Selective A2A adenosine receptor activation reduces skin pressure ulcer formation and inflammation

Abstract

Activation of A2A adenosine receptors (A2A-AR) by ATL-146e (formerly DWH-146e) prevents inflammatory cell activation and adhesion. Recurrent ischemia-reperfusion (I/R) of the skin results in pressure ulcer formation, a major clinical problem. ATL-146e was evaluated in a novel reproducible rat model of pressure ulcer. A 9-cm2 region of dorsal rat skin was cyclically compressed at 50 mmHg using a surgically implanted metal plate and an overlying magnet to generate reproducible tissue necrosis. Osmotic minipumps were implanted into 24 rats divided into four equal groups to infuse vehicle (control), ATL-146e (0.004 μg · kg−1 · min−1), ATL-146e plus an equimolar concentration of A2A antagonist, ZM-241385, or ZM-241385 alone. Each group received 10 I/R cycles. In non-I/R-treated skin, ATL-146e has no effect on blood flow. I/R-treated skin of the ATL-146e group compared with the vehicle group had 65% less necrotic area, 31% less inhibition of average skin blood flow, and fewer extravasated leukocytes (23 ± 3 vs. 49 ± 6 per 500 μm2). These data suggest that ATL-146e, acting via an A2A-AR, reduces leukocyte infiltration and is a potent prophylactic for I/R injury in skin.