AASLD 2011: Vitamin D has a protective antifibrotic effect in rat model of liver

StephenW

Vitamin D has a protective antifibrotic effect in rat model of liver fibrosis
S. Reif1, 2; A. Bentov1, 2; E. Sharvit1, 2; E. Brazowski3; Y. Weisman1; S. Abramovitch1, 2
1. Department of Pediatrics, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel.
2. Pediatric Gastroenterology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.
3. Pathology, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel.

Background and Aim: In our previous In vitro study, we showed that HSCs proliferation induced by PDGF was suppressed by vitamin D. In addition, collagen I?1 promoter activity, mRNA and protein expression levels were all down-regulated after treatment with vitamin D. Furthermore, exposure to vitamin D led to up-regulation of MMP-9 activity and suppression of TIMP1 mRNA levels. Therefore, in the present study, we investigate the potential of vitamin D treatment to prevent development of liver fibrosis in in vivo model.
Methods: Rats were divided into four groups: no treatment (control), TAA treatment, vitamin D treatment and TAA with vitamin D treatment. Liver fibrosis was induced in rats by administration of thioacetamid (TAA) (200mg/Kg, i.p., twice weekly) for 10 weeks. Treatment with vitamin D (5?g/Kg i.p., twice weekly) was simultaneously given with TAA. Hepatic fibrosis scores were determinate after staining with hematoxylin & eosin and sirius-red. Collagen I deposition was determent following sirius-red staining. ?SMA expression was detected by western blotting
Results: Macroscopically, TAA treated group developed cirrhosis. However, rats received TAA with vitamin D treatment, showed almost normal morphology. Microscopically, the hepatic fibrosis score of the TAA treatment group was 3.9 + 0.1, while rats treated with TAA and vitamin D demonstrated only mild fibrosis and scored of 2.3 + 0.3 (P<0.05). No fibrosis was observed in the control rats or the group received vitamin D alone. Quantification of collagen content, following sirius-red staining demonstrated increased collagen deposition in rats treated with TAA by 16-fold compared to the untreated group. However, administration of TAA with vitamin D significantly decreased collagen levels by 4-fold compared to the TAA group. TAA treatment increased ?SMA expression to ~160%, while addition of vitamin D suppressed ?SMA expression to the control level. Neither hypercalcemia nor renal toxicity was found in rats receiving vitamin D treatment.
Conclusions: These results suggest that treatment of vitamin D can inhibit the development of cirrhosis in a rat model. Hence, vitamin D may play an important role in preventive treatment for liver fibrosis, and may have a potential therapy.                           



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StephenW

维生素D在大鼠肝纤维化模型的保护抗肝纤维化作用
S.赖夫1，2; A. Bentov 1，2; E. Sharvit 1，2; E. Brazowski 3; Y.韦斯曼1，S.阿布拉莫维奇1，2
1。儿科，特拉维夫Sourasky医学中心，特拉维夫，以色列。
2。小儿消化科，特拉维夫，以色列特拉维夫Sourasky医学中心。
3。病理学，特拉维夫Sourasky医学中心，以色列特拉维夫。

背景和目标：在我们以前的体外研究，我们发现，维生素D抑制PDGF诱导的HSC增殖，此外，胶原蛋白1启动子的活性，mRNA和蛋白表达水平都下调后，与维生素D治疗此外，暴露于维生素D导致MMP - 9活性和抑制TIMP1 mRNA水平的上调。因此，在本研究中，我们探讨维生素D治疗，以防止在体内模型肝纤维化的发展的潜力。
方法：没有治疗（对照组），维生素D治疗和TAA与维生素D治疗，治疗的TAA：大鼠分为四组。肝纤维化是诱发大鼠10周thioacetamid（TAA）（经口200mg/kg，IP，每周两次）行政。同时给予维生素D（5克/公斤的IP，每周两次）治疗的TAA。肝纤维化评分与苏木精和曙红和天狼星红染色后确定的。 I型胶原沉积determent以下天狼星红染色。 SMA的表达，Western印迹检测
结果：从宏观，TAA治疗组开发肝硬化。然而，与维生素D治疗的大鼠，TAA，表明几乎正常形态。镜下的TAA治疗组肝纤维化评分为3.9 ± 0.1，而与TAA和维生素D治疗组大鼠表明，只有轻度纤维化和2.3 ± 0.3（P <0.05）得分。在对照组无纤维化或本集团仅获得维生素D。胶原蛋白含量的定量分析后，天狼星红染色显示胶原沉积增加16倍，在治疗的TAA大鼠相比，模型组。然而，与维生素D的TAA管理显著下降了4倍相比，TAA组的胶原蛋白水平。增加TAA的治疗SMA的表达〜160％，同时添加维生素D抑制？SMA表达的控制水平。无论是高钙血症，也不被发现在接受维生素D治疗大鼠肾毒性。
结论：这些结果表明，维生素D治疗可以抑制肝硬化的大鼠模型中的发展。因此，维生素D可能发挥预防性治疗肝纤维化的重要作用，并可能有潜在的治疗。