We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with
sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of
adenosine A(2A) receptor (A(2A)R)
mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A(2A)R agonist
ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy
at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1(-/-) mice reduced
pulmonary injury that was restored by adoptive transfer of 10(6) purified iNKT cells. Reconstituted injury was reversed by
ATL146e unless the adoptively transferred iNKT cells were pretreated with the A(2A)R alkylating antagonist, FSPTP (5-amino-7-[2-(4-fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-ε]-1,2,4-triazolo[1,5-c]
pyrimidine), which completely prevented pro-tection. In NY1DD mice exposed to
hypoxia-reoxygenation, treatment with
ATL146e at the start of reoxygenation prevented further
lung injury. Together, these data indicate that activation of induced A(2A)Rs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent
hypoxia-reoxygenation-induced exacerbation of
pulmonary injury. A(2A) agonists have promise for treating diseases associated with iNKT or NK cell activation.