Adenosine A2A receptor plays an important role in radiation‐induced dermal injury

Abstract

Ionizing radiation is a common therapeutic modality and following irradiation dermal changes, including fibrosis and atrophy, may lead to permanent changes. We have previously demonstrated that occupancy of A2A receptor (A 2A R) stimulates collagen production, so we determined whether blockade or deletion of A 2A R could prevent radiation-induced fibrosis. After targeted irradiation (40 Gy) of the skin of wild-type (WT) or A 2A R knockout (A2ARKO) mice, the A 2A R antagonist ZM241385 was applied daily for 28 d. In irradiated WT mice treated with the A 2A R antagonist, there was a marked reduction in collagen content and skin thickness, and ZM241385 treatment reduced the number of myofibroblasts and angiogenesis. After irradiation, there is an increase in loosely packed collagen fibrils, which is significantly diminished by ZM241385. Irradiation also induced an increase in epidermal thickness, prevented by ZM241385, by increasing the number of proliferating keratinocytes. Similarly, in A2ARKO mice, the changes in collagen alignment, skin thickness, myofibroblast content, angiogenesis, and epidermal hyperplasia were markedly reduced following irradiation. Radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2ARKO mice. Radiation therapy is administered to a significant number of patients with cancer, and radiation reactions may limit this therapeutic modality. Our findings suggest that topical application of an A 2A R antagonist prevents radiation dermatitis and may be useful in the prevention or amelioration of radiation changes in the skin.-Perez-Aso, M., Mediero, A., Low, Y. C., Levine, J., Cronstein, B. N. Adenosine A2A receptor plays an important role in radiation-induced dermal injury. FASEB J. 30, 457-465 (2016). www.fasebj.org

Loss of CD73 prevents accumulation of alternatively activated macrophages and the formation of prefibrotic macrophage clusters in irradiated lungs

“…In one study, macrophages expressing M2‐like markers have been linked to disease outcome in radiation‐induced renal fibrosis (50). Instead, an accumulation of T cells and no role for macrophages (51) or a contribution of macrophages had been observed in radiation‐induced skin fibrosis (30, 52), but without stating the macrophage phenotype.…”

“…Of note, the role of adenosine and its receptors in fibrotic disease in vivo seems to largely depend on the tissue and the model investigated. Earlier reports revealed a critical role of ADORA2A signaling in dermal fibrosis induced, for example, by genetic loss of adenosine deaminase, systemic administration of bleomycin, and ionizing radiation, whereas ADORA2B activation was shown to play a major pathogenic role in the related models of pulmonary fibrosis (35, 51, 67, 68). These differences might be due to tissue‐specific expression patterns of adenosine receptors or other fibrosis‐modulating signaling molecules in resident cells or recruited immune cells, tissue‐specific damage responses, or both (67, 68).…”

Opposing Effects of Adenosine and Inosine in Human Subcutaneous Fibroblasts May Be Regulated by Third Party ADA Cell Providers

“…Overall, data enlighten the idea that adenosine, via preferential activation of A 2A receptors in fibroblasts, might be a key player in human subcutaneous connective tissue homeostasis and normal wound repair, while excessive scarring and dermal fibrosis may occur when this receptor is overexpressed ( Figure 6). For instance, adenosine A 2A receptor antagonists have been proposed to prevent radiation-induced dermal injury [50]. Disturbed adenosine homeostasis in the subcutaneous tissue may happen upon infiltration by ADA-bearing inflammatory cells and/or in situations occurring with increases in serum ADA levels, such as fibromyalgia and other chronic inflammatory conditions [51].…”

Adenosine A2A Receptor Agonist, 2-p-(2-Carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine Hydrochloride Hydrate, Inhibits Inflammation and Increases Fibroblast Growth Factor-2 Tissue Expression in Carrageenan-Induced Rat Paw Edema

“…Several studies have reported the beneficial effect of topical application of A 2A agonist on injured skin (Montesinos et al, 2002;Arasa et al, 2014); however, the mechanism at the basis is still unclear. However, there is also evidence that under pathologic conditions or following skin physical injury, such as radiation induced injury, A 2A receptor activation is responsible for fibrosis (Perez-Aso et al, 2016). Here, we show that systemic administration of A 2A agonist CGS21680 to rats inhibits paw inflammation induced by subcutaneous injection of carrageenan, increases FGF-2 dermal expression, and ameliorates skin cytoarchitecture.…”