Polymerization of deoxygenated HbS is the primary event in the molecular pathogenesis of sickle cell disease (SCD). Recently it has been proposed that chronic inflammation plays an important role in the etiology of vaso-occlusive crisis (VOC) and long-term pathologic manifestations of SCD. SCD patients and transgenic mice (NY-S) expressing human betaS globin exhibit increased plasma levels of pro-inflammatory cytokines, increased numbers of circulating endothelial cells, leukocytosis, and elevated expression of cell-surface activation markers on leukocytes and endothelial cells. Adenosine acts through the A2A adenosine receptor (A2AAR) found on bone marrow-derived cells to inhibit inflammation. We used hypoxia/reoxygenation to trigger VOC in NY-S mice and assessed plasma cytokine levels, hypoxia-induced lung inflammation and pulmonary function following the subcutaneous administration of the highly selective adenosine A2A receptor agonist, ATL146e (10 ng/kg/min). Compared to vehicle treated NY-S mice, ATL146e-treated mice displayed: 1) decreased plasma IL-6 levels; 2) reduced severity of hypoxia-induced vascular congestion as evidenced by pulmonary histology; 3) decreased pulmonary hypoxia based on 2-nitroimidazole hypoxia staining in lung tissue sections and in vivo pulmonary accumulation of BRU59-21, a 99mTc-labeled 2-nitroimidazole; and 4) improved pulmonary function (decreased breathing frequency and minute volume, increased expiratory time) as measured using whole-body plethysmography. These data suggest that A2A adenosine agonists may be clinically useful for the treatment of sickle cell crisis. NIH grant #PO1 HL073361.