Hepatic neutrophil infiltration in the pathogenesis of alcohol-induced liver injury

Toxicology Mechanisms and Methods

Volumn 17, Issue 7, 2007, Pages 431-440

  Ramaiah, Shashi K ^a   Jaeschke, Hartmut ^b  

^a TEXAS A AND M UNIVERSITY   (United States)

^b UNIVERSITY OF KANSAS SCHOOL OF MEDICINE   (United States)

Author keywords

Inflammation; Injury; Liver; Neutrophils; Toxicity

Indexed keywords

ALCOHOL; BETA INTEGRIN; INTERCELLULAR ADHESION MOLECULE 1;

ALCOHOL LIVER DISEASE; ARTICLE; CELL DEATH; CELL MIGRATION; DISEASE COURSE; HISTOPATHOLOGY; HUMAN; LEUKOCYTE ACTIVATION; LIVER INJURY; LIVER PARENCHYMA; NEUTROPHIL CHEMOTAXIS; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL;

ANIMALIA; RODENTIA;

EID: 34548380904     PISSN: 15376516     EISSN: 15376524     Source Type: Journal    
DOI: 10.1080/00952990701407702     Document Type: Article

References (94)

1. Afford, S. C., Fisher, N. C., Neil, D. A., Fear, J., Brun, P., Hubscher, S. G., and Adams, D. H. 1998. Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis. J Pathol. 186:82-89.
2. Apte, U. M., Banerjee, A., McRee, R., Wellberg, E., and Ramaiah, S. K. 2005. Role of osteopontin in hepatic neutrophil infiltration during alcoholic steatohepatitis. Toxicol. Appl. Pharmacol. 207:25-38.
3. Bajt, M. L., Farhood, A., and Jaeschke, H. 2001. Effects of CXC chemokines on neutrophil activation and sequestration in hepatic vasculature. Am. J. Physiol. Gastrointest. Liver Physiol. 281:G1188-G1195.
4. Banerjee, A., Apte, U., Smith, R., and Ramaiah, S. 2006a. Higher neutrophil infiltration mediated by osteopontin is the likely factor for increased susceptibility of females to alcoholic liver disease. J. Pathol. 208:473-485.
5. Banerjee, A., Burghardt, R. C., Johnson, G. A., White, F. J., and Ramaiah, S. K. 2006b. The temporal expression of osteopontin (SPP-1) in the rodent model of alcoholic steatohepatitis: a potential biomarker. Toxicol. Pathol. 34:373-384.
6. Bautista, A. P. 1997. Chronic alcohol intoxication induces hepatic injury through enhanced macrophage inflammatory protein-2 production and intercellular adhesion molecule-1 expression in the liver. Hepatology 25:335-342.
7. Bautista, A. P. 2000. Impact of alcohol on the ability of Kupffer cells to produce chemokines and its role in alcoholic liver disease. J. Gastroenterol. Hepatol. 15:349-356.
8. Bautista, A. P. 2002. Neutrophilic infiltration in alcoholic hepatitis. Alcohol 27:17-21.
9. Bautista, A. P., and Spitzer, J. J. 1992. Platelet activating factor stimulates and primes the liver, Kupffer cells and neutrophils to release superoxide anion. Free Radic. Res. Commun. 17:195-209.
10. Bilzer, M., and Lauterburg, B. H. 1991. Effects of hypochlorous acid and chloramines on vascular resistance, cell integrity, and biliary glutathione disulfide in the perfused rat liver: modulation by glutathione. J. Hepatol. 13:84-89.
11. Bode, C., and Bode, J. C. 2005. Activation of the innate immune system and alcoholic liver disease: effects of ethanol per se or enhanced intestinal translocation of bacterial toxins induced by ethanol?. Alcohol Clin. Exp. Res. 29(Suppl):166S-171S.
12. Casey, C. A., Nanji, A., Cederbaum, A. I., Adachi, M., and Takahashi, T. 2001. Alcoholic liver disease and apoptosis. Alcohol Clin. Exp. Res. 25:49S-53S.
