Adenosine A2A receptors in diffuse dermal fibrosis: pathogenic role in human dermal fibroblasts and in a murine model of scleroderma.
OBJECTIVE
Adenosine regulates inflammation and tissue repair, and adenosine A2A receptors promote wound healing by stimulating collagen matrix production. We therefore examined whether adenosine A2A receptors contribute to the pathogenesis of dermal fibrosis.


METHODS
Collagen production by primary human dermal fibroblasts was analyzed by real-time polymerase chain reaction, 14C-proline incorporation, and Sircol assay. Intracellular signaling for dermal collagen production was investigated using inhibitors of MEK-1 and by demonstration of ERK phosphorylation. In vivo effects were studied in a bleomycin-induced dermal fibrosis model using adenosine A2A receptor-deficient wild-type littermate mice, C57BL/6 mice, and mice treated with adenosine A2A receptor antagonist. Morphometric features and levels of hydroxyproline were determined as measures of dermal fibrosis.


RESULTS
Adenosine A2A receptor occupancy promoted collagen production by primary human dermal fibroblasts, which was blocked by adenosine A2A, but not A1 or A2B, receptor antagonism. Adenosine A2A receptor ligation stimulated ERK phosphorylation, and A2A receptor-mediated collagen production by dermal fibroblasts was blocked by MEK-1 inhibitors. Adenosine A2A receptor-deficient and A2A receptor antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis.


CONCLUSIONS
These results demonstrate that adenosine A2A receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the treatment and prevention of dermal fibrosis in diseases such as scleroderma.
Chan
E S L
ES
New York University School of Medicine, New York, New York 10016, USA.
Fernandez
P
P
Merchant
A A
AA
Montesinos
M C
MC
Trzaska
S
S
Desai
A
A
Tung
C F
CF
Khoa
D N
DN
Pillinger
M H
MH
Reiss
A B
AB
Tomic-Canic
M
M
Chen
J F
JF
Schwarzschild
M A
MA
Cronstein
B N
BN
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015870:Gene Expression; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045743:Scleroderma, Diffuse / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D014227:Triazines / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D003094:Collagen; D048369:MAP Kinase Kinase 1; D006909:Hydroxyproline