TNFα is required for cholestasis-induced liver fibrosis in the mouse

TNFα, a mediator of hepatotoxicity in several animal models, is elevated in acute and chronic liver diseases. Therefore, we investigated whether hepatic injury and fibrosis due to bile duct ligation (BDL) would be reduced in TNFα knockout mice (TNFα−/−). Survival after BDL was 60% in wild-type mice (TNFα+/+) and 90% in TNFα−/− mice. Body weight loss and liver to body weight ratios were reduced in TNFα−/− mice compared to TNFα+/+ mice. Following BDL, serum alanine transaminases (ALT) levels were elevated in TNFα+/+ mice (268.6 ± 28.2 U/L) compared to TNFα−/− mice (105.9 U/L ± 24.4). TNFα −/− mice revealed lower hepatic collagen expression and less liver fibrosis in the histology. Further, α-smooth muscle actin, an indicator for activated myofibroblasts, and TGF-β mRNA, a profibrogenic cytokine, were markedly reduced in TNFα−/− mice compared to TNFα+/+ mice. Thus, our data indicate that TNFα induces hepatotoxicity and promotes fibrogenesis in the BDL model

Heme oxygenase-1 overexpression increases liver injury after bile duct ligation in rats

AIM: To investigate the effects of heme oxygenase-1 (HO-1) against oxidant-induced injury caused by bile duct ligation (BDL)

Overexpression of Manganese Superoxide Dismutase Prevents Alcohol-induced Liver Injury in the Rat

Mitochondria are thought to play a major role in hepatic oxidative stress associated with alcohol-induced liver injury. Thus, the hypothesis that delivery of the mitochondrial isoform of superoxide dismutase (Mn-SOD) via recombinant adenovirus would reduce alcohol-induced liver injury was tested. Rats were given recombinant adenovirus containing Mn-SOD (Ad.SOD2) or beta-galactosidase (Ad.lacZ) and then fed alcohol enterally for 4 weeks. Mn-SOD expression and activity of Ad.SOD2 in liver mitochondria of infected animals was increased nearly 3-fold compared with Ad.lacZ-infected controls. Mitochondrial glutathione levels in Ad.lacZ-infected animals were decreased after 4 weeks of chronic ethanol, as expected, but were unchanged in Ad.SOD2-infected animals. Alanine aminotransferase was elevated significantly by ethanol, an effect that was prevented by Ad.SOD2. Moreover, pathology (e.g. the sum of steatosis, inflammation, and necrosis) was elevated dramatically by ethanol in Ad.lacZ-treated rats. This effect was also blunted in animals infected with Ad.SOD2. Neutrophil infiltration was increased about 3-fold in livers from both Ad.lacZ- and Ad.SOD2-infected rats by ethanol treatment. Moreover, ESR-detectable free radical adducts in bile were increased about 8-fold by ethanol. Using (13)C-labeled ethanol, it was determined that nearly 60% of total adducts were due to the alpha-hydroxyethyl radical adduct. This increase in radical formation was blocked completely by Ad.SOD2 infection. Furthermore, apoptosis of hepatocytes was increased about 5-fold by ethanol, an effect also blocked by Ad.SOD2. Interestingly, tumor necrosis factor-alpha mRNA was elevated to the same extent in both Ad.lacZ- and Ad.SOD2-infected animals follows ethanol exposure. These data suggest that hepatocyte mitochondrial oxidative stress is involved in alcohol-induced liver damage and likely follows Kupffer cell activation, cytokine production, and neutrophil infiltration. These results also support the hypothesis that mitochondrial oxidant production is a critical factor in parenchymal cell death caused by alcohol

イシュ カンリュウ カン ニ オケル イシュ エキセイ ハンノウ ノ カン ヒジッシツ サイボウ エ ノ エイキョウ ト カン キノウ ヒョウカ

京都大学0048新制・課程博士博士(医学)甲第9479号医博第2492号新制||医||799(附属図書館)UT51-2002-G237京都大学大学院医学研究科外科系専攻(主査)教授 田中 紘一, 教授 千葉 勉, 教授 山岡 義生学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Quantitative Measurement of Electron Density in Method of Dual-Energy X-Ray CT

The electron density is indispensable to the treatment planning for heavy-ion radiotherapy, so that the precise measurement of that is important for advancing radiotherapy. Usually the electron density for the radiotherapy is derived from an image based on CT number by conventional CT. CT number include ambiguilty due to the beam hardening. In a method of dual-energy x-ray CT, the information on an electron density can be obtained directly using monochromatic x-rays. The precision of the electron density was experimentally proved to be about 1%.The 8th Conference on Biology and Synchrotron Radiatio

Study on Dual-Energy X-ray Computed Tomography using Synchrotron Radiation

The electron density is one of the most important element for thetreatment planning in the radiotherapy, because this information isused for the range estimation of the heavy-ion beam. Although theelectron density has been converted from CT number obtained byconventional x-ray computed tomography(CT) at present, it is notenough for the more detailed planning due to uncertainties that arisefrom the beam hardening effect and the conversion process. In order totake more accurate electron density, we have developed the dual-energyx-ray CT system using the synchrotron radiation. The dual-energy x-rayCT has no influence of the beam hardening because of scanning usingmonochromatic x-rays. The experiments were carried out using twomonochromatic x-rays at the monochromatic beam-lines in KEK-AR andSPring-8. As the result, it was succeeded that the electron densitiesby the dual-energy x-ray CT were agreement with the theoretical valueswith the accuracy less than 1% for some materials. In addition, as theapplication for more practical use in diagnostics, the CT using themixture of main and harmonics x-rays produced by the monochromator hasbeen investigated. From the preliminary experiments, it was found thatthe accuracy was as same as that by dual-energy x-ray CT. We willdescribe the dual-energy x-ray CT system and discuss thequantitativity and the image characteristic for this system.Eighth International Conference on Synchrotron Radiation Instrumentatio