APCP treatment in SCD mice decreases multiorgan damage, including lung, spleen, and liver. (A) H&E staining of lungs, spleens, and livers of SCD mice with or without APCP treatment (magnification ×200). (B-D) Semiquantitative analysis of H&E-stained sections showed decreased lung congestion, spleen necrosis, and liver necrosis in SCD mice following APCP treatment. (E) BALF total cell count, (F) BALF albumin concentration, and (G) BALF IL-6 concentration in SCD mice with or without APCP treatment. (H) MPO activity in multiple organs, including lung, spleen, and liver in SCD mice with or without APCP treatment. Data are expressed as mean ± SEM. *P < .05 vs SCD, Student t test. (I) Working model: CD73 is essential for induction of plasma adenosine in SCD. Elevated plasma adenosine contributes to erythrocyte sickling, tissue injury, and dysfunction by engagement of ADORA2B on erythrocytes to induce 2,3-BPG mutase activity and 2,3-BPG production. AMPK is a key enzyme that functions downstream of ADORA2B to activate 2,3-BPG mutase and promote 2,3-BPG production and subsequent erythrocyte sickling. Preclinically, inhibition of CD73 is a promising therapeutic strategy to treat SCD or prevent hypoxia-induced tissue damage. APCP treatment decreases multiorgan damage, including lung, spleen, and liver in SCD mice.