Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, USA.
Am J Transplant. 2012 Aug;12(8):2052-61. doi: 10.1111/j.1600-6143.2012.04069.x. Epub 2012 Jun 13.
This study investigated whether amphiregulin (AR), a ligand of the epidermal growth factor receptor (EGFR), improves liver regeneration after small-for-size liver transplantation. Livers of male C57BL/6 mice were reduced to ~50% and ~30% of original sizes and transplanted. After transplantation, AR and AR mRNA increased in 50% but not in 30% grafts. 5-Bromodeoxyuridine (BrdU) labeling, proliferating cell nuclear antigen (PCNA) expression and mitotic index increased substantially in 50% but not 30% grafts. Hyperbilirubinemia and hypoalbuminemia occurred and survival decreased after transplantation of 30% but not 50% grafts. AR neutralizing antibody blunted regeneration in 50% grafts whereas AR injection (5 μg/mouse, iv) stimulated liver regeneration, improved liver function and increased survival after transplantation of 30% grafts. Phosphorylation of EGFR and its downstream signaling molecules Akt, mTOR, p70S6K, ERK and JNK increased markedly in 50% but not 30% grafts. AR stimulated EGFR phosphorylation and its downstream signaling pathways. EGFR inhibitor PD153035 suppressed regeneration of 50% grafts and largely abrogated stimulation of regeneration of 30% grafts by AR. AR also increased cyclin D1 and cyclin E expression in 30% grafts. Together, liver regeneration is suppressed in small-for-size grafts, as least in part, due to decreased AR formation. AR supplementation could be a promising therapy to stimulate regeneration of partial liver grafts.
本研究旨在探讨表皮生长因子受体（EGFR）配体 Amphiregulin（AR）是否能促进小体积肝移植后的肝再生。将雄性 C57BL/6 小鼠的肝脏缩小至原始大小的 50%和 30%，并进行移植。移植后，50%的移植物中 AR 和 AR mRNA 增加，而 30%的移植物中则没有增加。5-溴脱氧尿苷（BrdU）标记、增殖细胞核抗原（PCNA）表达和有丝分裂指数在 50%的移植物中显著增加，但在 30%的移植物中则没有。30%的移植物移植后出现高胆红素血症和低白蛋白血症，生存率降低，而 50%的移植物则没有。AR 中和抗体削弱了 50%的移植物的再生，而 AR 注射（5μg/只，静脉注射）则刺激了 30%的移植物的肝再生，改善了肝功能，提高了生存率。在 50%的移植物中，EGFR 及其下游信号分子 Akt、mTOR、p70S6K、ERK 和 JNK 的磷酸化明显增加，但在 30%的移植物中则没有。AR 刺激了 EGFR 的磷酸化及其下游信号通路。EGFR 抑制剂 PD153035 抑制了 50%的移植物的再生，并在很大程度上抑制了 AR 对 30%的移植物再生的刺激作用。AR 还增加了 30%的移植物中细胞周期蛋白 D1 和 E 的表达。总之，小体积移植物的肝再生受到抑制，至少部分原因是 AR 形成减少。AR 的补充可能是刺激部分肝移植再生的一种有前途的治疗方法。
