Dermal fibrosis is a hallmark of systemic sclerosis. We have previously demonstrated that stimulation of adenosine A2A receptor promotes collagen production in vitro while blockade of the adenosine A2A receptor attenuates development of dermal fibrosis in vivo in a bleomycin-induced murine model of scleroderma. These findings parallel our observations on models of hepatic fibrosis where adenosine A2A receptor antagonists retard chemically-induced murine cirrhosis. We have recently shown that levels of the fibrogenic cytokine, IL-13 are elevated in the skin in a murine model of high tissue adenosine (adenosine deaminase deficiency). Furthermore, an A2A receptor antagonist reverses the IL-13 increase and decreases message for IL-13 receptor 1. To better understand the mechanisms by which adenosine A2A receptor antagonism protects against dermal fibrogenesis in scleroderma, we will study:
Specific Aim 1 The effect of adenosine on IL-13 responsiveness in dermal fibroblasts Specific Aim 2 The effect of adenosine and IL-13 on Fli1 function Specific Aim 3 The effect of adenosine on CCN2. Ultimately, we hope that these studies will allow us to consider the use of small molecules such as adenosine receptor antagonists in the therapy of dermal fibrosis in scleroderma.
NARRATIVE Uncontrolled and excessive fibrous tissue formation may result in diffuse skin and organ fibrosis such as that seen in scleroderma. The studies proposed herein are designed to further confirm the role of adenosine and its receptors in promoting fibrosis in the skin as well as the mechanisms by which adenosine receptors stimulate tissue matrix production. A better understanding of the role of adenosine and its receptors in dermal fibrosis could facilitate the development of new agents that prevent or ameliorate the skin fibrosis that characterizes scleroderma, for which no effective treatment exists at present.
| Fernández, Patricia; Perez-Aso, Miguel; Smith, Gideon et al. (2013) Extracellular generation of adenosine by the ectonucleotidases CD39 and CD73 promotes dermal fibrosis. Am J Pathol 183:1740-1746 |
| Chan, Edwin S L; Liu, Hailing; Fernandez, Patricia et al. (2013) Adenosine A(2A) receptors promote collagen production by a Fli1- and CTGF-mediated mechanism. Arthritis Res Ther 15:R58 |
| Chan, Edwin S L; Cronstein, Bruce N (2013) Mechanisms of action of methotrexate. Bull Hosp Jt Dis (2013) 71 Suppl 1:S5-8 |
| Smith, Gideon P; Chan, Edwin S L (2010) Molecular pathogenesis of skin fibrosis: insight from animal models. Curr Rheumatol Rep 12:26-33 |
