Abstract
Sickle cell disease (SCD) is an inherited hemolytic disorder, defined by a point mutation in the β-globin gene. Stress conditions such as infection, inflammation, dehydration, and hypoxia trigger erythrocyte sickling. Sickled red blood cells (RBCs) hemolyze more rapidly, show impaired deformability, and increased adhesive properties to the endothelium. In a proinflammatory, pro-coagulative environment with preexisting endothelial dysfunction, sickled RBCs promote vascular occlusion. Hepatobiliary involvement related to the sickling process, such as an acute sickle hepatic crisis, is observed in about 10% of acute sickle cell crisis incidents. In mice, ligation of CD40 with an agonistic antibody leads to a macrophage activation in the liver, triggering a sequence of systemic inflammation, endothelial cell activation, thrombosis, and focal ischemia. We found that anti-CD40 antibody injection in sickle cell mice induces a systemic inflammatory and hemodynamic response with accelerated hemolysis, extensive vaso-occlusion, and large ischemic infarctions in the liver mimicking an acute hepatic crisis. Administration of the tumor necrosis factor-α (TNF-α) blocker, etanercept, and the heme scavenger protein, hemopexin attenuated end-organ damage. These data collectively suggest that anti-CD40 administration offers a novel acute liver crisis model in humanized sickle mice, allowing for evaluation of therapeutic proof-of-concept.
Highlights
Sickle cell disease (SCD) is a monogenic autosomal recessive disorder defined by a missense mutation in the b-globin gene, forming the sickle hemoglobin (HbS) [1]
In response to agonistic anti-CD40 antibody treatment, sickle cell mice developed an acute hepatitis with histological features of vessel-occlusion and ischemia
As further validation of our model, we found that the treatment of sickle cell mice with the tumor necrosis factor-a (TNF-a) blocker etanercept or plasma-derived human hemopexin significantly reduced anti-CD40-induced acute inflammation and liver necrosis
Summary
Sickle cell disease (SCD) is a monogenic autosomal recessive disorder defined by a missense mutation in the b-globin gene, forming the sickle hemoglobin (HbS) [1]. The term “sickle cell crisis” summarizes clinically heterogeneous acute disease complications such as vascular-occlusive crisis, hemolytic crisis, sequestration syndrome with enlargement of liver and spleen and, aplastic or hypoplastic crisis [1, 9]. It is associated with life-threatening conditions such as acute chest syndrome (ACS), stroke, avascular necrosis, renal dysfunction, aplastic, and splenic sequestration crisis. The sequelae of aggravated hemolysis, hypercoagulability and, increased adhesion of RBCs, leukocytes, and platelets to the endothelium aggravate local hypoxia and result in vaso-occlusive crisis (VOC) and end-organ ischemia [1, 7, 12, 13]
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