Adenosine Promotion of Cellular Migration in Bronchial Epithelial Cells Is Mediated by the Activation of Cyclic Adenosine Monophosphate–Dependent Protein Kinase A

Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198-5815, USA.
Journal of Investigative Medicine (Impact Factor: 1.69). 12/2007; 55(7):378-85. DOI: 10.2310/6650.2007.00019
Source: PubMed


Migration of neighboring cells into the injury is important for rapid repair of damaged airway epithelium. We previously reported that activation of the A(2A )receptors (A(2A)ARs) mediates adenosine-stimulated epithelial wound healing, suggesting a role for adenosine in migration. Because A(2A)AR increases cyclic adenosine monophosphate (cAMP) levels in many cells, we hypothesized that cAMP-dependent protein kinase A (PKA) is involved in adenosine-mediated cellular migration. To test this hypothesis, we stimulated a human bronchial epithelial cell line with adenosine and/or A(2A)AR agonist (5'-(N-cyclopropyl)-carboxamido-adenosine [CPCA]) in the presence or absence of adenosine deaminase inhibitor (erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride [EHNA]). Cells treated with adenosine or CPCA demonstrated a concentration-dependent increase in migration. Similar results were observed in the presence and absence of EHNA. To confirm A(2A) involvement, we pretreated the cells for 1 hour with the A(2A) receptor antagonist ZM241385 and then stimulated them with either adenosine or CPCA. To elucidate PKA's role, cells were pretreated for 1 hour with either a PKA inhibitor (KT5720) or a cAMP antagonist analogue (Rp-cAMPS) and then stimulated with adenosine and/or CPCA. Pretreatment with KT5720 or Rp-cAMPS resulted in a significant decrease in adenosine-mediated cellular migration. PKA activity confirmed that bronchial epithelial migration requires cAMP and PKA activity. When cells were wounded and stimulated with CPCA, an increase in PKA activity occurred. Pretreatment for 1 hour with either KT5720 or Rp-cAMPS resulted in a significant decrease in adenosine-mediated PKA activation. These data suggest that adenosine activation of A(2A)AR augments epithelial repair by increasing airway cellular migration by PKA-dependent mechanisms.

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    • "The type of response following the activation of adenosine receptors depends on the responding cell and the adenosine receptors which it expresses. For example, within the lung increased extracellular adenosine levels during injury have been shown to induce cellular migration to promote repair [16]. However, immune cells are typically inhibited by high local extracellular adenosine levels in order to prevent excessive collateral damage to healthy tissue that can result during an inflammatory response [13,14,17,18]. "
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