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研究生(外文):Heng-Cheng Chu
論文名稱(外文):The Effects of Minocycline on Fas-Mediated Fulminant Hepatitis in Mice
指導教授(外文):You-Chen ChaoChing-Len LiaoHuey-Kang Sytwu
中文關鍵詞:猛爆性肝炎minocyclineFascaspasecytochrome c粒腺體
外文關鍵詞:Fulminant hepatitisminocyclineFascaspasecytochrome cmitochondria
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1.Minocycline在軟骨、神經與牙周組織中具有抗發炎與抗細胞凋亡 (antiapoptotic) 之功效;而此二特性在肝臟疾病之治療製藥學發展上實扮演著樞紐性之角色。因此,我們評估minocycline對於C57BL/6J小鼠經由投予致死劑量之作用型anti-Fas單株抗體 (Jo2)所引起之猛爆性肝炎的影響。
2.藉由腹腔注射每克體重零點六微克之Jo2 抗體導致小鼠發生猛爆性肝炎,其血清中之丙氨酸轉胺酶和天門冬氨酸鹽轉胺酶(alanine/aspartate transaminase)活性因而上升,肝臟之組織結構隨之改變,進而使生物體產生死亡。不過,小鼠經預處理三劑之minocycline(每公斤體重五毫克)卻能有效地減緩此致死效應。此外,若在給予小鼠致死劑量之Jo2抗體的同時,或是延遲三十分鐘後投予minocycline,雖然不若預處理般效果明顯,仍然可以改善小鼠之存活曲線。
3.Jo2抗體所誘發之小鼠肝臟中caspase-3與caspase-9的活化,能被minocycline預處理所抑制。然而,直接將minocycline 加入到從Jo2抗體注射後之小鼠所分離出的肝臟萃取物中,並無法阻斷生物體外(in vitro)caspase之活化。 此外, minocycline能有效地抑制Jo2抗體所引發之小鼠肝臟粒腺體cytochrome c的釋放。然而,minocycline預處理並無法緩解Jo2抗體所觸發之caspase-8之活化與Bid蛋白質的裂解。
4.我們的結果顯示minocycline對於Fas接受體媒介之猛爆性肝炎的保護作用牽涉到粒腺體之細胞凋亡路徑,可能藉由阻斷cytochrome c之釋放,因而避免下游caspase之活化。

1.Minocycline has anti-inflammatory and anti-apoptotic effects on cartilage, neurons and periodontal tissues, and both properties are central to the pharmaceutical treatment of liver diseases. We investigated the effects of minocycline on fulminant hepatitis in C57BL/6J mice induced by lethal challenge of the activating anti-Fas antibody, Jo2.
2.Intraperitoneal injection of Jo2 (0.6ug g-1) to mice resulted in fulminant hepatitis, as evidenced by increase of serum alanine/aspartate transaminase activities and histopathological alterations in liver sections, as well as animal death. Nevertheless, mice pretreated with three doses of minocycline (5 mg kg -1) resisted this lethal effect significantly. Minocycline treatment improved the survival kinetics, although to a lesser extent, when mice were challenged simultaneously with Jo2 or even treated 30 min after the lethal challenge.
3.Jo2-induced activation of caspase-3 or -9 in liver tissues was inhibited by minocycline pretreatment, and yet the direct addition of minocycline to liver extracts from Jo2-challenged mice failed to block caspase activation in vitro. Moreover, minocycline efficiently suppressed the release of cytochrome c from mitochondria of the liver tissues from Jo2-challenged mice. In contrast, the activation of caspase-8 or truncation of Bid by Jo2 was not mitigated with minocycline pretreatment in mouse livers.
4.Our results suggest that easing of Fas-triggered fulminant hepatitis by minocycline may involve a mitochondrial apoptotic pathway, probably through preventing cytochrome c release and thereby blocking downstream caspase activation.

Full Article
General Pharmacology and Pharmacy
Division of Gastroenterology and Hepatology

AMIN, A.R., ATTUR, M.G., THAKKER, G.D., PATEL, P.D., VYAS, P.R., PATEL, R.N., PATEL, I.R. & ABRAMSON, S.B. (1996). A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci U S A, 93, 14014-9.
ANDO, K., MORIYAMA, T., GUIDOTTI, L.G., WIRTH, S., SCHREIBER, R.D., SCHLICHT, H.J., HUANG, S.N. & CHISARI, F.V. (1993). Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis. J Exp Med, 178, 1541-54.
ASHKENAZI, A. & DIXIT, V.M. (1998). Death receptors: signaling and modulation. Science, 281, 1305-8.
