Sickle Cell Disease and Acute Chest Syndrome: Mechanisms and Pathogenenesis

Abstract

Acute chest syndrome (ACS) is the major lung complication and leading cause of death in sickle cell disease (SCD). It is characterized by a rapid disease onset, pulmonary infiltration, hypoxemia, and several other clinical indications. Postmortem ACS lungs are characterized by histological evidence of alveolar capillary barrier disruption, fat emboli, and alveolar wall necrosis. Ischemia-reperfusion injury activation of invariant natural killer T lymphocytes is thought to heighten baseline pulmonary inflammation in SCD that may prime the lung for ACS development. Multiple factors, including hypoxia, infection, infarction, thrombosis, and fat emboli that are implicated in ACS pathogenesis are also associated with acute hemolysis. ACS is typically preceded by acute intravascular hemolysis, and the magnitude of anemia is linked to the severity of the lung injury. The heme hypothesis posits that the lung injury in ACS is caused by acute inflammation directly involving extracellular heme, a prototypical erythroid DAMP molecule released by hemolysis. In support of this model, the infusion of purified heme triggers a lethal acute lung injury in transgenic SCD mice that exhibit many of the characteristics of severe ACS. Additional experimental data indicate heme-induced ACS may involve vaso-occlusion and the release of neutrophil extracellular traps in the lung. Clinically, the risk of patients developing ACS is influenced by steady-state plasma concentrations of heme, and by polymorphisms in the gene encoding heme oxygenase-1, the rate-limiting heme degradation enzyme. Extracellular heme is therefore an ideal converging axis in the pathogenesis of ACS.