13. Chosay, J. G., Essani, N. A., Dunn, C. J., and Jaeschke, H. 1997. Neutrophil margination and extravasation in sinusoids and venules of liver during endotoxin-induced injury. Am. J. Physiol. 272:G1195-G1200.
14. Christensen, E., and Gluud, C. 1995. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables. Gut 37:113-118.
15. Colletti, L.M., Kunkel, S. L., Walz, A., Burdick, M. D., Kunkel, R. G., Wilke, C. A., and Strieter, R. M. 1996. The role of cytokine networks in the local liver injury following hepatic ischemia/reperfusion in the rat. Hepatology 23:506-514.
16. Day, C. P., and James, O. F. 1998. Hepatic steatosis: innocent bystander or guilty party?. Hepatology 27:1463-1466.
17. Denhardt, D., Giachelli, C. M., and Rittling, S. R. 2001. Role of osteopontin in cellular signaling and toxicant injury. Ann. Rev. Pharmacol. Toxicol. 41:723-749.
18. Diehl, A. M. 2002. Liver disease in alcohol abusers: clinical perspective. Alcohol 27:7-11.
19. Enomoto, N., Yamashita, S., Kono, H., Schemmer, P., Rivera, C. A., Enomoto, A., Nishiura, T., Nishimura, T., Brenner, D. A., and Thurman, R. G. 1999. Development of a new, simple rat model of early alcohol-induced liver injury based on sensitization of Kupffer cells. Hepatology 29:1680-1689.
20. Essani, N. A., Fisher, M. A., Farhood, A., Manning, A. M., Smith, C. W., and Jaeschke, H. 1995. Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role on the pathophysiology of murine endotoxin shock and acute liver failure. Hepatology 21:1632-1639.
21. Essani, N. A., Fisher, M. A., Simmons, C. A., Hoover, J. L., Farhood, A., and Jaeschke, H. 1998. Increased P-selectin gene expression in the liver vasculature and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock. J. Leukoc. Biol. 63:288-296.
22. Faouzi, S., Burckhardt, B. E., Hanson, J. C., Campe, C. B., Schrum, L. W., Rippe, R. A., and Maher, J. J. 2001. Anti-Fas induces hepatic chemokines and promotes inflammation by an NF-kappa B-independent, caspase-3-dependent pathway. J. Biol. Chem. 276:49077-49082.
23. Francki, A., and Sage, E. H. 2001. SPARC and the kidney glomerulus: matricellular proteins exhibit diverse functions under normal and pathological conditions. Trends Cardiovasc. Med. 11:32-37.
24. French, S. W. 2002. Alcoholic hepatitis: inflammatory cell-mediated hepatocellular injury. Alcohol 27:43-46.
25. Galambos, J. T. 1972. Natural history of alcoholic hepatitis. Histological changes. Gastroenterology 63:1026-1035.
26. Gujral, J. S., Farhood, A., Bajt, M. L., and Jaeschke, H. 2003. Neutrophils aggravate acute liver injury during obstructive choleostasis in bile-duct ligated mice. Hepatology 38:355-363.
27. Gujral, J. S., Hinson, J. A., Farhood, A., and Jaeschke, H. 2004. NADPH oxidase-derived oxidant stress is critical for neutrophil cytotoxicity during endotoxemia. Am. J. Physiol. Gastrointest. Liver Physiol. 287:G234-G252.
28. Hill, D. A., Jean, P. A., and Roth, R. A. 1999. Bile duct epithelial cells exposed to α-naphthylisothiocyanate produce a factor that causes neutrophil-dependent hepatocellular injury in vitro. Toxicol. Sci. 47:118-125.
29. Ho, J. S., Buchweitz, J. P., Roth, R. A., and Ganey, P. E. 1996. Identification of factors from rat neutrophils responsible for cytotoxicity to isolated hepatocytes. J. Leukoc. Biol. 59:716-724.
30. Horie, Y., Kato, S., Ohki, E., Tamai, H., Yamagishi, Y., and Ishii, H. 2000. Hepatic microvascular dysfunction in endotoxemic rats after acute ethanol administration. Alcoholism Clin. Exper. Res. 24:691-698.
