Evidence for the Critical Role of Immunosuppressive A_2AR in Lung Protection from Inflammatory Damage

Abstract

<div><p>(A) In <i>A_2AR</i> gene-deficient mice, number of PMNs (left graph) and amount of protein recovered (center graph) 48 h after IT LPS injection by BAL was significantly higher than in similarly treated wild-type control mice, reflecting increased lung damage in the absence of A_2AR. The arterial oxygen tension (right graph) was lower in <i>A_2AR</i> gene-deficient mice as compared with wild-type mice.</p> <p>(B) Pharmacologic inactivation of A_2AR leads to exacerbated inflammatory lung tissue damage and decreased lung funciton. After estimation of biologically relevant half-life of A_2AR antagonist ZM241385 (ZM) in vivo (unpublished data), the IT LPS-injected mice were administered ZM241385 at a dose of 10 mg/kg body weight every 6 h subcutaneously to ensure sufficient levels of the antagonist. This dosing regimen of the A_2AR antagonist caused significant more lung tissue damage, as reflected by increased number of PMNs (left graph) and protein levels (center graph) in the BAL fluid obtained after 48 h. In parallel experiments, the A_2AR antagonist decreased lung function (right graph) as compared to untreated wild-type mice, in agreement with results of experiments with <i>A_2AR</i> gene-deficient mice.</p></div