoidal endothelial cell and hepatocyte death following cold ischemia-warm reperfusion of the rat liver. HEPATOLOGY 2004;39:1110-1119.
58. Takei Y, Marzi I, Gao WS, Gores GJ, Lemasters JJ, Thurman RG. Leukocyte adhesion and cell death following orthotopic liver transplantation in the rat. Transplantation 1991;51:959-965.
59. Bachmann S, Caldwell-Kenkel JC, Oleksy I, Steffen R, Thurman RG, Lemasters JJ. Warm Carolina rinse solution prevents graft failure from storage injury after orthotopic rat liver transplantation with arterialization. Transpl Int 1992;5:108-114.
60. Bachmann S, Peng XX, Currin RT, Thurman RG, Lemasters JJ. Glycine in Carolina rinse solution reduces reperfusion injury, improves graft function, and increases graft survival after rat liver transplantation. Transplant Proc 1995;27:741-742.
61. Lemasters JJ, Thurman RG. Reperfusion injury after liver preservation for transplantation. Annu Rev Pharmacol Toxicol 1997;37:327-338.
62. Marzi I, Cowper K, Takei Y, Lindert K, Lemasters JJ, Thurman RG. Methyl palmitate prevents Kupffer cell activation and improves survival after orthotopic liver transplantation in the rat. Transpl Int 1991;4:215-220.
63. Currin RT, Caldwell-Kenkel JC, Lichtman SN, Bachmann S, Takei Y, Kawano S, et al. Protection by Carolina rinse solution, acidotic pH, and glycine against lethal reperfusion injury to sinusoidal endothelial cells of rat livers stored for transplantation. Transplantation 1996;62:1549-1558.
64. Giakoustidis DE, Iliadis S, Tsantilas D, Papageorgiou G, Kontos N, Kostopoulou E, et al. Blockade of Kupffer cells by gadolinium chloride reduces lipid peroxidation and protects liver from ischemia/reperfusion injury. Hepatogastroenterology 2003;50:1587-1592.
65. Rentsch M, Puellmann K, Sirek S, Iesalnieks I, Kienle K, Mueller T, et al. Benefit of Kupffer cell modulation with glycine versus Kupffer cell depletion after liver transplantation in the rat: effects on postischemic reperfusion injury, apoptotic cell death graft regeneration and survival. Transpl Int 2005;18:1079-1089.
66. Borghi-Scoazec G, Scoazec JY, Durand F, Bernuau J, Belghiti J, Feldmann G, et al. Apoptosis after ischemia-reperfusion in human liver allografts. Liver Transpl Surg 1997;3:407-415.
67. Gao W, Bentley RG, Madden JF, Clavien PA. Apoptosis of sinusoidal endothelial cells is a critical mechanism of preservation injury in rat liver transplantation. HEPATOLOGY 1998;27:1652-1660.
68. Sun X, Kimura T, Kobayashi T, Noriki S, Imamura Y, Fukuda M, et al. Viability of liver grafts from fasted donor rats: relationship to sinusoidal endothelial cell apoptosis. J Hepatobiliary Pancreat Surg 2001;8:268-273.
69. Grasl-Kraupp B, Ruttkay-Nedecky B, Koudelka H, Bukowska K, Bursch W, Schulte-Hermann R. In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note. HEPATOLOGY 1995;21:1465-1468.
70. Ohno M, Takemura G, Ohno A, Misao J, Hayakawa Y, Minatoguchi S, et al. "Apoptotic" myocytes in infarct area in rabbit hearts may be oncotic myocytes with DNA fragmentation: analysis by immunogold electron microscopy combined with In situ nick end-labeling. circ 1998;98:1422-1430.
71. Natori S, Higuchi H, Contreras P, Gores GJ. The caspase inhibitor IDN-6556 prevents caspase activation and apoptosis in sinusoidal endothelial cells during liver preservation injury. Liver Transpl 2003;9:278-284.
