Adenosine A2A receptors in diffuse dermal fibrosis: Pathogenic role in human dermal fibroblasts and in a murine model of scleroderma

E. S L Chan, P. Fernandez, A. A. Merchant, M. C. Montesinos, S. Trzaska, A. Desai, C. F. Tung, D. N. Khoa, M. H. Pillinger, A. B. Reiss, Marjana Tomic-Canic, J. F. Chen, M. A. Schwarzschild, B. N. Cronstein

Research output: Contribution to journalArticle

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Abstract

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. Conclusion. 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.

Original languageEnglish
Pages (from-to)2632-2642
Number of pages11
JournalArthritis and Rheumatism
Volume54
Issue number8
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

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Adenosine A2A Receptors
Fibrosis
Fibroblasts
Skin
Collagen
Mitogen-Activated Protein Kinase Kinases
Adenosine
Adenosine A2 Receptor Antagonists
Phosphorylation
Collagen Receptors
Hydroxyproline
Bleomycin
Inbred C57BL Mouse
Proline
Wound Healing
Ligation
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Chan, E. S. L., Fernandez, P., Merchant, A. A., Montesinos, M. C., Trzaska, S., Desai, A., ... Cronstein, B. N. (2006). Adenosine A2A receptors in diffuse dermal fibrosis: Pathogenic role in human dermal fibroblasts and in a murine model of scleroderma. Arthritis and Rheumatism, 54(8), 2632-2642. https://doi.org/10.1002/art.21974

Adenosine A2A receptors in diffuse dermal fibrosis : Pathogenic role in human dermal fibroblasts and in a murine model of scleroderma. / Chan, E. S L; Fernandez, P.; Merchant, A. A.; Montesinos, M. C.; Trzaska, S.; Desai, A.; Tung, C. F.; Khoa, D. N.; Pillinger, M. H.; Reiss, A. B.; Tomic-Canic, Marjana; Chen, J. F.; Schwarzschild, M. A.; Cronstein, B. N.

In: Arthritis and Rheumatism, Vol. 54, No. 8, 01.08.2006, p. 2632-2642.

Research output: Contribution to journalArticle

Chan, ESL, Fernandez, P, Merchant, AA, Montesinos, MC, Trzaska, S, Desai, A, Tung, CF, Khoa, DN, Pillinger, MH, Reiss, AB, Tomic-Canic, M, Chen, JF, Schwarzschild, MA & Cronstein, BN 2006, 'Adenosine A2A receptors in diffuse dermal fibrosis: Pathogenic role in human dermal fibroblasts and in a murine model of scleroderma', Arthritis and Rheumatism, vol. 54, no. 8, pp. 2632-2642. https://doi.org/10.1002/art.21974
Chan, E. S L ; Fernandez, P. ; Merchant, A. A. ; Montesinos, M. C. ; Trzaska, S. ; Desai, A. ; Tung, C. F. ; Khoa, D. N. ; Pillinger, M. H. ; Reiss, A. B. ; Tomic-Canic, Marjana ; Chen, J. F. ; Schwarzschild, M. A. ; Cronstein, B. N. / Adenosine A2A receptors in diffuse dermal fibrosis : Pathogenic role in human dermal fibroblasts and in a murine model of scleroderma. In: Arthritis and Rheumatism. 2006 ; Vol. 54, No. 8. pp. 2632-2642.
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abstract = "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. Conclusion. 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.",
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AU - Montesinos, M. C.

AU - Trzaska, S.

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AU - Tung, C. F.

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AU - Pillinger, M. H.

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