Epidermal growth factor receptor as a target for anti-proliferative treatment of proliferative cholangitis in hepatolithiasis.
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.


CONCLUSIONS
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.
Li
Fuyu
F
Department of Hepatobiliary Surgery, West China Hospital of Sichuan University, Chengdu, China.
Zhou
Yong
Y
Cheng
Nansheng
N
Mao
Hui
H
Jiang
Lisheng
L
Li
Ning
N
Li
Quansheng
Q
de Jong
Mechteld C
MC
Pawlik
Timothy M
TM
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002761:Cholangitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D020347:Lithiasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D020032:Tyrphostins / Q000494:pharmacology*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D024042:Collagen Type I; D004791:Enzyme Inhibitors; D019394:Ki-67 Antigen; C524680:Muc5ac protein, rat; D055271:Mucin 5AC; D011799:Quinazolines; D020032:Tyrphostins; D019014:fas Receptor; C101044:RTKI cpd; D066246:ErbB Receptors; D001973:Bromodeoxyuridine