Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice
Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice
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DOI：
10.1038/labinvest.2008.91
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发表时间：
2008-11-01
影响因子：
5
通讯作者：
Roeb, Elke
中科院分区：
文献类型：
--
作者：
Palacios, Rebeca Salguero;Roderfeld, Martin;Roeb, Elke
硫代乙酰胺（TAA）诱导的肝纤维化的病理生理机制尚未完全了解。特别是，肝星状细胞（HSC）的作用仍不清楚。因此，我们研究了HSC的增殖和转分化以及TAA诱导的纤维化的潜在分子机制。通过在饮用水中添加TAA诱导小鼠肝纤维化。通过评估丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平以及测量胶原沉积来确定肝损伤。此外，α-平滑肌肌动蛋白、胶质细胞酸性蛋白、（GFAP，HSC的特异性肝脏生物标志物），富含半胱氨酸和甘氨酸的蛋白2（CRP 2，HSC转分化的特异性标志物）、金属蛋白酶组织抑制剂-1、基质金属蛋白酶-9（MMP-9）、白细胞介素通过实时PCR评估IL-1 β、IL-6、血小板衍生生长因子（PDGF-B、PDGF-D）、肿瘤坏死因子（TNF）-α和转化生长因子（TGF）-β 1。GFAP和CRP 2的转录在TAA诱导的纤维形成过程中瞬时上调（最大点（p.m.）GFAP为第10周，CRP 2为第14周）。IL-1 β、IL-6、TGF-β 1和PDGF-B也表现出类似的瞬时表达模式（下午）。第12周），而TNF-α和PDGF-D随着持续的肝损伤而持续增加。特别是，不仅中性粒细胞，而且巨噬细胞和白细胞作为MMP-9表达的主要来源。GFAP和CRP 2表达模式表明短暂增加的HSC激活过程中TAA诱导的肝纤维化。GFAP转录的增加率与PDGF-B的相关性最好，而CRP 2水平与PDGF-B、PDGF-D和IL-1b表达相关。本研究首次证实了在毒性诱导的肝纤维化中观察到短暂增加的HSC活化模式。因此，饮用水中的TAA是诱导小鼠肝纤维化的可再现状态而无实质损伤的有效且优雅的模型。
The pathophysiological mechanisms of thioacetamide (TAA)-induced hepatic fibrogenesis are not yet fully understood. In particular, the role of hepatic stellate cells (HSCs) remains unclear. We therefore examined proliferation and transdifferentiation of HSC as well as the underlying molecular mechanisms in TAA-induced fibrosis. Hepatic fibrogenesis was induced in mice by addition of TAA to drinking water. Liver damage was determined by assessment of alanine aminotransferase and aspartate aminotransferase levels, and measurement of collagen deposition. Additionally, expression patterns of alpha-smooth muscle actin, glial fibrillary acidic protein (GFAP, specific hepatic biomarker for HSC), cysteine-and glycine-rich protein 2 (CRP2, specific marker of HSC transdifferentiation), tissue inhibitor of metalloproteinases-1, matrix metalloproteinase-9 (MMP-9), interleukins (IL-1 beta, IL-6), platelet-derived growth factors (PDGF-B, PDGF-D), tumor necrosis factor (TNF)-alpha, and (transforming growth factor (TGF)-beta 1 were assessed by real-time PCR. Transcription of GFAP and CRP2 were transiently upregulated during TAA-induced fibrogenesis (punctum maxima (p. m.) week 10 for GFAP and week 14 for CRP2). Similar transient expression patterns were demonstrated for IL-1 beta, IL-6, TGF-beta 1, and PDGF-B (p. m. week 12) whereas TNF-alpha and PDGF-D continuously increased with ongoing liver injury. In particular, not only neutrophil granulocytes, but also macrophages and leukocytes served as a major source for MMP-9 expression. GFAP and CRP2 expression patterns demonstrated transiently increased HSC-activation during TAA-induced hepatic fibrogenesis. The rate of increase of transcription of GFAP correlated best with PDGF-B, whereas CRP2 levels correlated with PDGF-B, PDGF-D, and IL-1b expression. This study demonstrates for the first time that transiently increased activation patterns of HSC are observed in toxically induced hepatic fibrosis. Thus, TAA in drinking water is an effective and elegant model to induce reproducible states of liver fibrosis without parenchymal damage in mice.