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.
Aging is the most significant risk factor for the majority of chronic diseases, including liver disease. The cellular, molecular, and pathophysiological mechanisms that promote age-induced hepatovascular changes are unknown due to our inability to visualize changes in liver pathophysiology in live mice over time. We performed quantitative liver intravital microscopy (qLIM) in live C57BL/6J mice to investigate the impact of aging on the hepatovascular system over a 24-month period. qLIM revealed that age-related hepatic alterations include reduced liver sinusoidal blood flow, increased sinusoidal vessel diameter and loss of small hepatic vessels. The ductular cell structure deteriorates with age, resulting in altered expression of hepatic junctional proteins. Furthermore, qLIM imaging revealed increased inflammation in the aged liver, which was linked to increased expression of proinflammatory macrophages, hepatic neutrophils, liver sinusoidal endothelial cells, and procoagulants. Finally, we detected elevated NF-κB pathway activity in aged livers. Overall, these findings emphasize the importance of inflammation in age-related hepatic vasculo-epithelial alterations and highlight the utility of qLIM in studying age-related effects in organ pathophysiology.
Hemophilia A is an inherited bleeding disorder caused by defective or deficient coagulation factor-VIII (FVIII) activity. Until recently, the only treatment for prevention of bleeding involved intravenous administration of FVIII. Gene therapy with adeno associated vectors (AAV) has shown some efficacy in hemophilia A patients. However, limitations persist due to AAV-induced cellular stress, immunogenicity, and reduced durability of gene expression. Herein, we examined the efficacy of liver-directed gene transfer in FVIII knock out mice by AAV8-GFP. Surprisingly, compared to control mice, FVIII knockout (F8TKO) mice showed significant delay in AAV8-GFP transfer in the liver. We found that the delay in liver directed gene transfer in F8TKO mice was associated with absence of liver sinusoidal endothelial cell (LSEC) fenestration, which led to aberrant expression of several sinusoidal endothelial proteins causing increased capillarization and decreased permeability of LSECs. This is the first study to link impaired liver-directed gene transfer to liver-endothelium maladaptive structural changes associated with FVIII deficiency in mice.
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