Sakamoto Kouichi, Khai Ngin Cin, Wang Yuqing, Irie Rie, Takamatsu Hideo, Matsufuji Hiroshi, Kosai Ken-Ichiro
Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
Department of Pediatric Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan.
Int J Mol Med. 2016 Dec;38(6):1673-1682. doi: 10.3892/ijmm.2016.2784. Epub 2016 Oct 20.
In contrast to hepatocyte growth factor (HGF), the therapeutic potential and pathophysiologic roles of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in liver diseases remain relatively unknown. To address the lack of effective pharmacologic treatments for cholestatic liver injuries, as well as to clarify the biologic features of these growth factors, we explored the effects of HB-EGF and HGF in mice with cholestatic liver injury induced by bile duct ligation (BDL). The mice were assessed 3, 5 and/or 14 days after BDL (acute, subacute and/or chronic phases, respectively) and intravenous injection of adenoviral vector expressing LacZ (control), HB-EGF, HGF, or HB-EGF and HGF. HB-EGF, HGF, or a combination of the growth factors exerted potent antioncotic (antinecrotic), antiapoptotic, anticholestatic, and regenerative effects on hepatocytes in vivo, whereas no robust antiapoptotic or regenerative effects were detected in interlobular bile ducts. Based on serum transaminase levels, the acute protective effects of HB-EGF on hepatocytes were greater than those of HGF. On the other hand, liver fibrosis and cholestasis during the chronic phase were more potently inhibited by HGF compared with HB-EGF. Compared with either growth factor alone, combining HB-EGF and HGF produced greater anticholestatic and regenerative effects during the chronic phase. Taken together, these findings suggest that HB-EGF and HGF inhibited BDL-induced cholestatic liver injury, predominantly by exerting acute cytoprotective and chronic antifibrotic effects, respectively; combining the growth factors enhanced the anticholestatic effects and liver regeneration during the chronic phase. Our results contribute to a better understanding of the pathophysiologic roles of HB-EGF and HGF, as well as to the development of novel effective therapies for cholestatic liver injuries.
与肝细胞生长因子（HGF）相比，肝素结合表皮生长因子样生长因子（HB-EGF）在肝脏疾病中的治疗潜力和病理生理作用仍相对不为人知。为了解决胆汁淤积性肝损伤缺乏有效药物治疗的问题，并阐明这些生长因子的生物学特性，我们探讨了HB-EGF和HGF对胆管结扎（BDL）诱导的胆汁淤积性肝损伤小鼠的影响。在BDL后3、5和/或14天（分别为急性、亚急性和/或慢性期）对小鼠进行评估，并静脉注射表达LacZ（对照）、HB-EGF、HGF或HB-EGF和HGF的腺病毒载体。HB-EGF、HGF或生长因子组合在体内对肝细胞发挥了强大的抗肿胀（抗坏死）、抗凋亡、抗胆汁淤积和再生作用，而在小叶间胆管中未检测到强大的抗凋亡或再生作用。基于血清转氨酶水平，HB-EGF对肝细胞的急性保护作用大于HGF。另一方面，与HB-EGF相比，HGF在慢性期更有效地抑制肝纤维化和胆汁淤积。与单独使用任何一种生长因子相比，联合使用HB-EGF和HGF在慢性期产生了更大的抗胆汁淤积和再生作用。综上所述，这些发现表明，HB-EGF和HGF分别主要通过发挥急性细胞保护和慢性抗纤维化作用来抑制BDL诱导的胆汁淤积性肝损伤；联合使用生长因子可增强慢性期的抗胆汁淤积作用和肝脏再生。我们的结果有助于更好地理解HB-EGF和HGF的病理生理作用，以及开发针对胆汁淤积性肝损伤的新型有效疗法。