31. Iimuro, Y., Frankenberg, M. V., Arteel, G. E., Bradford, B. U., Wall, C. A., and Thurman, R. G. 1997. Female rats exhibit greater susceptibility to early alcohol-induced liver injury than males. Am. J. Physiol. Gastrointest. Liver Physiol. 272:G1186-G1194.
32. Ito, Y., Abril, E. R., Bethea, N. W., McCuskey, M. K., Cover, C., Jaeschke, H., and McCuskey, R. S. 2006. Mechanisms and pathophysiological implications of sinusoidal endothelial cell gap formation following treatment with galactosamine/endotoxin in mice. Am. J. Physiol. Gastrointest. Liver Physiol. 291:G211-G218.
33. Jaeschke, H. 1997. Cellular adhesion molecules: regulation and functional significance in the pathogenesis of liver diseases. Am. J. Physiol. 273:G602-G611.
34. Jaeschke, H. 2000. Reactive oxygen and mechanisms of inflammatory liver injury. J. Gastroenterol. Hepatol. 15:718-724.
35. Jaeschke, H. 2002. Neutrophil-mediated tissue injury in alcoholic hepatitis. Alcohol 27:23-27.
36. Jaeschke, H. 2003. Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. Am. J. Physiol. Gastrointest. Liver Physiol. 284:G15-G26.
37. Jaeschke, H., Farhood, A., Bautista, A. P., Spolarics, Z., and Spitzer, J. J. 1993. Complement activates Kupffer cells and neutrophils during reperfusion after hepatic ischemia. Am. J. Physiol. 264:G801-G809.
38. Jaeschke, H., Farhood, A., and Smith, C.W. 1990. Neutrophils contribute to ischemia-reperfusion injury in rat liver in vivo. FASEB J. 4:3355-3359.
39. Jaeschke, H., Farhood, A., and Smith, C. W. 1991. Neutrophil-induced liver cell injury in endotoxin shock is a CD11b/CD18-dependent mechanism. Am. J. Physiol. 261:G1051-G1056.
40. Jaeschke, H., Fisher, M. A., Lawson, J. A., Simmons, C. A., Farhood, A., and Jones, D. A. 1998. Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil mediated necrosis in a murine endotoxin shock model. J. Immunol. 160:3480-3486.
41. Jaeschke, H., and Hasegawa, T. 2006. Role of neutrophils in acute inflammatory liver injury. Liver Int. 26:912-919.
42. Jaeschke, H., Ho, Y. S., Fisher, M. A., Lawson, J. A., and Farhood, A. 1999. Glutathione peroxidase-deficient mice are more susceptible to neutrophil-mediated hepatic parenchymal cell injury during endotoxemia: importance of an intracellular oxidant stress. Hepatology 29:443-450.
43. Jaeschke, H., and Smith, C. W. 1997. Mechanisms of neutrophil-induced parenchymal cell injury. J. Leukoc. Biol. 61:647-653.
44. Janeway, C. A., and Medhitov, R. 2002. Innate immune recognition. Annu. Rev. Immunol. 20:197-216.
45. Karaa, A., Kamoun, W. S., and Clemens, M. G. 2005. Chronic ethanol sensitizes the liver to endotoxin via effects on endothelial nitric oxide synthase regulation. Shock 24:447-454.
46. Kawashima, R., Mochida, S., Matsui, A., YouLuTuZ, Y., Ishikawa, K., Toshima, K., Yamanobe, F., Inao, M., Ikeda, H., Ohno, A., Nagoshi, S., Uede, T., and Fujiwara, K. 1999. Expression of osteopontin in Kupffer cells and hepatic macrophages and stellate cells in rat liver after carbon tetrachloride intoxication: a possible factor for macrophage migration into hepatic necrotic areas. Bichem. Biophys. Res. Commun. 256:527-531.
47. Kim, T. H., Mars, W. M., Stolz, D. B., Petersen, B. E., and Michalopoulos, G. K. 1997. Extracellular matrix remodeling at the early stages of liver regeneration in the rat. Hepatology 26:896-904.