ATILLASOY, E. & BERK, P.D. (1995). Fulminant hepatic failure: pathophysiology, treatment, and survival. Annu Rev Med, 46, 181-91.
BAJT, M.L., LAWSON, J.A., VONDERFECHT, S.L., GUJRAL, J.S. & JAESCHKE, H. (2000). Protection against Fas receptor-mediated apoptosis in hepatocytes and nonparenchymal cells by a caspase-8 inhibitor in vivo: evidence for a postmitochondrial processing of caspase-8. Toxicol Sci, 58, 109-17.
BOCKER, R., ESTLER, C.J. & LUDEWIG-SANDIG, D. (1991). Evaluation of the hepatotoxic potential of minocycline. Antimicrob Agents Chemother, 35, 1434-6.
BROGDEN, R.N., SPEIGHT, T.M. & AVERY, G.S. (1975). Minocycline: A review of its antibacterial and pharmacokinetic properties and therapeutic use. Drugs, 9, 251-91.
CHANG, B., NISHIKAWA, M., SATO, E. & INOUE, M. (2003). Mice lacking inducible nitric oxide synthase show strong resistance to anti-Fas antibody-induced fulminant hepatitis. Arch Biochem Biophys, 411, 63-72.
CHEN, M., ONA, V.O., LI, M., FERRANTE, R.J., FINK, K.B., ZHU, S., BIAN, J., GUO, L., FARRELL, L.A., HERSCH, S.M., HOBBS, W., VONSATTEL, J.P., CHA, J.H. & FRIEDLANDER, R.M. (2000). Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med, 6, 797-801.
DU, Y., MA, Z., LIN, S., DODEL, R.C., GAO, F., BALES, K.R., TRIARHOU, L.C., CHERNET, E., PERRY, K.W., NELSON, D.L., LUECKE, S., PHEBUS, L.A., BYMASTER, F.P. & PAUL, S.M. (2001). Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease. Proc Natl Acad Sci U S A, 98, 14669-74.
FELDMANN, G., HAOUZI, D., MOREAU, A., DURAND-SCHNEIDER, A.M., BRINGUIER, A., BERSON, A., MANSOURI, A., FAU, D. & PESSAYRE, D. (2000). Opening of the mitochondrial permeability transition pore causes matrix expansion and outer membrane rupture in Fas-mediated hepatic apoptosis in mice. Hepatology, 31, 674-83.
GALLE, P.R., HOFMANN, W.J., WALCZAK, H., SCHALLER, H., OTTO, G., STREMMEL, W., KRAMMER, P.H. & RUNKEL, L. (1995). Involvement of the CD95 (APO-1/Fas) receptor and ligand in liver damage. J Exp Med, 182, 1223-30.
GOLUB, L.M., GOODSON, J.M., LEE, H.M., VIDAL, A.M., MCNAMARA, T.F. & RAMAMURTHY, N.S. (1985a). Tetracyclines inhibit tissue collagenases. Effects of ingested low-dose and local delivery systems. J Periodontol, 56, 93-7.
GOLUB, L.M., WOLFF, M., LEE, H.M., MCNAMARA, T.F., RAMAMURTHY, N.S., ZAMBON, J. & CIANCIO, S. (1985b). Further evidence that tetracyclines inhibit collagenase activity in human crevicular fluid and from other mammalian sources. J Periodontal Res, 20, 12-23.
GOUGH, A., CHAPMAN, S., WAGSTAFF, K., EMERY, P. & ELIAS, E. (1996). Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. Bmj, 312, 169-72.
GREEN, D.R. (1998). Apoptotic pathways: the roads to ruin. Cell, 94, 695-8.
GREEN, D.R. & REED, J.C. (1998). Mitochondria and apoptosis. Science, 281, 1309-12.
GREENWALD, R.A., GOLUB, L.M., LAVIETES, B., RAMAMURTHY, N.S., GRUBER, B., LASKIN, R.S. & MCNAMARA, T.F. (1987). Tetracyclines inhibit human synovial collagenase in vivo and in vitro. J Rheumatol, 14, 28-32.
HIRAMATSU, N., HAYASHI, N., KATAYAMA, K., MOCHIZUKI, K., KAWANISHI, Y., KASAHARA, A., FUSAMOTO, H. & KAMADA, T. (1994). Immunohistochemical detection of Fas antigen in liver tissue of patients with chronic hepatitis C. Hepatology, 19, 1354-9.
KLEIN, N.C. & CUNHA, B.A. (1995). Tetracyclines. Med Clin North Am, 79, 789-801.
