The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis
The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis
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DOI：
10.1002/hep.22437
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发表时间：
2008-10-01
期刊：
影响因子：
13.5
通讯作者：
Avila, Matias A.
中科院分区：
文献类型：
--
作者：
Perugorria, Maria J.;Latasa, M. Ujue;Avila, Matias A.
肝损伤对慢性伤害性刺激的愈合反应可能导致肝纤维化，这是一种以细胞外基质过度沉积为特征的病症。纤维化细胞，包括肝星状细胞和肌成纤维细胞，响应于多种细胞因子、生长因子和炎症介质而被激活。表皮生长因子家族成员参与了这一过程。双调蛋白（AR）是一种表皮生长因子受体（EGFR）配体，在肝损伤时特异性诱导。在这里，我们讨论了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。检测肝纤维化的组织学和分子标志物。此外，还评价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表达在孤立的枯否细胞和肝纤维化细胞的炎症刺激和血小板源性生长因子，分别。我们证明，与AR+/+动物相比，AR-/-小鼠中α-平滑肌肌动蛋白的表达和胶原沉积显著减少。AR-/-小鼠还显示金属蛋白酶组织抑制剂-1和结缔组织生长因子的表达减少，这两个基因在培养的纤维化细胞中对AR治疗有反应。AR还刺激细胞增殖，并对分离的纤维化细胞产生有效的抗凋亡作用。结论：在不同EGFR配体中，AR在肝纤维化中发挥着特异性作用。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EGFR系统在肝纤维化中的作用。
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 CCl4 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 a-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.