Chronic p-selectin deficiency leads to senescence induced exacerbated organ injury in sickle cell disease mice Ravi Vats1, Eun-Mi Ju1, Egemen Tutuncuoglu1, Jesus Tejero1,2, Enrico Novelli1,2,3, Prithu Sundd1,2,3, , and Tirthadipa Pradhan-Sundd1,2,3 Affiliations: 1. Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA. 2. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 3. Division of Hematology-Oncolcogy, University of Pittsburgh School of Medicine, Pittsburgh, PA Abstract: Sickle cell disease (SCD) is caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, vaso-occlusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vaso-occlusive events in SCD patients, however, the chronic effect of P-selectin inhibition in SCD remains to be determined. Here, we used quantitative liver intravital microscopy in our recently generated P-selectin deficient SCD mice to show that chronic P-selectin deficiency attenuates liver ischemia, but fails to prevent hepatobiliary injury. Remarkably, we find that this failure in resolution of hepatobiliary injury in P-selectin deficient SCD mice is associated with the increase in cellular senescence and reduced epithelial cell proliferation in the liver. These findings highlight the importance to investigate the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in SCD patients.