This project will test theability of anti-inflammatory agents to block decrease in blood flow directly measured in the skin, deep tissue and bone marrow of subjects with sickle cell disease. We hypothesize that therapeutic interventions that interrupt adhesive interactions between sickle erythrocytes, leukocytes, platelets and vascular endothelium will lessen or abrogate the vaso occlusion, hemoglobin desaturations, and release of measures of vascular damage induced by intermittent hypoxia. While sickle cell disease (SCD) is thought of as acute episodes of marked RBC sickling, sicklerelated vaso occlusion occurs continually even during non-crisis periods. The cumulative effect of these acute and chronic processes is end-organ damage. Recent data from animal models underscore the critical importance of leukocyte adhesion to the vascular endothelium. It is therefore likely that therapies that interfere with the formation of the adhesive interactions between leukocytes, sickle red cells and vascular endothelium will decrease vascular and end-organ damage. RBC siekling is triggered by hypoxia. Sleep studies in SCD children demonstrate that 10 to 40 episodes of desaturation occur each night with oxygen saturation dropping to 75 to 85%. We directly measured decreases in blood flow in response to nitrogen-induced hypoxia in subjects with sickle cell disease. These decreases are six-times greater than normal controls (p<.001). We will develop this model ofvaso occlusion in humans and extend the studies to include measurement of hypoxia-induced changes in inflammatory mediators (slCAM, sVCAM), markers of vascular damage (circulating endothelial cells (EC) and EC activation), and measures of deep tissue blood flow (ultrasound and BOLD MRI). These parameters will be measured in response to nitrogen-induced hypoxia as well as hypoxic episodes naturally occurring during sleep. We will then use anti-inflammat0ry agents to block the changes in blood flow and increase in markers of vascular damage detected in these well-characterized models. If these agents are successful, we have direct evidence in humans that inflammation plays a role in vas0 occlusion. Furthermore, this model may serve to text candidate treatments for sickle cell disease. While not within the scope of the present proposal, we anticipate that therapeutic interventions that abrogate hypoxiainduced blood flow decreases; hypoxie responses and changes in markers of vascular damage detected in these human models will decrease frequency of crisis and lessen the degree of end-organ damage if tested in larger clinical trials.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHL1)
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University of Southern California
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Chandrakasan, Shanmuganathan; Malik, Punam (2014) Gene therapy for hemoglobinopathies: the state of the field and the future. Hematol Oncol Clin North Am 28:199-216
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