Lobular - but not periovular - inhibition of collagen deposition in the liver of S-Mansoni infected mice using interferon-gamma
Lobular - but not periovular - inhibition of collagen deposition in the liver of S-Mansoni infected mice using interferon-gamma
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DOI：
10.1016/s0168-8278(97)80258-9
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发表时间：
1997-04-01
影响因子：
25.7
通讯作者：
Grimaud, JA
中科院分区：
文献类型：
--
作者：
Lortat-Jacob, H;Baltzer, F;Grimaud, JA
背景/目标：干扰素-γ（IFN-γ）在包括肝星状细胞（Ito细胞）在内的多种间充质细胞中增强抗增殖和抗纤维化活性，因此代表了治疗肝纤维化的可能药物。然而，IFN γ与硫酸乙酰肝素结合，并被这些分子定位在组织内的限制区域。例如，在大鼠肝脏中，已经显示在注射后，IFN γ被硫酸乙酰肝素浓缩在限制区域中。本研究的目的是分析，在肝脏组织水平，IFN γ的抗纤维化活性。方法：血吸虫感染引起的慢性炎症引起肝纤维化周围的寄生虫卵（门静脉纤维化）和肝实质（小叶纤维化）。感染小鼠用重组IFN γ治疗，并通过生化剂量、肝组织的组织学和形态学检查以及电子显微镜分析来评估肝脏的胶原含量。在对照组小鼠中，在卵周围发现胶原蛋白并浸润实质，与弥漫性炎症细胞阵列相关，而在治疗组小鼠中，胶原蛋白仅存在于卵周围并被致密的炎症细胞层包围。因此，在孤立的肉芽肿和剩余的实质中测量胶原蛋白。我们发现，IFN-γ强烈减少实质胶原蛋白（74%），但对肉芽肿胶原蛋白含量没有影响。结论：这些数据表明，IFN-γ并没有采取行动，在肝脏中的均匀方式。由于肉芽肿几乎完全没有硫酸乙酰肝素，这些数据可能表明，除其他假设外，结合IFN γ的硫酸乙酰肝素定位或介导肉芽肿外的细胞因子活性。
Background/Aims: Interferon-gamma (IFN gamma) elicits anti-proliferative and antifibrogenic activity in a variety of mesenchymal cells, including hepatic stellate cells (Ito cells), and therefore represents a possible drug for liver fibrosis. However, IFN gamma binds to heparan sulfate, and is localized by these molecules in a restricted area within the tissue. For example, in rat liver, it has been shown that following injection, IFN gamma was concentrated in a restricted area by heparan sulfate. The aim of this study was to analyze, at the tissular level in the liver, the antifibrogenic activity of IFN gamma.Methods: Chronic inflammation due to Schistosoma infection induces hepatic fibrogenesis around the parasite eggs (portal fibrosis) and in the parenchyma (lobular fibrosis). Infected mice were treated with recombinant IFN gamma, and the collagen content of the liver was evaluated by means of biochemical dosages, histologic and morphometric examination of liver tissue, and electron microscopic analysis.Results: IFN gamma reduced the whole liver collagen content by 28% compared to control mice. In control mice, collagen was found around eggs and infiltrating the parenchyma, associated with a diffuse array of inflammatory cells, while in treated mice the collagen was present only around eggs and surrounded by a dense layer of inflammatory cells. Therefore, collagen was measured in isolated granulomas and in the remaining parenchyma. We found that IFN gamma strongly reduced the parenchymal collagen (74%), but had no effect on the granuloma collagen content.Conclusions: Together these data demonstrate that IFN gamma did not act in a homogeneous manner in the liver. Since granulomas are almost completely devoid of heparan sulfate, these data could suggest, among others hypotheses, that heparan sulfate which binds IFN gamma either localizes or mediates the cytokine activity outside the granulomas.