Topic Overview:

The prevention and treatment of acute chest syndrome (ACS) is a major clinical concern in sickle cell disease (SCD). However, the mechanism underlying the pathogenesis of ACS remains elusive. Ofori-Acquah and colleagues tested the hypothesis that the hemolysis byproduct hemin may elicit events that induce ACS. Infusion of a low dose of hemin caused acute intravascular hemolysis and an auto-amplification of extracellular hemin in transgenic sickle mice but not in sickle-trait littermates. The sickle mice developed multiple symptoms typical of ACS and succumbed rapidly. Pharmacologic inhibition of TLR4 and hemopexin replacement therapy prior to hemin infusion protected sickle mice from developing ACS. Replication of the ACS-like phenotype in nonsickle mice revealed that the mechanism of lung injury due to extracellular hemin is independent of SCD. Using genetic and bone marrow chimeric tools, Ofori-Acquah confirmed that TLR4, expressed in nonhematopoietic vascular tissues, mediates this lethal type of acute lung injury. Respiratory failure was averted after the onset of ACS-like symptoms in sickle mice by treating them with recombinant hemopexin. The study unveils a mechanism that helps to explain the pathogenesis of ACS and provides proof of principle for therapeutic strategies to prevent and treat this condition in mice.