Matrix replacement and repair is required for wound healing but when the process is overly exuberant, as in scar or keloid formation, or when it occurs inappropriately, as in Scleroderma and other fibrosing diseases, it can lead to morbidity and, in the case of Scleroderma, mortality. Although it is clear that growth factors play a central role in fibrosis the role of small molecules in pathologic fibrosis has not been well explored. We have recently demonstrated that the purine nucleoside adenosine, acting through the adenosine A2A receptor, plays a central role in the fibrosis that develops in experimental models of hepatic cirrhosis and scleroderma. We propose here to further determine whether adenosine and adenosine receptors play a role in pathologic fibrosis and to dissect the molecular mechanism by which adenosine A2A receptors on fibroblasts stimulate overproduction of collagen and other matrix constituents. To this end we have proposed to study: I. The role of adenosine receptors in pathologic fibrosis. We will study the development of hypertrophic scarring in a model of dermal scarring and diffuse dermal fibrosis induced by bleomycin treatment in wild type, adenosine A1, A2A, A2B and A3 receptor knockout mice, mice that generate less extracellular adenosine (ecto-5'Nucleotidase and nucleoside triphosphate pyrophosphatase knockout mice) and mice treated with adenosine receptor antagonists;II. Signaling at adenosine A2A receptors for fibrosis In preliminary experiments we have observed that adenosine A2A receptor stimulation diminishes nuclear fli1 levels, a constitutive repressor of CTGF expression, a change which may mediate the pro- fibrotic effects of adenosine and the A2A receptor. We will dissect the signaling pathways from adenosine A2A receptors to suppression of fli1 expression and nuclear localization using a combination of pharmacologic and siRNA-mediated knockdown techniques;III. Cross-talk between adenosine A2A receptors and receptors for "anti-fibrotic" cytokines We have previously demonstrated that interferon-3, an anti-fibrotic cytokine, diminishes adenosine A2A receptor expression and, more dramatically, function. We will study the mechanism by which interferon-3 downregulates adenosine A2A receptor function with a combination of pharmacologic and molecular (siRNA-mediated knockdown) methods. In future experiments we will examine the role of adenosine receptors in keloid formation and other clinically- relevant forms of pathologic fibrosis (e.g. radiation fibrosis). Because adenosine receptor antagonists are under development for the treatment of a variety of medical conditions it may be possible to quickly bring the information garnered in these studies to the clinic.
The synthesis of new fibrous tissue is a normal process which is critical for wound healing and tissue repair, however excess fibrous tissue formation is a significant medical issue in conditions ranging from Scleroderma (diffuse skin and organ fibrosis that can be life-threatening) to disfiguring scarring or tendon enlargement. Our laboratory has found that adenosine and its receptors play a central role in diffuse fibrosis in animal models of Scleroderma and hypertrophic scarring. We propose studies designed to further confirm the role of adenosine and its receptors in scarring and to discover the mechanism by which adenosine receptors stimulate production of excess fibrous tissue. A better understanding of the role of adenosine and its receptors in fibrosis and the medical problems resulting from fibrosis could facilitate the development of new agents that will prevent the development of enlarged scars or ameliorate the fibrosis that characterizes Scleroderma.
|Perez-Aso, Miguel; Fernandez, Patricia; Mediero, Aranzazu et al. (2014) Adenosine 2A receptor promotes collagen production by human fibroblasts via pathways involving cyclic AMP and AKT but independent of Smad2/3. FASEB J 28:802-12|
|Cronstein, Bruce N; Sunkureddi, Prashanth (2013) Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis. J Clin Rheumatol 19:19-29|
|Rolita, Lydia; Spegman, Adele; Tang, Xiaoqin et al. (2013) Greater number of narcotic analgesic prescriptions for osteoarthritis is associated with falls and fractures in elderly adults. J Am Geriatr Soc 61:335-40|
|Mediero, Aranzazu; Perez-Aso, Miguel; Cronstein, Bruce N (2013) Activation of adenosine A(2A) receptor reduces osteoclast formation via PKA- and ERK1/2-mediated suppression of NF*B nuclear translocation. Br J Pharmacol 169:1372-88|
|Perez-Aso, Miguel; Feig, Jessica L; Mediero, Aránzazu et al. (2013) Adenosine A2A receptor and TNF-? regulate the circadian machinery of the human monocytic THP-1 cells. Inflammation 36:152-62|
|He, Wenjie; Mazumder, Amitabha; Wilder, Tuere et al. (2013) Adenosine regulates bone metabolism via A1, A2A, and A2B receptors in bone marrow cells from normal humans and patients with multiple myeloma. FASEB J 27:3446-54|
|Mediero, Aranzazu; Cronstein, Bruce N (2013) Adenosine and bone metabolism. Trends Endocrinol Metab 24:290-300|
|You, Xin; Williams, Adrienne; Dervieux, Thierry et al. (2013) Fibroblasts from methotrexate-sensitive mice accumulate methotrexate polyglutamates but those from methotrexate-resistant mice do not. Clin Exp Rheumatol 31:433-5|
|Bingham, Taiese Crystal; Parathath, Saj; Tian, Heather et al. (2012) Cholesterol 27-hydroxylase but not apolipoprotein apoE contributes to A2A adenosine receptor stimulated reverse cholesterol transport. Inflammation 35:49-57|
|Reiss, Allison B; Cronstein, Bruce N (2012) Regulation of foam cells by adenosine. Arterioscler Thromb Vasc Biol 32:879-86|
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