72. Kienle K, Rentsch M, Muller T, Engelhard N, Vogel M, Jauch KW, et al. Expression of BCL-2 in liver grafts after adenoviral transfer improves survival following prolonged ischemia and reperfusion in rat liver transplantation. Transplant Proc 2005;37:439-441.
73. Sindram D, Kohli V, Madden JF, Clavien PA. Calpain inhibition prevents sinusoidal endothelial cell apoptosis in the cold ischemic rat liver. Transplantation 1999;68:136-140.
74. Contreras JL, Vilatoba M, Eckstein C, Bilbao G, Anthony TJ, Eckhoff DE. Caspase-8 and caspase-3 small interfering RNA decreases ischemia/reperfusion injury to the liver in mice. Stir 2004;136:390-400.
75. Yamabe K, Shimizu S, Kamiike W, Waguri S, Eguchi Y, Hasegawa J, et al. Prevention of hypoxic liver cell necrosis by in vivo human bcl-2 gene transfection. Biochem Biophys Res Commun 1998;243:217-223.
76. Kane DJ, Ord T, Anton R, Bredesen DE. Expression of bcl-2 inhibits necrotic neural cell death. J Neurosci Res 1995;40:269-275.
77. Dinarello CA. Interleukin-1 beta, interleukin-18, and the interleukin-1 beta converting enzyme. Ann N Y Acad Sci 1998;856:1-11.
78. Decaudin D, Geley S, Hirsch T, Castedo M, Marchetti P, Macho A, et al. Bcl-2 and Bcl-XL antagonize the mitochondrial dysfunction preceding nuclear apoptosis induced by chemotherapeurtic agents. Cancer Res 1997;57:62-67.
79. Kon K, Kim JS, Jaeschke H, Lemasters JJ. Mitochondrial permeability transition in aceraminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. HEPATOLOGY 2004;40:1170-1179.
80. Kim JS, Ohshima S, Pediaditakis P, Lemasters JJ. Nitric oxide protects rat hcpatocytes against reperfusion injury mediated by the mitochondrial permeability transition. HEPATOLOGY 2004;39:1533-1543.
81. Li J, Bombeck CA, Yang S, Kim YM, Billiar TR. Nitric oxide suppresses apoptosis via interrupting caspase activation and mitochondrial dysfunction in cultured hepatocytes. J Biol Chem 1999;274:17325-17333.
82. Kim J-S, Cai X, Smith EK, Jin Y, Uchiyama A, Lemasters JJ. Mitochondrial permeability transition-mediated apoptosis after ischemia/reperfusion of cultured mouse hepatocytes: role of X-linked inhibitor of apoptosis protein (XIAP). Gastroenterology 2005;128(Suppl 2):A708.
83. Salvesen GS, Duckett CS. IAP proteins: blocking the road to death's door. Nat Rev Mol Cell Biol 2002;3:401-410.
84. Vaux DE, Silke J. Mammalian mitochondrial IAP binding proteins. Biochem Biophys Res Commun 2003;304:499-504.
85. Kim J-S, Cai X, Smith EK, Jin Y, Deshmukh M, Lemasters JJ. Increased apoptosis after ischemia/reperfusion to XIAP deficient hepatocytes: reversal by an xiap-expressing adenovirus. HEPATOLOGY 2005;42(Suppl 1):501A.
86. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 1997;277:818-821.
87. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 2003;114:181-190.
88. Peter ME, Krammer PH. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 2003;10:26-35.
89. Guicciardi ME, Gores GJ. The death receptor family and the extrinsic pathway. In: Yin X-M, Dong Z, editors. Essentials of Apoptosis: A Guide for Basic and Clinical Research. Totowa: Humana Press, 2003:57-84.
90. Barnhart BC, Peter ME. The TNF receptor 1: a split personality complex. Cell 2003;114:148-150.
91. Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, et al. Two CD95 (APO-1/Fas) signaling pathways. EMBO J 1998;17:1675-1687.
