The Research Institute at Nationwide Children's Hospital, Center for Clinical and Translational Research, Columbus, OH 43205, USA.
Lab Invest. 2012 May;92(5):703-12. doi: 10.1038/labinvest.2012.3. Epub 2012 Feb 13.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a cytoprotective agent in several organ systems but its roles in liver fibrosis are unclear. We studied the roles of HB-EGF in experimental liver fibrosis in mice and during hepatic stellate cell (HSC) activation. Thioacetamide (TAA; 100 mg/kg) was administered by intraperitoneal injection three times a week for 4 weeks to wild-type HB-EGF(+/+) or HB-EGF-null (HB-EGF(-/-)) male mice. Livers were examined for histology and expression of key fibrotic markers. Primary cultured HSCs isolated from untreated HB-EGF(+/+) or HB-EGF(-/-) mice were examined for fibrotic markers and/or cell migration either during culture-induced activation or after exogenous HB-EGF (100 ng/ml) treatment. TAA induced liver fibrosis in both HB-EGF(+/+) and HB-EGF(-/-) mice. Hepatic HB-EGF expression was decreased in TAA-treated HB-EGF(+/+) mice by 37.6% (P<0.05) as compared with animals receiving saline alone. HB-EGF(-/-) mice treated with TAA showed increased hepatic α-smooth muscle actin-positive cells and collagen deposition, and, as compared with HB-EGF(+/+) mice, TAA-stimulated hepatic mRNA levels in HB-EGF(-/-) mice were, respectively, 2.1-, 1.7-, 1.8-, 2.2-, 1.2- or 3.3-fold greater for α-smooth muscle actin, α1 chain of collagen I or III (COL1A1 or COL3A1), transforming growth factor-β1, connective tissue growth factor or tissue inhibitor of metalloproteinase-1 (P<0.05). HB-EGF expression was detectable in primary cultured HSCs from HB-EGF(+/+) mice. Both endogenous and exogenous HB-EGF inhibited HSC activation in primary culture, and HB-EGF enhanced HSC migration. These findings suggest that HB-EGF gene knockout in mice increases susceptibility to chronic TAA-induced hepatic fibrosis and that HB-EGF expression or action is associated with suppression of fibrogenic pathways in HSCs.
肝素结合表皮生长因子样生长因子（HB-EGF）在几个器官系统中是一种细胞保护剂，但它在肝纤维化中的作用尚不清楚。我们研究了 HB-EGF 在实验性肝纤维化小鼠模型和肝星状细胞（HSC）激活中的作用。硫代乙酰胺（TAA；100mg/kg）每周通过腹腔注射三次，连续 4 周给予野生型 HB-EGF(+/+)或 HB-EGF 敲除（HB-EGF(-/-)）雄性小鼠。检查肝脏的组织学和关键纤维化标志物的表达。从未处理的 HB-EGF(+/+)或 HB-EGF(-/-)小鼠中分离出原代培养的 HSC，在培养诱导激活期间或在外源性 HB-EGF（100ng/ml）处理后，检查纤维化标志物和/或细胞迁移。TAA 诱导 HB-EGF(+/+)和 HB-EGF(-/-)小鼠的肝纤维化。与单独接受盐水的动物相比，TAA 处理的 HB-EGF(+/+)小鼠的肝 HB-EGF 表达减少了 37.6%（P<0.05）。与 HB-EGF(+/+)小鼠相比，用 TAA 处理的 HB-EGF(-/-)小鼠的肝α-平滑肌肌动蛋白阳性细胞和胶原沉积增加，并且 TAA 刺激的 HB-EGF(-/-)小鼠肝 mRNA 水平分别为α-平滑肌肌动蛋白、I 型或 III 型胶原（COL1A1 或 COL3A1）、转化生长因子-β1、结缔组织生长因子或金属蛋白酶组织抑制剂-1 的 2.1、1.7、1.8、2.2、1.2 或 3.3 倍（P<0.05）。HB-EGF 在来自 HB-EGF(+/+)小鼠的原代培养的 HSC 中可检测到。内源性和外源性 HB-EGF 均抑制原代培养的 HSC 激活，HB-EGF 增强 HSC 迁移。这些发现表明，在小鼠中敲除 HB-EGF 基因增加了对慢性 TAA 诱导的肝纤维化的易感性，并且 HB-EGF 的表达或作用与 HSC 中纤维生成途径的抑制有关。
