title: Role of thromboxane A2 in early BDL-induced portal hypertension.
abstract: Although the mechanisms of cirrhosis-induced portal hypertension have been studied extensively, the role of thromboxane A(2) (TXA(2)) in the development of portal hypertension has never been explicitly explored. In the present study, we sought to determine the role of TXA(2) in bile duct ligation (BDL)-induced portal hypertension in Sprague-Dawley rats. After 1 wk of BDL or sham operation, the liver was isolated and perfused with Krebs-Henseleit bicarbonate buffer at a constant flow rate. After 30 min of nonrecirculating perfusion, the buffer was recirculated in a total volume of 100 ml. The perfusate was sampled for the enzyme immunoassay of thromboxane B(2) (TXB(2)), the stable metabolite of TXA(2). Although recirculation of the buffer caused no significant change in sham-operated rats, it resulted in a marked increase in portal pressure in BDL rats. The increase in portal pressure was found concomitantly with a significant increase of TXB(2) in the perfusate (sham vs. BDL after 30 min of recirculating perfusion: 1,420 +/- 803 vs. 10,210 +/- 2,950 pg/ml; P < 0.05). Perfusion with a buffer containing indomethacin or gadolinium chloride for inhibition of cyclooxygenase (COX) or Kupffer cells, respectively, substantially blocked the recirculation-induced increases in both portal pressure and TXB(2) release in BDL group. Hepatic detection of COX gene expression by RT-PCR revealed that COX-2 but not COX-1 was upregulated following BDL, and this upregulation was confirmed at the protein level by Western blot analysis. In conclusion, these results clearly demonstrate that increased hepatic TXA(2) release into the portal circulation contributes to the increased portal resistance in BDL-induced liver injury, suggesting a role of TXA(2) in liver fibrosis-induced portal hypertension. Furthermore, the Kupffer cell is likely the source of increased TXA(2), which is associated with upregulation of the COX-2 enzyme.
authors.affiliation: Department of Biology, University of North Carolina at Charlotte, 9201 University City Boulevard, Charlotte, NC 28223, USA.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yokoyama
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Xu
authors.forename: Nicole
authors.initials: N
authors.lastname: Kresge
authors.forename: Steve
authors.initials: S
authors.lastname: Keller
authors.forename: Amir H
authors.initials: AH
authors.lastname: Sarmadi
authors.forename: Rajiv
authors.initials: R
authors.lastname: Baveja
authors.forename: Mark G
authors.initials: MG
authors.lastname: Clemens
authors.forename: Jian X
authors.initials: JX
authors.lastname: Zhang
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D051546:Cyclooxygenase 2; D006975:Hypertension, Portal / Q000473:pathology / Q000503:physiopathology*; D007527:Isoenzymes / Q000096:biosynthesis; D007728:Kupffer Cells / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D011169:Portal Vein / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013928:Thromboxane A2 / Q000502:physiology*; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007527:Isoenzymes; D013929:Thromboxane B2; D013928:Thromboxane A2; D007770:L-Lactate Dehydrogenase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000410:Alanine Transaminase