Perugorria Maria J, Latasa M Ujue, Nicou Alexandra, Cartagena-Lirola Hugo, Castillo Josefa, Goñi Saioa, Vespasiani-Gentilucci Umberto, Zagami Maria G, Lotersztajn Sophie, Prieto Jesús, Berasain Carmen, Avila Matias A
Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Spain.
Hepatology. 2008 Oct;48(4):1251-61. doi: 10.1002/hep.22437.
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.
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.
肝脏对慢性有害刺激的伤口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。包括肝星状细胞和成肌纤维细胞在内的纤维化细胞会因多种细胞因子、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这一过程的情况已被提出。双调蛋白（AR）是一种在肝损伤时特异性诱导产生的表皮生长因子受体（EGFR）配体。在此，我们探讨了AR在实验性肝纤维化中的体内作用。为此，通过慢性给予四氯化碳在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志物。此外，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，分别响应炎症刺激和血小板衍生生长因子。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明显减少。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降低——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发挥强大的抗凋亡作用。
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系统在肝纤维化发生中的作用。
