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P-selectin deficiency promotes liver senescence in sickle cell disease mice
Ravi Vats1,2, Tomasz W Kaminski1, Eun-Mi Ju1
1Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Insights
Chronic P-selectin deficiency in sickle cell disease (SCD) mice reduced liver ischemia but did not prevent liver injury. This failure was linked to increased cellular senescence and reduced cell proliferation in the liver.
Area of Science:
- Hematology
- Immunology
- Hepatology
Background:
- Sickle cell disease (SCD) involves erythrocyte sickling, vasoocclusion, and hemolysis due to a beta-globin gene mutation.
- P-selectin inhibition can prevent vasoocclusive events in SCD, but its long-term impact on liver health is unknown.
Purpose of the Study:
- To investigate the chronic effects of P-selectin deficiency on liver pathophysiology in a mouse model of SCD.
- To determine if P-selectin inhibition prevents hepatobiliary injury in the long term.
Main Methods:
- Utilized quantitative liver intravital microscopy.
- Employed a recently generated P-selectin-deficient mouse model of SCD.
Main Results:
- Chronic P-selectin deficiency attenuated liver ischemia in SCD mice.
- Hepatobiliary injury was not prevented in P-selectin-deficient SCD mice.
- Increased cellular senescence and reduced epithelial cell proliferation were observed in the livers of these mice.
Conclusions:
- Long-term P-selectin inhibition may not fully resolve liver injury in SCD.
- Cellular senescence and impaired epithelial regeneration contribute to persistent hepatobiliary damage.
- Further research is needed on the long-term consequences of P-selectin inhibition therapy in SCD patients.
Abstract:
Sickle cell disease (SCD) is caused by a homozygous mutation in the β-globin gene, which leads to erythrocyte sickling, vasoocclusion, and intense hemolysis. P-selectin inhibition has been shown to prevent vasoocclusive events in patients with SCD; 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 of investigating the long-term effects of chronic P-selectin inhibition therapy on liver pathophysiology in patients with SCD.
