Department of Hepatobiliary Surgery, West China Hospital of Sichuan University, Chengdu, China.
J Surg Res. 2011 Mar;166(1):87-94. doi: 10.1016/j.jss.2009.09.058. Epub 2009 Nov 11.
In recent years, with a deeper understanding of pathologic changes in hepatolithiasis, more and more attention has been paid to the relationship of postoperative remnant proliferative cholangitis (PC) with stone recurrence and biliary restenosis, but effective management strategies have not yet been developed. Thus, the aim of this study was to determine whether epidermal growth factor receptor inhibitor (AG-1478) could inhibit hyperplasia and lithogenic potentiality of PC.
The PC animal model was established via retrograde insertion of a 5-0 nylon thread into the common bile duct through Vater's papilla. The common bile duct in the therapeutic group received a single intraluminal administration of AG-1478, followed by weekly intraperitoneal injections of AG-1478. Subsequently, influence of EGFR inhibitor on hyperplasia, apoptosis, and lithogenic potential of PC were evaluated via histology, expression changes of EGFR, BrdU, Ki-67, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), Fas, mucin 5 AC, and collagen I.
EGFR inhibitor AG-1478 was effective not only in inhibiting the mRNA and protein expression of EGFR, BrdU, and Ki-67, but also in increasing Fas mRNA expression and TUNEL-positive cells, as a result leading to the inhibition of hyperplasia of the biliary epithelium, submucosal gland, and collagen fibers in the diseased bile duct. Additionally, collagen I expression and fibrous thickness of the bile duct wall was significantly reduced, thereby reducing the incidence of biliary tract stricture secondary to PC. Also of note, treatment with AG-1478 could efficiently decrease the lithogenic potential of PC via inhibition of mucin 5AC expression and mucoglycoprotein secretion, hereby facilitating prevention of stone recurrence.
EGFR antagonist AG-1478 had a potent anti-proliferative and anti-fibrotic effectiveness on PC and, therefore, holds promise as a candidate of PC treatment.
近年来，随着对肝胆管结石病病理变化认识的深入，术后残留增生性胆管炎（PC）与结石复发和胆管再狭窄的关系越来越受到重视，但尚未制定出有效的治疗策略。因此，本研究旨在确定表皮生长因子受体抑制剂（AG-1478）是否能抑制 PC 的增生和成石潜能。
通过经 Vater 乳头逆行插入 5-0 尼龙线将 PC 动物模型建立于胆总管内。治疗组的胆总管内单次腔内给予 AG-1478，随后每周腹腔内给予 AG-1478。随后，通过组织学、EGFR、BrdU、Ki-67、末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）、Fas、黏蛋白 5AC 和胶原 I 的表达变化，评估 EGFR 抑制剂对 PC 增生、凋亡和成石潜能的影响。
EGFR 抑制剂 AG-1478 不仅能有效抑制 EGFR、BrdU 和 Ki-67 的 mRNA 和蛋白表达，还能增加 Fas mRNA 表达和 TUNEL 阳性细胞，从而抑制病变胆管的胆管上皮、黏膜下腺和胶原纤维的增生。此外，胶原 I 表达和胆管壁纤维厚度显著降低，从而降低了 PC 导致的胆管狭窄的发生率。值得注意的是，AG-1478 的治疗能通过抑制黏蛋白 5AC 表达和黏糖蛋白分泌有效地降低 PC 的成石潜能，从而有利于预防结石复发。
EGFR 拮抗剂 AG-1478 对 PC 具有强大的抗增殖和抗纤维化作用，因此有望成为 PC 治疗的候选药物。
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