LACRONIQUE, V., MIGNON, A., FABRE, M., VIOLLET, B., ROUQUET, N., MOLINA, T., PORTEU, A., HENRION, A., BOUSCARY, D., VARLET, P., JOULIN, V. & KAHN, A. (1996). Bcl-2 protects from lethal hepatic apoptosis induced by an anti-Fas antibody in mice. Nat Med, 2, 80-6.
LAWRENSON, R.A., SEAMAN, H.E., SUNDSTROM, A., WILLIAMS, T.J. & FARMER, R.D. (2000). Liver damage associated with minocycline use in acne: a systematic review of the published literature and pharmacovigilance data. Drug Saf, 23, 333-49.
LI, H., ZHU, H., XU, C.J. & YUAN, J. (1998). Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell, 94, 491-501.
LI, P., NIJHAWAN, D., BUDIHARDJO, I., SRINIVASULA, S.M., AHMAD, M., ALNEMRI, E.S. & WANG, X. (1997). Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 91, 479-89.
LIN, S., WEI, X., XU, Y., YAN, C., DODEL, R., ZHANG, Y., LIU, J., KLAUNIG, J.E., FARLOW, M. & DU, Y. (2003). Minocycline blocks 6-hydroxydopamine-induced neurotoxicity and free radical production in rat cerebellar granule neurons. Life Sci, 72, 1635-41.
LUO, X., BUDIHARDJO, I., ZOU, H., SLAUGHTER, C. & WANG, X. (1998). Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell, 94, 481-90.
MALASSAGNE, B., FERRET, P.J., HAMMOUD, R., TULLIEZ, M., BEDDA, S., TREBEDEN, H., JAFFRAY, P., CALMUS, Y., WEILL, B. & BATTEUX, F. (2001). The superoxide dismutase mimetic MnTBAP prevents Fas-induced acute liver failure in the mouse. Gastroenterology, 121, 1451-9.
MALCOLM, A., HEAP, T.R., ECKSTEIN, R.P. & LUNZER, M.R. (1996). Minocycline-induced liver injury. Am J Gastroenterol, 91, 1641-3.
MIYACHI, Y., YOSHIOKA, A., IMAMURA, S. & NIWA, Y. (1986). Effect of antibiotics on the generation of reactive oxygen species. J Invest Dermatol, 86, 449-53.
OGASAWARA, J., WATANABE-FUKUNAGA, R., ADACHI, M., MATSUZAWA, A., KASUGAI, T., KITAMURA, Y., ITOH, N., SUDA, T. & NAGATA, S. (1993). Lethal effect of the anti-Fas antibody in mice. Nature, 364, 806-9.
OKAMOTO, T. (1999). Pentoxifylline inhibits anti-Fas antibody-induced hepatitis by affecting downstream of CPP32-like activity in mice. Int J Mol Med, 4, 601-3.
OKAMOTO, T. (2000). The protective effect of glycyrrhizin on anti-Fas antibody-induced hepatitis in mice. Eur J Pharmacol, 387, 229-32.
OKAMOTO, T., KAWASAKI, T. & HINO, O. (2003). Osthole prevents anti-Fas antibody-induced hepatitis in mice by affecting the caspase-3-mediated apoptotic pathway. Biochem Pharmacol, 65, 677-81.
PETER, M.E. & KRAMMER, P.H. (1998). Mechanisms of CD95 (APO-1/Fas)-mediated apoptosis. Curr Opin Immunol, 10, 545-51.
REED, J.C. (2001). Apoptosis-regulating proteins as targets for drug discovery. Trends Mol Med, 7, 314-9.
RODRIGUEZ, I., MATSUURA, K., KHATIB, K., REED, J.C., NAGATA, S. & VASSALLI, P. (1996a). A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection. J Exp Med, 183, 1031-6.
RODRIGUEZ, I., MATSUURA, K., ODY, C., NAGATA, S. & VASSALLI, P. (1996b). Systemic injection of a tripeptide inhibits the intracellular activation of CPP32-like proteases in vivo and fully protects mice against Fas-mediated fulminant liver destruction and death. J Exp Med, 184, 2067-72.
SADOWSKI, T. & STEINMEYER, J. (2001). Minocycline inhibits the production of inducible nitric oxide synthase in articular chondrocytes. J Rheumatol, 28, 336-40.
SAIVIN, S. & HOUIN, G. (1988). Clinical pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet, 15, 355-66.
SANCHEZ MEJIA, R.O., ONA, V.O., LI, M. & FRIEDLANDER, R.M. (2001). Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. Neurosurgery, 48, 1393-9; discussion 1399-401.
