Pharmacological blockade of adenosine A(2A) receptors diminishes scarring

1Division of Translational Medicine, Department of Medicine, New York University School of Medicine, 550 First Ave., MSB255, New York, NY 10016, USA. .
The FASEB Journal (Impact Factor: 5.04). 07/2012; 26(10):4254-63. DOI: 10.1096/fj.12-209627
Source: PubMed


Adenosine A2A receptor (A(2A)R) stimulation promotes wound healing and is required for the development of fibrosis in murine models of scleroderma and cirrhosis. Nonetheless, the role of A(2A)R in the formation of scars following skin trauma has not been explored. Here, we examined the effect of pharmacological blockade of A(2A)R, with the selective adenosine A(2A)R-antagonist ZM241385 (2.5 mg/ml), in a murine model of scarring that mimics human scarring. We found that application of the selective adenosine A(2A)R antagonist ZM241385 decreased scar size and enhanced the tensile strength of the scar. Within the scar itself, collagen alignment and composition (marked reduction in collagen 3), but not periostin, biglycan, or fibronectin accumulation, was improved by application of ZM241385. Moreover, A(2A)R blockade reduced the number of myofibroblasts and angiogenesis but not macrophage infiltration in the scar. Taken together, our work strongly suggests that pharmacological A(2A)R blockade can be used to diminish scarring while improving the collagen composition and tensile strength of the healed wound.-Perez-Aso, M., Chiriboga, L., Cronstein, B. N. Pharmacological blockade of adenosine A(2A) receptors diminishes scarring.

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    • "Controversy still exists regarding adenosine participation in wound healing and scarring. For instance, the adenosine A2A receptor promotes skin fibrosis and scarring [71] and increases collagen production in human dermal fibroblasts [72] probably by activating the Gs/cyclicAMP pathway [73], yet it remains controversial how A2A receptors increase collagen production since cyclicAMP has been found to decrease the synthesis of collagen and DNA by fibroblasts [74]. Thus, further studies are required to test long-term effects of extracellular adenosine, which may originate from the hydrolysis of ATP released from fibroblasts stimulated either mechanically (e.g. "
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    ABSTRACT: Chronic musculoskeletal pain involves connective tissue remodeling triggered by inflammatory mediators, such as bradykinin. Fibroblast cells signaling involve changes in intracellular Ca2+ ([Ca2+]i). ATP has been related to connective tissue mechanotransduction, remodeling and chronic inflammatory pain, via P2 purinoceptors activation. Here, we investigated the involvement of ATP in bradykinin-induced Ca2+ signals in human subcutaneous fibroblasts. Bradykinin, via B2 receptors, caused an abrupt rise in [Ca2+]i to a peak that declined to a plateau, which concentration remained constant until washout. The plateau phase was absent in Ca2+-free medium; [Ca2+]i signal was substantially reduced after depleting intracellular Ca2+ stores with thapsigargin. Extracellular ATP inactivation with apyrase decreased the [Ca2+]i plateau. Human subcutaneous fibroblasts respond to bradykinin by releasing ATP via connexin and pannexin hemichannels, since blockade of connexins, with 2-octanol or carbenoxolone, and pannexin-1, with 10Panx, attenuated bradykinin-induced [Ca2+]i plateau, whereas inhibitors of vesicular exocytosis, such as brefeldin A and bafilomycin A1, were inactive. The kinetics of extracellular ATP catabolism favors ADP accumulation in human fibroblast cultures. Inhibition of ectonucleotidase activity and, thus, ADP formation from released ATP with POM-1 or by Mg2+ removal from media reduced bradykinin-induced [Ca2+]i plateau. Selective blockade of the ADP-sensitive P2Y12 receptor with AR-C66096 attenuated bradykinin [Ca2+]i plateau, whereas the P2Y1 and P2Y13 receptor antagonists, respectively MRS 2179 and MRS 2211, were inactive. Human fibroblasts exhibited immunoreactivity against connexin-43, pannexin-1 and P2Y12 receptor. Bradykinin induces ATP release from human subcutaneous fibroblasts via connexin and pannexin-1-containing hemichannels leading to [Ca2+]i mobilization through the cooperation of B2 and P2Y12 receptors.
    Full-text · Article · Sep 2013 · Cell Communication and Signaling
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    • "In previous studies, we have demonstrated that occupancy of adenosine A2A receptors by an appropriate agonist, such as CGS-21680, promotes more rapid wound closure in both normal mice and diabetic rats and the enhancement in dermal wound healing is accompanied by an increase in matrix (collagen) in the wounds [2-4]. We have recently shown that pharmacological A2AR blockade can be used to diminish scarring while improving the collagen composition and tensile strength of the healed wound [5]. Adenosine A2A receptor agonists such as CGS21680 do not promote wound healing in mice lacking adenosine A2A receptors and these same A2A receptor-deficient mice are protected from the development of hepatic and dermal fibrosis as well [6,7]. "
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    ABSTRACT: Introduction Adenosine, acting through the A2A receptor, promotes tissue matrix production in the skin and the liver and induces the development of dermal fibrosis and cirrhosis in murine models. Since expression of A2A receptors is increased in scleroderma fibroblasts, we examined the mechanisms by which the A2A receptor produces its fibrogenic effects. Methods The effects of A2A receptor ligation on the expression of the transcription factor, Fli1, a constitutive repressor for the synthesis of matrix proteins, such as collagen, is studied in dermal fibroblasts. Fli1 is also known to repress the transcription of CTGF/CCN2, and the effects of A2A receptor stimulation on CTGF and TGF-β1 expression are also examined. Results A2A receptor occupancy suppresses the expression of Fli1 by dermal fibroblasts. A2A receptor activation induces the secretion of CTGF by dermal fibroblasts, and neutralization of CTGF abrogates the A2A receptor-mediated enhancement of collagen type I production. A2AR activation, however, resulted in a decrease in TGF-β1 protein release. Conclusions Our results suggest that Fli1 and CTGF are important mediators of the fibrogenic actions of adenosine and the use of small molecules such as adenosine A2A receptor antagonists may be useful in the therapy of dermal fibrosis in diseases such as scleroderma.
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    ABSTRACT: Purpose of review: One well described feature of wound healing is the ingrowth of new capillaries or angiogenesis. At its peak, the capillary content in healing wounds may reach three or more times that of normal uninjured tissue. This new vasculature is required to restore oxygenation and allow the growth of new tissue to fill the wound space. This review examines the assumption that a capillary content in excess of normal density is essential for adequate healing. Recent findings: The regulation of wound angiogenesis has been demonstrated to involve both proangiogenic and antiangiogenic stimuli, with the level of capillary growth reliant upon both sets of factors. Several studies now show that normal skin wounds heal adequately even when the angiogenic response is artificially reduced. In normal skin, a reduction of capillary growth to a level consistent with normal tissue does not affect wound closure and may even lead to highly favorable long term healing outcomes. Summary: The angiogenic response in normal wounds may exceed what is needed for optimal repair.
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