title: Prostaglandin E receptors in bile ducts of hepatolithiasis patients and the pathobiological significance for cholangitis.
abstract: OBJECTIVE
  In hepatolithiasis, chronic proliferative cholangitis may influence the progression of the disease. Prostaglandin (PG) E(2) experimentally causes morphologic changes to intrahepatic bile ducts, analogous to the changes found in cholangitis. This study was designed to gain an understanding of the involvement of PGE(2) and PGE receptor (EP) subtypes in the development of cholangitis.
  
  
  METHODS
  The expression levels of secretory-type group IIA phospholipase A(2) (sPLA(2)-IIA) and cyclooxygenase (COX)-2 as well as EP subtypes were determined in the bile ducts with change of cholangitis. In in vitro experiments, growth promotion and mucin secretagogue properties of biliary epithelial cells in response to EP-selective agonists or antagonists were studied.
  
  
  RESULTS
  The messenger RNA (mRNA) level of sPLA(2)-IIA and the protein and mRNA levels of COX-2 were significantly increased in the bile ducts of patients with hepatolithiasis compared with the levels of the bile ducts of control subjects. These changes were associated with a concomitant increase in PGE(2) and total mucin concentrations in the bile. The mRNAs of EP subtypes EP(2), EP(3), and EP(4) but not EP(1) were amplified in the bile ducts. Treatment with an EP(4)-selective agonist (ONO-AE1-329) caused a dose-dependent increase in DNA synthesis, colony number, and mucin secretion in the cells. Conversely, treatment with an EP(4)-selective antagonist (ONO-AE3-208) abolished the biological effects of PGE(2) on the cells.
  
  
  CONCLUSIONS
  In hepatolithiasis, an enhanced synthesis of sPLA(2)-/COX-2-derived PGE(2) and its actions mediated via the EP(4) receptor in the bile ducts may be of pathobiological significance for chronic proliferative cholangitis.
authors.affiliation: Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan. shodaj@md.tsukuba.ac.jp
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ueda
authors.forename: Toru
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Takesi
authors.initials: T
authors.lastname: Todoroki
authors.forename: Toru
authors.initials: T
authors.lastname: Asano
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ichikawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nimura
authors.forename: Naomi
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000368:Aged; D001653:Bile Ducts, Intrahepatic / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis; D002761:Cholangitis / Q000378:metabolism*; D042883:Choledocholithiasis / Q000378:metabolism*; D002908:Chronic Disease; D000242:Cyclic AMP / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D042882:Gallstones / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D007527:Isoenzymes / Q000378:metabolism; D007564:Japan; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009077:Mucins / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011448:Prostaglandin Antagonists / Q000008:administration & dosage; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D012720:Severity of Illness Index
chemical_list: D015415:Biomarkers; D007527:Isoenzymes; D008565:Membrane Proteins; D009077:Mucins; D011448:Prostaglandin Antagonists; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D015232:Dinoprostone