Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis
Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis
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DOI：
10.1002/hep.510230538
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发表时间：
1996-05
期刊：
影响因子：
13.5
通讯作者：
G. S. Baroni;L. D’Ambrosio;P. Curto;A. Casini;R. Mancini;A. Jezequel;A. Benedetti
中科院分区：
文献类型：
--
作者：
G. S. Baroni;L. D’Ambrosio;P. Curto;A. Casini;R. Mancini;A. Jezequel;A. Benedetti
干扰素γ（IFN-γ）在体外抑制肝星状细胞（HSC）的活化，HSC是肝纤维化中主要的细胞外基质产生细胞。本研究旨在确定IFN-γ在二甲基亚硝胺（DMN）诱导的肝纤维化大鼠模型中的体内作用，其中HSC活化代表对细胞损伤的早期反应。用DMN、IFN-γ、DMN + IFN-γ或盐水处理1或3周后处死大鼠。使用免疫组织化学鉴定增殖（结蛋白阳性/溴脱氧尿苷（BrdU）阳性细胞）和活化（α-平滑肌肌动蛋白[α-SMA]阳性细胞）HSC。胶原沉积通过比色法和形态测定法测定。通过点计数技术测量结蛋白和肌动蛋白阳性细胞以及纤维化组织的实质延伸，并表示为面积百分比。蛋白质印迹法测定层粘连蛋白和纤连蛋白的积累。通过北方印迹法评价I型前胶原、纤连蛋白和层粘连蛋白的信使RNA（mRNA）水平。在单独用盐水或IFN-γ处理的大鼠中未观察到差异。IFN-γ减少了肝损伤诱导的HSC活化，表现为与DMN组相比，DMN + IFN-γ处理动物中观察到的增殖HSC数量减少和α-SMA阳性细胞占据的实质面积减少。这与DMN + IFN-γ组中胶原蛋白、层粘连蛋白和纤连蛋白蓄积减少以及I型前胶原蛋白、纤连蛋白和层粘连蛋白mRNA水平降低相关。因此，本研究表明IFN-γ通过抑制HSC活化减少体内细胞外基质沉积。
Interferon gamma (IFN‐γ) inhibits in vitro the activation of hepatic stellate cells (HSC), the primary extracellular matrix‐producing cells in liver fibrosis. This study was undertaken to determine in vivo the effect of IFN‐γ in the rat model of liver fibrosis induced by dimethylnitrosamine (DMN), where HSC activation represents an early response to cell injury. Rats were killed after 1 or 3 weeks of treatment with DMN, IFN‐γ, DMN + IFN‐γ, or saline. Immunohistochemistry was used to identify proliferating (desmin‐ positive/bromodeoxyuridine (BrdU)‐positive cells) and activated (α‐ smooth‐muscle actin [α‐SMA]‐positive cells) HSCs. Collagen deposition was determined colorimetrically and by morphometry. The parenchymal extension of desmin‐ and actin‐positive cells and of fibrotic tissue was measured by point‐counting technique and expressed as a percentage of area. Western blot was used to determine laminin and fibronectin accumulation. The levels of messenger RNA (mRNA) for procollagen type I, fibronectin, and laminin were evaluated by Northern blot. No differences were observed in rats treated with either saline or IFN‐γ alone. IFN‐γ reduced HSC activation induced by liver injury, as shown by the decreased number of proliferating HSC and the reduction of parenchymal area occupied by α‐SMA‐positive cells observed in DMN + IFN‐γ‐treated animals compared with the DMN group. This was associated with reduced collagen, laminin, and fibronectin accumulation and lower levels of mRNA for procollagen type I, fibronectin, and laminin in the DMN + IFN‐γ group. Thus, this study indicates that IFN‐γ reduces extracellular matrix deposition in vivo by inhibition of HSC activation.