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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis.
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The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis.

机译：表皮生长因子受体配体双调蛋白参与小鼠肝纤维化的发展。

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摘要

The hepatic wound-healing response to chronic noxious stimuli may lead to liver fibrosis, a condition characterized by excessive deposition of extracellular matrix. Fibrogenic cells, including hepatic stellate cells and myofibroblasts, are activated in response to a variety of cytokines, growth factors, and inflammatory mediators. The involvement of members of the epidermal growth factor family in this process has been suggested. Amphiregulin (AR) is an epidermal growth factor receptor (EGFR) ligand specifically induced upon liver injury. Here, we have addressed the in vivo role of AR in experimental liver fibrosis. To this end, liver fibrosis was induced in AR+/+ and AR-/- mice by chronic CCl(4) administration. Histological and molecular markers of hepatic fibrogenesis were measured. Additionally, the response of cultured human and mouse liver fibrogenic cells to AR was evaluated. We observed that AR was expressed in isolated Kupffer cells and liver fibrogenic cells in response to inflamatory stimuli and platelet-derived growth factor, respectively. We demonstrate that the expression of alpha-smooth muscle actin and collagen deposition were markedly reduced in AR-/- mice compared to AR+/+ animals. AR-/- mice also showed reduced expression of tissue inhibitor of metalloproteinases-1 and connective tissue growth factor, two genes that responded to AR treatment in cultured fibrogenic cells. AR also stimulated cell proliferation and exerted a potent antiapoptotic effect on isolated fibrogenic cells. CONCLUSION: These results indicate that among the different EGFR ligands, AR plays a specific role in liver fibrosis. AR may contribute to the expression of fibrogenic mediators, as well as to the growth and survival of fibrogenic cells. Additionally, our data lend further support to the role of the EGFR system in hepatic fibrogenesis.
机译：肝脏对慢性有害刺激的伤口愈合反应可能导致肝纤维化，其特征是细胞外基质过多沉积。响应于各种细胞因子，生长因子和炎性介质，纤维化细胞（包括肝星状细胞和成肌纤维细胞）被激活。已经提出表皮生长因子家族成员参与该过程。双调蛋白（AR）是一种表皮生长因子受体（EGFR）配体，在肝损伤后被特异性诱导。在这里，我们已经解决了AR在实验性肝纤维化中的体内作用。为此，通过慢性CCl（4）给药在AR + / +和AR-/-小鼠中诱导肝纤维化。测量了肝纤维化的组织学和分子标记。另外，评估了培养的人和小鼠肝纤维化细胞对AR的反应。我们观察到，AR分别在分离的库普弗细胞和肝纤维化细胞中表达，分别响应于炎症刺激和血小板衍生的生长因子。我们证明，与AR + / +动物相比，AR-/-小鼠的α-平滑肌肌动蛋白和胶原沉积的表达明显减少。 AR-/-小鼠还显示出金属蛋白酶-1和结缔组织生长因子的组织抑制剂的表达降低，这两个基因在培养的纤维化细胞中对AR产生了反应。 AR还刺激细胞增殖，并对分离的成纤维细胞产生有效的抗凋亡作用。结论：这些结果表明，在不同的EGFR配体中，AR在肝纤维化中起特定作用。 AR可能有助于纤维化介质的表达以及纤维化细胞的生长和存活。此外，我们的数据进一步支持了EGFR系统在肝纤维化中的作用。

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