48. Kono, H., Uesugi, T., Froh, M., Rusyn, I., Blair, U., Bradford, B. C., and Thurman, R. G. 2001. ICAM-1 is involved in the mechanism of alcohol-induced liver injury: studies with knock out mice. Am. J. Physiol. Gastrointest. Liver Physiol. 280:1289-1295.
49. Kubes, P., Payne, D., and Woodman, R. C. 2002. Molecular mechanisms of leukocyte recruitment in postischemic liver microcirculation. Am. J. Physiol. Gastrointest. Liver Physiol. 283:G139-G147.
50. Murohisa, G., Kobayashi, Y., Kawasaki, T., Nakamura, S., and Nakamura, H. 2002. Involvement of platelet activating factor in hepatic apoptosis and necrosis in chronic ethanol fed rats given endotoxin. Liver 22:394-403.
51. Lawson, J. A., Burns, A. R., Farhood, A., Bajt, M. L., Collins, R. G., Smith, C. W., and Jaeschke, H. 2000. Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice. Hepatology 32:990-998.
52. Lawson, J. A., Fisher, M. A., Simmons, C. A., Farhood, A., and Jaeschke, H. 1998. Parenchymal cell apoptosis as a signal for sinusoidal sequestration and transendothelial migration of neutrophils in murine models of endotoxin and Fas-antibody induced liver injury. Hepatology 28:761-767.
53. Lentsch, A. B., Yoshidome, H., Cheadle, W. G., Miller, F. N., and Edwards, M. J. 1998. Chemokine involvement in hepatic ischemia/reperfusion injury in mice: roles for macrophage inflammatory protein-2 and KC. Hepatology 27:507-512.
54. Lieber, C. S. 2000. Hepatic, metabolic, and nutritional disorders of alcoholism: from pathogenesis to therapy. Crit. Rev. Clin. Lab. Sci. 37:551-584.
55. Limaye, P., Apte, U., Shankar, K., Bucci, T., Warbritton, A., and Mehendale, H. 2003. Calpain released from dying hepatocytes mediates progression of acute liver injury induced by model hepatotoxicants. Toxicol. Appl. Pharmacol. 191:211-226.
56. Limaye, P. B., Bhave, V. S., Palkar, P. S., Apte, U. M., Sawant, S. P., Yu, S., Latendresse, J. R., Reddy, J. K., and Mehendale, H. M. 2006. Upregulation of calpastatin in regenerating and developing rat liver: role in resistance against hepatotoxicity. Hepatology 44:379-388.
57. Linderoth, G., Jepsen, P., Schonheyder, H. C., Johnsen, S. P., and Sorensen, H. T. 2006. Short-term prognosis of community-acquired bacteremia in patients with liver cirrhosis or alcoholism: a population-based cohort study. Alcohol Clin. Exp. Res. 30:636-641.
58. MacSween, R. N., and Burt, A. D. 1986. Histological spectrum of alcoholic liver disease. Semin. Liver Dis. 6:221-232.
59. Maher, J. J. 2002. Alcoholic steatosis and steatohepatitis. Semin. Gastrointest. Dis. 13:31-39.
60. Maher, J. J., Scott, M. K., Saito, J. M., and Burton, M. C. 1997. Adenovirus-mediated expression of cytokine-induced neutrophil chemoattractant in rat liver induces a neutrophilic hepatitis. Hepatology 25:624-630.
61. Mathurin, P., Duchatelle, V., Ramond, M. J., Degott, C., Bedossa, P., Erlinger, S., Benhamou, J. P., Chaput, J. C., Rueff, B., and Poynard, T. 1996. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology 110:1847-1853.
62. Mathurin, P., Mendenhall, C. L., Carithers Jr., R. L., Ramond, M. J., Maddrey, W. C., Garstide, P., Rueff, B., Naveau, S., Chaput, J. C., and Poynard, T. 2002. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH. J. Hepatol. 36:480-487.
