Epidermal Growth Factor Receptor as a Target for Anti-Proliferative Treatment of Proliferative Cholangitis in Hepatolithiasis
Epidermal Growth Factor Receptor as a Target for Anti-Proliferative Treatment of Proliferative Cholangitis in Hepatolithiasis
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DOI：
10.1016/j.jss.2009.09.058
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发表时间：
2011-03-01
影响因子：
2.2
通讯作者：
Pawlik, Timothy M.
中科院分区：
文献类型：
--
作者：
Li, Fuyu;Zhou, Yong;Pawlik, Timothy M.
背景近年来，随着对肝内胆管结石病理变化认识的深入，术后残余增生性胆管炎（PC）与结石复发和胆道再狭窄的关系越来越受到重视，但尚未形成有效的治疗策略。因此，本研究的目的是确定表皮生长因子受体抑制剂（AG-1478）是否可以抑制PC的增生和成石潜力。通过经Vater乳头逆行插入5-0尼龙线至胆总管内建立PC动物模型。治疗组的胆总管接受AG-1478的单次管腔内给药，随后每周腹腔内注射AG-1478。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、粘蛋白5 AC和I型胶原表达的变化，评价EGFR抑制剂对PC增生、凋亡和成石性的影响。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，而且能增加Fas mRNA表达和TUNEL阳性细胞，从而抑制病变胆管中胆管上皮、粘膜下腺体和胶原纤维的增生。此外，I型胶原表达和胆管壁纤维厚度显著降低，从而降低继发于PC的胆道狭窄的发生率。另外值得注意的是，AG-1478治疗可通过抑制粘蛋白5AC表达和粘糖蛋白分泌有效降低PC的成石潜力，从而有助于预防结石复发。EGFR拮抗剂AG-1478对PC具有有效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。(C)2011 Elsevier Inc. All rights reserved.
Background. 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.Methods. 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.Results. 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.Conclusion. 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. (C) 2011 Elsevier Inc. All rights reserved.