92. Peter ME, Krammer PH. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ 2003;10:26-35.
93. Li S, Zhao Y, He X, Kim TH, Kuharsky DK, Rabinowich H, et al. Relief of extrinsic pathway inhibition by the Bid-dependent mitochondrial release of Smac in Fas-mediated hepatocyte apoptosis. J Biol Chem 2002;277:26912-26920.
94. Ni R, Tomita Y, Matsuda K, Ichihata A, Ishimura K, Ogasawara J, et al. Fas-mediated apoptosis in primary cultured mouse hepatocytes. Exp Cell Res 1994;215:332-337.
95. Ueno Y, Ishii M, Yahagi K, Mano Y, Kisara N, Nakamura N, et al. Fas-mediated cholangiopathy in the murine model of graft versus host disease. HEPATOLOGY 2000;31:966-974.
96. Cardier JE, Schulte T, Kammer H, Kwak J, Cardier M. Fas (CD95, APO-1) antigen expression and function in murine liver endothelial cells: implications for the regulation of apoptosis in liver endothelial cells. FASEB J 1999;13:1950-1960.
97. Saile B, Knittel T, Matches N, Schott P, Ramadori G. CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair. Am J Pathol 1997;151:1265-1272.
98. Muschen M, Warskulat U, Douillard P, Gilbert E, Haussinger D. Regulation of CD95 (APO-1/Fas) receptor and ligand expression by lipopolysaccharide and dexamethasone in parenchymal and nonparenchymal rat liver cells. HEPATOLOGY 1998;27:200-208.
99. Bennett M, Macdonald K, Chan SW, Luzio JP, Simari R, Weissberg P. Cell surface trafficking of Fas: a rapid mechanism or p53-mediated apoptosis. Science 1998;282:290-293.
100. Sodeman T, Bronk SF, Roberts PJ, Miyoshi H, Gores GJ. Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas. Am J Physiol Gastrointest Liver Physiol 2000;278:G992-G999.
101. Reinehr R, Becker S, Hongen A, Haussinger D. The Src family kinase Yes triggers hyperosmotic activation or the epidermal growth factor receptor and CD95. J Biol Chem 2004;279:23977-23987.
102. Reinehr R, Becker S, Eberle A, Grether-Bcck S, Haussinger D. Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. J Biol Chem 2005;280:27179-27194.
103. Reinehr R, Becker S, Wettstein M, Haussinger D. Involvement or the Src family kinase yes in bile salt-induced apoptosis. Gastroenterology 2004;127:1540-1557.
104. Berke G. The CTL's kiss of death. Cell 1995;81:9-12.
105. Kagi D, Vignaux F, Ledermann B, Burki K, Depraetere V, Nagata S, et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 1994;265:528-530.
106. Lapinski TW, Kowalczuk O, Prokopowicz D, Chyczewski L. Serum concentration of sFas and sFasL in healthy HBsAg carriers, chronic viral hepatitis B and C patients. World J Gastroenterol 2004;10:3650-3653.
107. Song IH, Binh VQ, Duy DN, Bock TC, Kremsner PG, Luty AJ, et al. Variations in the serum concentrations of soluble Fas and soluble Fas ligand in Vietnamese patients infected with hepatitis B virus. J Med Virol 2004;73:244-249.
108. Takaku S, Nakagawa Y, Shimizu M, Norose Y, Maruyama I, Wakita T, et al. Induction of hepatic injury by hepatitis C virus-specific CD8+ murine cytotoxic T lymphocytes in transgenic mice expressing the viral structural genes. Biochem Biophys Res Commun 2003;301:330-337.
109. Kondo T, Suda T, Fukuyama H, Adachi M, Nagata S. Essential roles of the Fas ligand in the development of hepatitis. Nat Med 1997;3:409-413.
