RT Journal Article
SR Electronic
T1 Prevention of Liver Fibrosis by the Purinoceptor Antagonist Pyridoxal-Phosphate-6-Azophenyl-2',4'-Disulfonate (PPADS)
JF In Vivo
JO In Vivo
FD International Institute of Anticancer Research
SP 957
OP 965
VO 21
IS 6
A1 DRANOFF, JONATHAN A.
A1 KRUGLOV, EMMA A.
A1 ABREU-LANFRANCO, ODALIZ
A1 NGUYEN, TRONG
A1 ARORA, GAURAV
A1 JAIN, DHANPAT
YR 2007
UL http://iv.iiarjournals.org/content/21/6/957.abstract
AB Background: Hepatic stellate cells (HSC) are important mediators of liver fibrosis. HSC express purinergic receptors for extracellular ATP that induce fibrogenesis. Pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (PPADS) is a highly bioavailable purinoceptor inhibitor. We sought to determine whether PPADS could prevent experimental liver fibrosis in rats. Materials and Methods: The effect of PPADS as an inhibitor of HSC purinoceptors was compared to the effect of suramin using confocal video microscopy. Rats were treated with CCl4, dimethylnitrosamine, or common bile duct ligation in the presence or absence of PPADS. Fibrosis in liver sections was assessed using Trichrome and Sirius red stains. In HSC isolated from experimental animals, proliferation was determined by bromodeoxyuridine uptake, apoptosis was determined using Annexin V flow cytometry, and transcription of α(1)-procollagen and fibronectin were determined using quantitative RT-PCR. Results: Both PPADS and suramin inhibited HSC purinoceptor activation, but PPADS had a more durable effect. PPADS completely blocked the development of cirrhosis due to CCl4 or dimethylnitrosamine but not due to bile duct ligation. PPADS inhibited HSC proliferation, but had no effect on HSC apoptosis. PPADS inhibited transcription of α(1)-procollagen and fibronectin by HSC. Conclusion: Blockade of purinergic receptors is a novel approach to prevention of non-biliary liver fibrosis. The primary action of PPADS is to inhibit HSC proliferation and fibrogenesis. Future design of purinergic receptor inhibitors may be an effective pharmacologic treatment to prevent liver fibrosis. Copyright © 2007 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved