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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL070595-05
Application #
7446747
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$266,262
Indirect Cost
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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
Ulker, Pinar; Gunduz, Filiz; Meiselman, Herbert J et al. (2013) Nitric oxide generated by red blood cells following exposure to shear stress dilates isolated small mesenteric arteries under hypoxic conditions. Clin Hemorheol Microcirc 54:357-69
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Ulker, Pinar; Yaras, Nazmi; Yalcin, Ozlem et al. (2011) Shear stress activation of nitric oxide synthase and increased nitric oxide levels in human red blood cells. Nitric Oxide 24:184-91
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Patel, Nitin; Tahara, Stanley M; Malik, Punam et al. (2011) Involvement of miR-30c and miR-301a in immediate induction of plasminogen activator inhibitor-1 by placental growth factor in human pulmonary endothelial cells. Biochem J 434:473-82
Uyuklu, Mehmet; Canpolat, Murat; Meiselman, Herbert J et al. (2011) Wavelength selection in measuring red blood cell aggregation based on light transmittance. J Biomed Opt 16:117006
Simmonds, Michael J; Meiselman, Herbert J; Marshall-Gradisnik, Sonya M et al. (2011) Assessment of oxidant susceptibility of red blood cells in various species based on cell deformability. Biorheology 48:293-304
Baskurt, Oguz K; Uyuklu, Mehmet; Meiselman, Herbert J (2010) Time course of electrical impedance during red blood cell aggregation in a glass tube: comparison with light transmittance. IEEE Trans Biomed Eng 57:969-78
Ulker, Pinar; Meiselman, Herbert J; Baskurt, Oguz K (2010) Nitric oxide generation in red blood cells induced by mechanical stress. Clin Hemorheol Microcirc 45:169-75

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