110. Pianko S, Patella S, Ostapowicz G, Desmond P, Sievert W. Fas-mediated hepatocyte apoptosis is increased by hepatitis C virus infection and alcohol consumption, and may be associated with hepatic fibrosis: mechanisms of liver cell injury in chronic hepatitis C virus infection. J Viral Hepat 2001;8:406-413.
111. Feldstein AE, Canbay A, Angulo P, Taniai M, Burgart LJ, Lindor KD, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology 2003;125:437-443.
112. Ryo K, Kamogawa Y, Ikeda I, Yamauchi K, Yonehara S, Nagata S, et al. Significance of Fas antigen-mediated apoptosis in human fulminant hepatic failure. Am J Gastroenterol 2000;95:2047-2055.
113. Kasahara I, Saitoh K, Nakamura K. Apoptosis in acute hepatic failure: histopathological study of human liver tissue using the tunel method and immunohistochemistry. J Med Dent Sci 2000;47:167-175.
114. Sakaida I, Kimura T, Yamasaki T, Fukumoto Y, Watanabe K, Aoyama M, et al. Cytochrome c is a possible new marker for fulminant hepatitis in humans. J Gastroenterol 2005;40:179-185.
115. Lacronique V, Mignon A, Fabre M, Viollet B, Rouquet N, Molina T, et al. Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice. Nat Med 1996;2:80-86.
116. Hsu H, Xiong J, Goeddel DV. The TNF receptor I-associated protein TRADD signals cell death and NF-kappa B activation. Cell 1995;81:495-504.
117. Volpes R, van den Oord JJ, De Vos R, Desmet VJ. Hepatic expression of type A and type B receptors for tumor necrosis factor. J Hepatol 1992;14:361-369.
118. Yamada Y, Webber EM, Kirillova I, Peschon JJ, Fausto N. Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor. HEPATOLOGY 1998;28:959-970.
119. Mohammed FF, Smookler DS, Taylor SE, Fingleton B, Kassiri Z, Sanchez OH, et al. Abnormal TNF activity in Timp3-/- mice leads to chronic hepatic inflammation and failure of liver regeneration. Nat Genet 2004;36:969-977.
120. Conzelmann LO, Zhong Z, Thurman R, Lemasters JJ. Role of TNFR1-receptors in graft injury and regeneration after liver transplantation in knockout mice. Gastroenterology 2002;123(Suppl):87.
121. Bird GL, Sheron N, Goka AK, Alexander GJ, Williams RS. Increased plasma tumor necrosis factor in severe alcoholic hepatitis. Ann Intern Med 1990;112:917-920.
122. Spahr L, Giostra E, Frossard JL, Bresson-Hadni S, Rubbia-Brandt L, Hadengue A. Soluble TNF-R1, but not tumor necrosis factor alpha, predicts the 3-month mortality in patients with alcoholic hepatitis. J Hepatol 2004;41:229-234.
123. Torre F, Rossol S, Pelli N, Basso M, Delfino A, Picciotto A. Kinetics of soluble tumour necrosis factor (TNF)-alpha receptors and cytokines in the early phase of treatment for chronic hepatitis C: comparison between Interferon (IFN)-alpha alone, IFN-alpha plus amantadine or plus ribavirin. Clin Exp Immunol 2004;136:507-512.
124. Fang JW, Shen WW, Meager A, Lau JY. Activation of the tumor necrosis factor-alpha system in the liver in chronic hepatitis B virus infection. Am J Gastroenterol 1996;91:748-753.
125. Rudiger HA, Clavien PA. Tumor necrosis factor alpha, but not Fas, mediates hepatocellular apoptosis in the murine ischemic liver. Gastroenterology 2002;122:202-210.
126. Streetz K, Leifeld L, Grundmann D, Ramakers J, Eckert K, Spengler U, et al. Tumor necrosis factor alpha in the pathogenesis of human and murine fulminant hepatic failure. Gastroenterology 2000;119:446-460.
127. Yin XM, Ding WX. Death receptor activation-induced hepatocyte apoptosis and liver injury. Curr Mol Med 2003;3:491-508.