63. Mehendale, H. M., and Limaye, P. B. 2005. Calpain: a death protein that mediated progression of death injury. Trends Pharmacol. Sci. 26:232-236.
64. Murohisa, G., Kobayashi, Y., Kawasaki, T., Nakamura, S., and Nakamura, H. 2002. Involvement of platelet-activating factor in hepatic apoptosis and necrosis in chronic ethanol-fed rats given endotoxin. Liver 22:394-403.
65. Nagy, L. 2003. Recent insights into the role of the innate immune system in the development of alcoholic liver disease. Exp. Biol.Med. 228:882-890.
66. Nanji, A. 2002. Alcoholic liver disease. In: Zakim, D., and Boyer, T. D. (Eds.), Hepatology, A Text Book of Liver Disease, W. B. Saunders, Philadelphia, pp. 839-922.
67. Nanji, A. A., Zhao, S., Lamb, R. G., Dannenberg, A. J., Sadrzadeh, S. M., and Waxman, D. J. 1994. Changes in cytochromes P-450, 2E1, 2B1, and 4A and phospholipases A and C in the intragastric feeding rat model for alcoholic liver disease: relationship to dietary fats and pathologic liver injury. Alcohol Clin. Exp. Res. 18:902-908.
68. Napirei, M., Basnakian, A. G., Apostolov, E. O., and Mannherz, H. G. 2006. Deoxyribonuclease 1 aggravates acetaminophen-induced liver necrosis in male CD-1 mice. Hepatology 43:297-305.
69. Okaya, T., and Lentsch, A. B. 2003. Cytokine cascades and the hepatic inflammatory response to ischemia and reperfusion. J. Invest. Surg. 16:141-147.
70. O'Regan, A., and Berman, J. S. 2000. Osteopontin: a key cytokine in cell-mediated and granulomatous inflammation. Int. J. Exp. Pathol. 81:373-390.
71. Pennington, H. L., Wilce, P. A., and Worrall, S. 1998. Chemokine and cell adhesion molecule mRNA expression and neutrophil infiltration in lipopolysaccharide-induced hepatitis in ethanol-fed rats. Alcohol Clin. Exp. Res. 22:1713-1718.
72. Pritchard, M. T., and Nagy, L. E. 2005. Ethanol-induced liver injury: potential roles for Egr-1. Alcoholism Clin. Exper. Res. 29:146S-150S.
73. Ramaiah, S. K., and Jaeschke, H. 2007. Role of neutrophils in the pathogenesis of acute inflammatory liver injury. Toxicol. Pathol. 35:in press
74. Ramaiah, S. K., Rivera, C., and Arteel, G. E. 2004. Early-phase alcoholic liver disease: an update on animal models, pathology and pathogenesis. Int. J. Toxicol. 23:217-231.
75. Rose, R., Banerjee, A., and Ramaiah, S. K. 2006. Calpain inhibition attenuates iNOS production and midzonal hepatic necrosis in a repeat dose model of endotoxemia in rats. Toxicol. Pathol. 34:785-794.
76. Rose, R., Banerjee, A., and Ramaiah, S. K. 2007, March 16. Characterization of a lipopolysaccharide mediated neutrophilic hepatitis model in Sprague Dawley rats. J. Appl. Toxicol. 27:[Epub ahead of print].
77. Scaffidi, P., Misteli, T., and Bianchi, M. E. 2002. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191-195.
78. Schlayer, H. J., Laaff, H., Peters, T., Woort-Menker, M., Estler, H. C., Karck, U., Schaefer, H. E., and Decker, K. 1988. Involvement of tumor necrosis factor in endotoxin-triggered neutrophil adherence to sinusoidal endothelial cells of mouse liver and its modulation in acute phase. J. Hepatol. 7:239-249.
79. Sodek, J., Zhu, B., Huynh, M. H., Brown, T. J., and Ringuette, M. 2002. Novel functions of the matricellular proteins osteopontin and osteonectin/SPARC. Connect. Tissue Res. 43:308-319.
