heme oxygenase 1 &Stasis

Sickle cell disease (SCO) is a devastating hemolytic disease characterized by recurring episodes of painful vaso-occlusion, leading to ischemia-reperfusion injury and organ damage. Despite significant advances in the knowledge of sickle hemoglobin and red blood cells, we still lack a clear understanding of the pathophysiology and treatment of vaso-occlusion. It is now understood that oxidative stress is a trigger for vascular inflammation which promotes vaso-occlusion. Recently the critical roles of endothelial cell activation and inflammation in vaso-occlusion have been recognized, in part due to the development of transgenic murine models of SCO. However, a critical gap exists in explaining how does the sickle patient defend or adapt to excessive hemolysis with the release of hemoglobin/heme/iron into the vasculature and the exuberant production of reactive oxygen species. To remove this heme burden and lessen the oxidative stress, the vasculature increases the expression of heme oxygenase-1 (HO-1). HO-1 is a highly adaptable anti-inflammatory defense against excessive heme burdens. We hypothesize that HO-1, an adaptive, anti- inflammatory gene, plays a critical role in the inhibition and resolution of vaso-occlusion in SCO. In Specific Aim 1, we will test whether HO-1 and its downstream products, including carbon monoxide, biliverdin/bilirubin and ferritin, manipulated pharmacologically or with gene therapy, will prevent hypoxia/reoxygenation-induced stasis, ameliorate organ pathology and prolong life span in transgenic sickle mice. In Specific Aim 2, we will identify the mechanisms whereby HO-1 modulates vasooclusion in transgenic sickle mice by examining the effects of HO-1 and its products on oxidative stress, NF-kB activation and endothelial cell adhesion molecule expression. We will demonstrate that adaptative increases in HO-1 activity in transgencic sickle mice are inadequate to handle the excessive heme burden. We believe that further upregulation of HO-1 activity and/or its downstream products will be important strategies to develop innovative new therapies to prevent and treat vaso-occlusion in SCO. This research on oxidative stress and inflammation using mouse models of SCO will identify new targets and drug therapies to alleviate the complications of SCO. We expect these new treatments will decrease sickle crises, prevent organ damage, improve quality and length of lives of sickle cell anemia patients.