Session Type: Abstract Submissions (ACR)
Ionizing radiation is a commonly used therapeutic modality and following irradiation dermal changes, including fibrosis and atrophy, may lead to such problems as contractures. The molecular basis for radiation fibrosis is not well understood. We have previously found that adenosine, acting at adenosine A2A receptors (A2AR), stimulates collagen production by human dermal fibroblasts and plays a central role in the development of dermal fibrosis in a murine model of scleroderma (bleomycin-induced dermal fibrosis). We therefore tested the hypothesis that A2AR play a role in radiation-induced fibrosis and studied the effect of adenosine A2AR blockade on development of radiation-induced changes of the skin.
Methods: After targeted irradiation (40Gy) to the skin on the dorsum of each mouse, the A2AR antagonist ZM241385 (2.5mg/ml in Carboxymethylcellulose 3%) was applied daily for 28 days. To determine the effect of irradiation on skin we measured skin, dermal and epithelial thickness, collagen alignment with SiriusRed stain, collagen deposition with the hydroxyproline assay and myofibroblast content by immunostaining for α-SMA.
Results: When compared to non-irradiated skin, irradiation induced an increase of the epidermal thickness (33.9±9.8 vs 94.2±13.3µm; p<0.01 N=4) but did not affect the skin fold or dermal thickness. In contrast, high dose ZM241385 (2.5mg/ml) completely prevented radiation-induced epidermal thickening (42.7±7.8µm; p<0.001 vs vehicle N=8). Direct measurement of collagen content (hydroxyproline) shows that the collagen increase after the radiation insult (control: 15.2±1.3 vs radiation: 21.6±1.4 µg/ml; p<0.05 N=5) is partially prevented by ZM241385 application (18.7±1.5 µg/mg N=8). Collagen alignment and packaging analysis by SiriusRed stain reveals that irradiation promotes a dramatic increase in loose packed collagen fibrils (421±104% of Control: p<0.05 N=9), which is significantly diminished by ZM241385 application (75±21% of Control; p<0.01 vs vehicle N=7). After irradiation-induced fibrosis, we detected an increase on myofibroblasts (α-SMA+ cells; 34±3 vs 83±10 cells per field; p<0.01 N=5) which was again prevented by ZM241385 application (57±5 cells per field; p<0.05 vs vehicle N=8).
Taken together, these data indicate that pharmacological blockade of A2AR prevents skin thickening in a murine model of irradiation-induced fibrosis, and suggests that topical application of an A2AR antagonist may be useful in the prevention or amelioration of radiation changes in the skin.
M. Perez Aso,
Y. C. Low,
B. N. Cronstein,
NIH, URL Pharma, OSI,
Bristol-Myers Squibb, Novartis, URL, Regeneron, Gismo Therapeutics,
Arthritis Foundation, SLE Foundation,
Patents on use of adenosine receptor antagonists to treat or prevent fibrosis. Multiple other patents.,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pharmacological-blockade-of-adenosine-a2a-receptors-a2ar-prevents-radiation-induced-dermal-injury/