128. Hatano E, Bennett BL, Manning AM, Qian T, Lemasters JJ, Brenner DA. NF-kappaB stimulates inducible nitric oxide synthase to protect mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis. Gastroenterology 2001;120:1251-1262.
129. Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, et al. Lethal effect of the anti-Fas antibody in mice. Nature 1993;364:806-809.
130. [Erratum appears in Nature 1993 Oct 7;365(6446):568.]
131. Galle PR, Hofmann WJ, Walczak H, Schaller H, Otto G, Stremmel W, et al. Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med 1995;182:1223-1230.
132. Schulze-Bergkamen H, Untergasser A, Dax A, Vogel H, Buchler P, Klar E, et al. Primary human hepatocytes-a valuable tool fot investigation of apoptosis and hepatitis B virus infection. J Hepatol 2003;38:736-744.
133. Diehl AM. Cytokine regulation of liver injury and repair. Immunol Rev 2000;174:160-171.
134. Fausto N. Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. HEPATOLOGY 2004;39:1477-1487.
135. Keppler D, Holstege A, Weckbecker G, Fauler J, Gasser T. Potentiation of antimetabolite action by uridylate trapping. Adv Enzyme Regul 1985;24:417-427.
136. Lehmann V, Freudenberg MA, Galanos G. Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine- treated mice. J Exp Med 1987;165:657-663.
137. Takahashi Y, Ganster RW, Gambotto A, Shao L, Kaizu T, Wu T, et al. Role of NF-kappaB on liver cold ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 2002;283:G1175-G1184.
138. Uehara T, Xi P, X, Bennett B, Satoh Y, Friedman G, Currin R, et al. c-Jun N-terminal kinase mediates hepatic injury after rat liver transplantation. Transplantation 2004;78:324-332.
139. Uehara T, Bennctt B, Sakata ST, Satoh Y, Bilter GK, Westwick JK, et al. JNK mediates hepatic ischemia reperfusion injury. J Hepatol 2005;42:850-859.
140. Mori E, Thomas M, Motoki K, Nakazawa K, Tahara T, Tomizuka K, et al. Human normal hepatocytes are susceptible to apoptosis signal mediated by both TRAIL-R1 and TRAIL-R2. Cell Death Differ 2004;11:203-207.
141. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999;5:157-163.
142. Zheng SJ, Wang P, Tsabary G, Chen YH. Critical roles of TRAIL in hepatic cell death and hepatic inflammation. J Clin Invest 2004;113:58-64.
143. Han LH, Sun WS, Ma CH, Zhang LN, Liu SX, Zhang Q, et al. Detection of soluble TRAIL in HBV infected patients and its clinical implications. World J Gastroenterol 2002;8:1077-1080.
144. Mundt B, Kuhnel F, Zender L, Paul Y, Tillmann H, Trautwein C, et al. Involvement of TRAIL and its receptors in viral hepatitis. FASEB J 2003;17:94-96.
145. Hao C, Song JH, Hsi B, Lewis J, Song DK, Petruk KC, et al. TRAIL inhibits tumor growth but is nontoxic to human hepatocytes in chimeric mice. Cancer Res 2004;64:8502-8506.
146. Ganten TM, Koschny R, Haas TL, Sykora J, Li-Weber M, Herzer K, et al. Proteasome inhibition sensitizes hepatocellular carcinoma cells, but not human hepatocytes, to TRAIL. HEPATOLOGY 2005;42:588-597.
147. Faubion WA, Guicciardi ME, Miyoshi H, Bronk SF, Roberts PJ, Svingen PA, et al. Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas. J Clin Invest 1999;103:137-145.
148. Guo GL, Lambert G, Negishi M, Ward JM, Brewer HB Jr, Kliewer SA, et al. Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity. J Biol Chem 2003;278:45062-45071.
149. Guicciardi ME, Gores GJ. Bile acid-mediated hepatocyte apoptosis and cholestatic liver disease. Dig Liver Dis 2002;34:387-392.
150. Higuchi H, Yoon JH, Grambihler A, Werneburg N, Bronk SF, Gores GJ. Bile acids stimulate cFLIP phosphorylation enhancing TRAIL-mediated apoptosis. J Biol Chem 2003;278:454-461.
151. Canbay A, Guicciardi ME, Higuchi H, Feldstein A, Bronk SF, Rydzewski R, et al. Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. J Clin Invest 2003;112:152-159.
152. Canbay A, Higuchi H, Bronk SF, Taniai M, Sebo TJ, Gores GJ. Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis. Gastroenterology 2002;123:1323-1330.
153. Reinehr R, Becker S, Keitel V, Eberle A, Grether-Beck S, Haussinger D. Bile salt-induced apoptosis involves NADPH oxidase isoform activation. Gastroenterology 2005;129:2009-2031.
154. Miyoshi H, Rust C, Roberts PJ, Burgart LJ, Gores GJ. Hepatocyte apoptosis after bile duct ligation in the mouse involves Fas. Gastroenterology 1999;117:669-677.
155. Higuchi H, Miyoshi H, Bronk SF, Zhang H, Dean N, Gores GJ. Bid antisense attenuates bile acid-induced apoptosis and cholestatic liver injury. J Pharmacol Exp Ther 2001;299:866-873.
156. Botla R, Spivey JR, Aguilar H, Bronk SF, Gores GJ. Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection. J Pharmacol Exp Ther 1995;272:930-938.
157. Canbay A, Feldstein A, Baskin-Bey E, Bronk SF, Gores GJ. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. J Pharmacol Exp Ther 2004;308:1191-1196.
158. Fickert P, Trauner M, Fuchsbichler A, Zollner G, Wagner M, Marschall HU, et al. Oncosis represents the main type of cell death in mouse models of cholestasis. J Hepatol 2005;42:378-385.
159. Gujtal JS, Liu J, Farhood A, Jaeschke H. Reduced oncotic necrosis in Fas receptor-deficient C57BL/6J-lpr mice after bile duct ligation. HEPATOLOGY 2004;40:998-1007.
160. Martinon F, Tschopp J. Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 2004;117:561-574.
161. Ribeiro PS, Cortez-Pinto H, Sola S, Castro RE, Ramalho RM, Baptista A, et al. Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients. Am J Gastroentcrol 2004;99:1708-1717.
162. Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol 2003;39:978-983.
163. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. HEPATOLOGY 2004;40:185-194.
164. Malhi HB, Werneburg N, Gores GJ. Hepatocyte lipoapoptosis is mediated by c-jun-n-terminal kinase (JNK) activation. Gastroenterology 2005;128:469.
165. Pessayre D, Fromenty B. NASH: a mitochondrial disease. J Hepatol 2005;42:928-940.
166. Schattenberg JM, Wang Y, Singh R, Rigoli RM, Czaja MJ. Hepatocyte CYP2E1 overexprcssion and steatohepatitis lead to impaired hepatic insulin signaling. J Biol Chem 2005;280:9887-9894.
167. Lee WM. Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure. HEPATOLOGY 2004;40:6-9.
168. Nelson SD. Molecular mechanisms of the hepatotoxiciry caused by acetaminophen. Semin Liver Dis 1990;10:267-278.
169. Cohen SD, Khairallah EA. Selective protein arylation and acetaminophen-induced hepatotoxicity. Drug Metab Rev 1997;29:59-77.
170. Masubuchi Y, Suda C, Horie T. Involvement of mitochondrial permeability transition in acetaminophen-induced liver injury in mice. J Hepatol 2005;42:110-116.
171. Ray SD, Mumaw VR, Raje RR, Fariss MW. Protection of acetaminophen-induced hepatocellular apoptosis and necrosis by cholesteryl hemisuccinate pretreatment. J Pharmacol Exp Ther 1996;279:1470-1483.