SCAFFIDI, C., FULDA, S., SRINIVASAN, A., FRIESEN, C., LI, F., TOMASELLI, K.J., DEBATIN, K.M., KRAMMER, P.H. & PETER, M.E. (1998). Two CD95 (APO-1/Fas) signaling pathways. Embo J, 17, 1675-87.
SCAFFIDI, C., SCHMITZ, I., ZHA, J., KORSMEYER, S.J., KRAMMER, P.H. & PETER, M.E. (1999). Differential modulation of apoptosis sensitivity in CD95 type I and type II cells. J Biol Chem, 274, 22532-8.
SEINO, K., SETOGUCHI, Y., OGINO, T., KAYAGAKI, N., AKIBA, H., NAKANO, H., TANIGUCHI, H., TAKADA, Y., YUZAWA, K., TODOROKI, T., FUKUCHI, Y., YAGITA, H., OKUMURA, K. & FUKAO, K. (2001). Protection against Fas-mediated and tumor necrosis factor receptor 1-mediated liver injury by blockade of FADD without loss of nuclear factor-kappaB activation. Ann Surg, 234, 681-8.
SONG, E., LEE, S.K., WANG, J., INCE, N., OUYANG, N., MIN, J., CHEN, J., SHANKAR, P. & LIEBERMAN, J. (2003). RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med, 9, 347-51.
STRAND, S., HOFMANN, W.J., GRAMBIHLER, A., HUG, H., VOLKMANN, M., OTTO, G., WESCH, H., MARIANI, S.M., HACK, V., STREMMEL, W., KRAMMER, P.H. & GALLE, P.R. (1998). Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis. Nat Med, 4, 588-93.
TILLEY, B.C., ALARCON, G.S., HEYSE, S.P., TRENTHAM, D.E., NEUNER, R., KAPLAN, D.A., CLEGG, D.O., LEISEN, J.C., BUCKLEY, L., COOPER, S.M. & ET AL. (1995). Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group. Ann Intern Med, 122, 81-9.
WHELAN, J. (2002). Caspase inhibitors for liver disease. Drug Discov Today, 7, 444-5.
WOO, M., HAKEM, A., ELIA, A.J., HAKEM, R., DUNCAN, G.S., PATTERSON, B.J. & MAK, T.W. (1999). In vivo evidence that caspase-3 is required for Fas-mediated apoptosis of hepatocytes. J Immunol, 163, 4909-16.
YAMAMOTO, M., MIURA, N., OHTAKE, N., AMAGAYA, S., ISHIGE, A., SASAKI, H., KOMATSU, Y., FUKUDA, K., ITO, T. & TERASAWA, K. (2000). Genipin, a metabolite derived from the herbal medicine Inchin-ko-to, and suppression of Fas-induced lethal liver apoptosis in mice. Gastroenterology, 118, 380-9.
YIN, X.M., WANG, K., GROSS, A., ZHAO, Y., ZINKEL, S., KLOCKE, B., ROTH, K.A. & KORSMEYER, S.J. (1999). Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature, 400, 886-91.
YRJANHEIKKI, J., KEINANEN, R., PELLIKKA, M., HOKFELT, T. & KOISTINAHO, J. (1998). Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci U S A, 95, 15769-74.
YRJANHEIKKI, J., TIKKA, T., KEINANEN, R., GOLDSTEINS, G., CHAN, P.H. & KOISTINAHO, J. (1999). A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A, 96, 13496-500.
ZENDER, L., HUTKER, S., LIEDTKE, C., TILLMANN, H.L., ZENDER, S., MUNDT, B., WALTEMATHE, M., GOSLING, T., FLEMMING, P., MALEK, N.P., TRAUTWEIN, C., MANNS, M.P., KUHNEL, F. & KUBICKA, S. (2003). Caspase 8 small interfering RNA prevents acute liver failure in mice. Proc Natl Acad Sci U S A, 100, 7797-802.
ZHANG, H., COOK, J., NICKEL, J., YU, R., STECKER, K., MYERS, K. & DEAN, N.M. (2000). Reduction of liver Fas expression by an antisense oligonucleotide protects mice from fulminant hepatitis. Nat Biotechnol, 18, 862-7.
ZHANG, H., TAYLOR, J., LUTHER, D., JOHNSTON, J., MURRAY, S., WYATT, J.R., WATT, A.T., KOO, S., YORK-DEFALCO, C., STECKER, K. & DEAN, N.M. (2003). Antisense Oligonucleotide Inhibition of Bcl-xL and Bid Expression in Liver Regulates Responses in a Mouse Model of Fas-Induced Fulminant Hepatitis. J Pharmacol Exp Ther, 31, 31.
FRIEDLANDER, R.M. (2002). Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature, 417, 74-8.

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