Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis.
1. Adenosine is a potent endogenous regulator of inflammation and tissue repair. Adenosine, which is released from injured and hypoxic tissue or in response to toxins and medications, may induce pulmonary fibrosis in mice, presumably via interaction with a specific adenosine receptor. We therefore determined whether adenosine and its receptors contribute to the pathogenesis of hepatic fibrosis. 2. As in other tissues and cell types, adenosine is released in vitro in response to the fibrogenic stimuli ethanol (40 mg dl(-1)) and methotrexate (100 nM). 3. Adenosine A(2A) receptors are expressed on rat and human hepatic stellate cell lines and adenosine A(2A) receptor occupancy promotes collagen production by these cells. Liver sections from mice treated with the hepatotoxins carbon tetrachloride (CCl(4)) (0.05 ml in oil, 50 : 50 v : v, subcutaneously) and thioacetamide (100 mg kg(-1) in PBS, intraperitoneally) released more adenosine than those from untreated mice when cultured ex vivo. 4. Adenosine A(2A) receptor-deficient, but not wild-type or A(3) receptor-deficient, mice are protected from development of hepatic fibrosis following CCl(4) or thioacetamide exposure. 5. Similarly, caffeine (50 mg kg(-1) day(-1), po), a nonselective adenosine receptor antagonist, and ZM241385 (25 mg kg(-1) bid), a more selective antagonist of the adenosine A(2A) receptor, diminished hepatic fibrosis in wild-type mice exposed to either CCl(4) or thioacetamide. 6. These results demonstrate that hepatic adenosine A(2A) receptors play an active role in the pathogenesis of hepatic fibrosis, and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis.
Chan
Edwin S L
ES
Division of Clinical Pharmacology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA.
Montesinos
Maria Carmen
MC
Fernandez
Patricia
P
Desai
Avani
A
Delano
David L
DL
Yee
Herman
H
Reiss
Allison B
AB
Pillinger
Michael H
MH
Chen
Jiang-Fan
JF
Schwarzschild
Michael A
MA
Friedman
Scott L
SL
Cronstein
Bruce N
BN
D000241:Adenosine / Q000378:metabolism; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D000431:Ethanol / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000503:physiopathology*; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000378:metabolism; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013853:Thioacetamide / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D058908:Adenosine A2 Receptor Agonists; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D013853:Thioacetamide; D002110:Caffeine; D000431:Ethanol; D002251:Carbon Tetrachloride; D053504:Matrix Metalloproteinases, Membrane-Associated; D000241:Adenosine; D008727:Methotrexate