80. Spahr, L., Garcia, I., Bresson-Hadni, S., Rubbia-Brandt, L., Guler, R., Olleros, M., Chvatcko, Y., and Hadenbue, A. 2004. Circulating concentrations of interleukin-18, interleukin-18 binding protein, and g-interferon in patients with alcoholic hepatitis. Liver Int. 24:582-587.
81. Spitzer, J. A., Zhang, P., and Mayer, A. M. 1994. Functional characterization of peripheral circulating and liver recruited neutrophils in endotoxic rats. J. Leukoc. Biol. 56:166-173.
82. Stadlbauer, V., Mookerjee, R. P., Lidder, S., Hodges, S. J., Davies, N. A., Williams, R., and Jalan, R. 2006. Failure of neutrophil function in decompensated alcoholic cirrhosis predicts survival (Abstract). Hepatology 44:369A.
83. Sweet, M. J., and Hume, D. A. 1996. Endotoxin signal transduction in macrophages. J. Leukoc. Biol. 60:8-26.
84. Taieb, J., Mathurin, P., Elbim, C., Cluzel, P., Arce-Vicioso, M., Bernard, B., Opolon, P., Gougerot-Pocidalo, M. A., Poynard, T., and Chollet-Martin, S. 2000. Blood neutrophil functions and cytokine release in severe alcoholic hepatitis: effect of corticosteroids. J. Hepatol. 32:579-586.
85. Thurman, R. G., Bradford, B. U., Iimuro, Y., Knecht, K. T., Arteel, G. E., Yin, M., Connor, H. D., Wall, C., Raleigh, J. A., Frankenberg, M. V., Adachi, Y., Forman, D. T., Brenner, D., Kaiiska, M., and Mason, R. P. 1998. The role of gut-derived bacterial toxins and free radicals in alcohol-induced liver injury. J. Gastroenterol. Hepatol. 13:S39-50.
86. Tsukamoto, H., Horne, W., Kamimura, S., Niemela, O., Parkkila, S., Yla-Herttuala, S., and Brittenham, G. M. 1995. Experimental liver cirrhosis induced by alcohol and iron. J. Clin. Invest. 96:620-630.
87. Tsukamoto, H., Lin, M., Ohata, M., Giulivi, C., French, S. W., and Brittenham, G. 1999. Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury. Am. J. Physiol. 277:G1240-G1250.
88. Uesugi, T., Froh, M., Arteel, G. E., Bradford, B. U., Wheeler, M. D., Gabele, E., Isayama, F., and Thurman, R. G. 2002. Role of lipopolysaccharide- binding protein in early alcohol-induced injury in mice. J. Immunol. 168:2963-2969.
89. Uesugi, T., Yin, M., Bradford, B. U., Wheeler, M. D., Uesugi, T., Froh, M., Goyert, S. M., and Thurman, R. G. 2001. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34:101-108.
90. Witthaut, R., Farhood, A., Smith, C. W., and Jaeschke, H. 1994. Complement and tumor necrosis factor-alpha contribute to Mac-1 (CD11b-CD18) up-regulation and systemic neutrophil activation during endotoxemia in vivo. J. Leukoc. Biol. 55:105-111.
91. Wong, J., Johnston, B., Lee, S. S., Bullard, D. C., Smith, C. W., Beaudet, A. L., and Kubes, P. 1997. A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J. Clin. Invest. 99:2782-2790.
92. Xu, J., Lee, G., Wang, H., Vierling, J. M., and Maher, J. J. 2004. Limited role of CXC chemokines in the pathogenesis of anaphthylisothiocyanate- induced liver injury. Am. J. Physiol. Gastrointest. Liver Physiol. 287:G734-G741.
93. Yamaguchi, Y., Ohshiro, H., Nagao, Y., Odawara, K., Okabe, K., Hidaka, H., Ishihara, K., Uchino, S., Furuhashi, T., Yamada, S., Mori, K., and Ogawa, M. 2000. Urinary trypsin inhibitor reduces C-X-C chemokine production in rat liver ischemia/reperfusion. J. Surg. Res. 94:107-115.
94. Ziol, M., Tepper, M., Lohez, M., Arcangeli, G., Ganne, N., Christidis, C., Trinchet, J. C., Beaugrand, M., Guillet, J. G., and Guettier, C. 2001. Clinical and biological relevance of hepatocyte apoptosis in alcoholic hepatitis. J. Hepatol. 34:254-260.