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Adenosine A_2A receptors promote adenosine-stimulated wound healing in bronchial epithelial cells

¹Pulmonary, Critical Care, and Sleep Medicine Section, Department of Internal Medicine, University of Nebraska Medical Center, and ²Research Service, Department of Veterans Affairs Medical Center, Omaha, Nebraska

Submitted 24 August 2005 ; accepted in final form 14 December 2005

Adenosine produces a wide variety of physiological effects through the activation of specific adenosine receptors (A₁, A_2A, A_2B, A₃). Adenosine, acting particularly at the A_2A adenosine receptor (A_2AAR), is a potent endogenous anti-inflammatory agent and sensor of inflammatory tissue damage. The complete healing of wounds is the final step in a highly regulated response to injury. Recent studies on epidermal wounds have identified the A_2AAR as the main adenosine receptor responsible for altering the kinetics of wound closure. We hypothesized that A_2AAR promotes wound healing in bronchial epithelial cells (BECs). To test this hypothesis, the human BEC line BEAS-2B and bovine BECs (BBECs) were used. Real-time RT-PCR of RNA from unstimulated BEAS-2B cells revealed transcriptional expression of A₁, A_2A, A_2B and A₃ receptors. Western blot analysis of lysates from BEAS-2B cells and BBECs detected a single band at 44.7 kDa in both the BECs, indicating the presence of A_2AAR. In a wound healing model, we found that adenosine stimulated wound repair in cultured BBECs in a concentration-dependent manner, with an optimal closure rate observed between 4 and 6 h. Similarly, the A_2AAR agonist 5'-(N-cyclopropyl)carboxamidoadenosine (CPCA) augmented wound closure, with a maximal closure rate occurring between 4 and 6 h. Inhibition of A_2AAR with ZM-241385, a known A_2AAR antagonist, impeded wound healing. In addition, ZM-241385 also attenuated adenosine-mediated wound repair. Kinase studies revealed that adenosine-stimulated airway repair activates PKA by ligating A_2AAR. Collectively, the data suggest that the A_2AAR is involved in BEC adenosine-stimulated wound healing and may prove useful in understanding purinergic-mediated actions on airway epithelial repair.

airway injury; airway repair

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