Targeted Treatment Of Acute Chest Syndrome In Transgenic Sickle Mice

Acute chest syndrome (ACS) is a major cause of morbidity and mortality in sickle cell disease (SCD). The diagnosis, prevention and treatment of ACS pose major clinical concerns in SCD partly because the mechanism underlying the pathogenesis of this syndrome remains elusive. Our group first reported that excess intravascular hemin causes a lethal acute lung injury (ALI) in transgenic SCD mice reminiscent of ACS (Ghosh and Ofori-Acquah, Blood 116 Suppl 1:944, 2010). Subsequently, large-scale genomics studies by Bean et al., (Blood 120:3822-8, 2012) and Galarneau et al., (Blood, 122:434-42, 2013) have implicated hemin catabolism and inflammation in the pathogenesis of ACS. In addition, we have reported recently that raised plasma free hemin increases the odds of ACS in children with SCD (Adisa et al., Br J Haematol. 2013). Collectively, these studies support a new theme of ACS pathogenesis involving extracellular hemin. In the current study, we validated the respiratory dysfunction of this ACS model, tested the hypothesis that toll-like receptor 4 (TLR4) mediates the associated lung injury, and examined the efficacy of two strategies to treat the condition in mice. Arterial blood gas analysis of SS mice with the ACS-like disease confirmed severe hypoxemia (PaO2; 40.23 ±3.85 mmHg, SO2; 58.72±6.6%, p Disclosures: No relevant conflicts of interest to declare.