172. El Hassan H, Anwar K, Macanas-Pirard P, Crabtree M, Chow SC, Johnson VL, et al. Involvement of mitochondria in acetaminophen-induced apoptosis and hepatic injury: roles of cytochrome c, Bax, Bid, and caspases. Toxicol Appl Pharmacol 2003;191:118-129.
173. Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H. Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol Sci 2002;67:322-328.
174. Puthalakath H, Strasser A. Keeping killers on alight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ 2002;9:505-512.
175. Cheng EH, Sheiko TV, Fisher JK, Craigen WJ, Korsmeyer SJ. VDAC2 inhibits BAK activation and mitochondrial apoptosis. Science 2003;301:513-517.
176. Sugiyama T, Shimizu S, Matsuoka Y, Yoneda Y, Tsujimoto Y. Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic BH3-only protein Bim. Oncogene 2002;21:4944-4956.
177. Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, et al. Loss of cydophilin D reveals a critical role for mitochondrial permeability transition in cell death. Nature 2005;434:658-662.
178. Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, et al. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. Nature 2005;434:652-658.
179. Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion-a target for cardioprotection. Cardiovasc Res 2004;61:372-385.
180. Waldmeier PC, Feldtrauer JJ, Qian T, Lemasters JJ. Inhibition of the mitochondrial permeability transition by the nonimmunosuppressive cyclosporin derivative NIM811. Mol Pharmacol 2002;62:22-29.
181. Zender L, Hutker S, Liedtke C, Tillmann HL, Zender S, Mundt B, et al. Caspase 8 small interfering RNA prevents acute liver failure in mice. Proc Natl Acad Sci U S A 2003;100:7797-7802.
182. Matsuki Y, Li L, Hsu HC, Yang PA, Zheng R, Edwards CK III, et al. Soluble Fas gene therapy protects against Fas-mediated apoptosis of hepatocytes but not the lethal effects of Fas-induced TNF-alpha production by Kupffer cells. Cell Death Differ 2002;9:626-635.
183. Song E, Lee SK, Wang J, Ince N, Ouyang N, Min J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 2003;9:347-351.
184. Wang J, Li W, Min J, Ou Q, Chen J. Fas siRNA reduces apoptotic cell death of allogeneic-transplanted hepatocytes in mouse spleen. Transplant Proc 2003;35:1594-1595.
185. Murphy F, Arthur M, Iredale J. Developing strategies for liver fibrosis treatment. Expert Opin Investig Drugs 2002;11:1575-1585.
186. Kweon YO, Paik YH, Schnabl B, Qian T, Lemasters JJ, Brenner DA. Gliotoxin-mediated apoptosis of activated human hepatic stellate cells. J Hepatol 2003;39:38-46.
187. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-218.
188. Anan AB, Werneburg N, Gores GJ. Proteasome inhibitors induce hepatic stellate cell apoptosis. HEPATOLOGY 2005;42(Suppl):142A.
189. Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal ot liver fibrosis. Apoptosis 2005;10:927-939.
190. Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest 2003;83:655-663.
191. Canbay A, Guicciardi ME, Higuchi H, Feldstein A, Bronk SF, Rydzewski R, et al. Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. J Clin Invest 2003;112:152-159.
192. Canbay A, Feldstein A, Baskin-Bey E, Bronk SF, Gores GJ. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duet ligated mouse. J Pharmacol Exp Ther 2004;308:1191-1196.
193. Friedman SL. Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol 2004;1:98-105.
194. Kim WH, Matsumoto K, Bessho K, Nakamura T. Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis. Am J Pathol 2005;166:1017-1028.
195. Oakley F, Meso M, Iredale JP, Green K, Marek CJ, Zhou X, et al. Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 2005;128:108-120.
196. Fallowfield JA, Iredale JP. Targeted treatments for cirrhosis. Expert Opin Ther Targets 2004;8:423-435.