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Tumor necrosis factor-alpha induces apoptosis of enterocytes in mice with fulminant hepatic failure
作者姓名:Song HL  Lu S  Liu P
作者单位:Hong-Li Song,Sa Lu,Pei Liu,Department of Infectious Diseases,The Second Affiliated Hospital,China Medical University,Shenyang 110004,Liaoning Province,China
基金项目:Supported by Research Foundation of Ministry of Public Health, No. 97100252
摘    要:AIM: To explore the alterations of intestinal mucosa morphology, and the effects of tumor necrosis factor a (TNFα) on enterocyte apoptosis in mice with fulminant hepatic failure (FHF). METHODS: Liver damage was induced by lipopolysaccharide (LPS)/TNF-α in D-galactosamine (GaIN) sensitized BALB/c mice. There were 40 mice in normal saline (NS)-treated group, 40 mice in LPS-treated group, 40 mice in GaIN-treated group, 120 mice in GaIN/ LPS-treated group and 120 mice in GaIN/ TNFα-treated group. Each group was divided into five subgroups of eight mice each. Serum samples and liver, intestinal tissues were respectively obtained at 2, 6,9,12 and 24 h after administration. Anti-TNFa monoclonal antibody was injected intravenously into GaIN/LPS-treated mice. Serum TNFα levels were determined by enzyme linked immunosorbent assays (ELISA). Serum ALT levels were determined using an automatic analyzer. The intestinal tissues were studied under light microscope and electron microscope at 2, 6, 9,12 and 24 h in mice with fulminant hepatic failure, respectively. Enterocyte apoptosis was determined by terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) method. The expression of tumor necrosis factor receptor 1 (TNFR1) in intestinal tissue was tested by immunohistochemistry Envision Two Steps. RESULTS: Gut mucosa was morphologically normal at all time points in all groups, but typical apoptotic cells could be seen in all experimental groups under electron microscope. Apoptosis rate of gut mucosal epithelial cells were significantly increased at 6, 9 and 12 h, peaked at 12 h in mice with fulminant hepatic failure. TNFa induced apoptosis of enterocytes in mice with FHF. The integrated OD (IOD) levels of TNFa receptor 1 protein expressed in the intestine of mice with GaIN/LPS and GaIN/ TNFα induced FHF at 2, 6, 9, 12 and 24 h after GaIN/LPS and GaIN/TNFα administration were 169.54±52.62/905.79±111.84,11 350.67±2 133.26/28 160.37±4 601.67, 25 781.00±2 277.75/122 352.30±49 412.40, 5 241.53±3 007.24/ 49 157.93±9 804.88, 7 086.13±1 031.15/3 283.45±127.67, respectively, compared with those in control groups (with NS, LPS and GaIN administration, respectively). IOD level of TNFR1 changed significantly at 6, 9 and 12 h after GaIN/LPS and GalN/TNFa administration. The expression of TNFR1 protein was significantly higher at 9 h after GaIN/LPS and GaIN/TNFα administration than that in control groups. Protein expression of TNFR1 was positively correlated with enterocyte apoptosis. CONCLUSION: TNFα can induce apoptosis of enterocytes in mice with FHF. Anti-TNFα IgG can inhibit this role.

关 键 词:Enterocyte  Apoptosis  Fulminant  hepatic  failure  TNFα  TNFR1  
收稿时间:2004 Jul 31

Tumor necrosis factor-alpha induces apoptosis of enterocytes in mice with fulminant hepatic failure
Song HL,Lu S,Liu P.Tumor necrosis factor-alpha induces apoptosis of enterocytes in mice with fulminant hepatic failure[J].World Journal of Gastroenterology,2005,11(24):3701-3709.
Authors:Song Hong-Li  Lu Sa  Liu Pei
Institution:Department of Infectious Diseases, The Second Affiliated Hospital, China Medical University, Shenyang 110004, Liaoning Province, China
Abstract:AIM: To explore the alterations of intestinal mucosa morphology, and the effects of tumor necrosis factor alpha (TNFalpha) on enterocyte apoptosis in mice with fulminant hepatic failure (FHF). METHODS: Liver damage was induced by lipopolysaccharide (LPS)/TNF-alpha in D-galactosamine (GalN) sensitized BALB/c mice. There were 40 mice in normal saline (NS)-treated group, 40 mice in LPS-treated group, 40 mice in GalN-treated group, 120 mice in GalN/ LPS-treated group and 120 mice in GalN/TNFalpha-treated group. Each group was divided into five subgroups of eight mice each. Serum samples and liver, intestinal tissues were respectively obtained at 2, 6, 9, 12 and 24 h after administration. Anti-TNFalpha monoclonal antibody was injected intravenously into GalN/LPS-treated mice. Serum TNFalpha levels were determined by enzyme-linked immunosorbent assays (ELISA). Serum ALT levels were determined using an automatic analyzer. The intestinal tissues were studied under light microscope and electron microscope at 2, 6, 9, 12 and 24 h in mice with fulminant hepatic failure, respectively. Enterocyte apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method. The expression of tumor necrosis factor receptor 1 (TNFR1) in intestinal tissue was tested by immunohistochemistry Envision Two Steps. RESULTS: Gut mucosa was morphologically normal at all time points in all groups, but typical apoptotic cells could be seen in all experimental groups under electron micro-scope. Apoptosis rate of gut mucosal epithelial cells were significantly increased at 6, 9 and 12 h, peaked at 12 h in mice with fulminant hepatic failure. TNFalpha induced apoptosis of enterocytes in mice with FHF. The integrated OD (IOD) levels of TNFalpha receptor 1 protein expressed in the intestine of mice with GalN/LPS and GalN/ TNFalpha-induced FHF at 2, 6, 9, 12 and 24 h after GalN/LPS and GalN/TNFalpha administration were 169.54+/-52.62/905.79+/-111.84, 11,350.67+/-2 ,133.26/28,160.37+/-4,601.67, 25,781.00 +/-2,277.75/122,352.30+/-49,412.40, 5,241.53+/-3,007.24/49,157.93+/-9,804.88, 7,086.13+/-1,031.15/3,283.45+/-127.67, respectively, compared with those in control groups (with NS, LPS and GalN administration, respectively). IOD level of TNFR1 changed significantly at 6, 9 and 12 h after GalN/LPS and GalN/TNFalpha administration. The expression of TNFR1 protein was significantly higher at 9 h after GalN/LPS and GalN/TNFalpha administration than that in control groups. Protein expression of TNFR1 was positively correlated with enterocyte apoptosis. CONCLUSION: TNFalpha can induce apoptosis of enterocytes in mice with FHF. Anti-TNFalpha IgG can inhibit this role.
Keywords:Enterocyte  Apoptosis  Fulminant hepatic failure  TNFα  TNFR1
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