Vaso-occlusion is the primary source of pathology in sickle cell disease and although there have been advances in our understanding of this phenomenon in the last few years, almost nothing is known of the physiological basis of sickle cell organ damage and the relative roles which red cell deformability and adhesion play. Since the nature of vaso-occlusive injury may vary from organ to organ, we will study three organs which suffer extensive damage in sickle cells disease: kidney, retina, and lung in collaboration with three laboratories which have specialized in these organs. We will use two animal models for these studies with which our laboratory has extensive experience: 1) the transgenic betaS mouse and 2) rat organ preparations in which human sickle cells and control AA cells will be infused while physiological function is monitored. We intend to define the role and sites of adhesion versus direct obstruction for sickle cells in each organ, and the physiological and biochemical bases of any differences which are detected. Our preliminary data already suggest that each organ may be a special case, different from the other microcirculatory beds which have been previously studied. Once specific organ damage is established and characterized, we will undertake to prevent it from occurring in the animal models. Such studies may result in protocols which will ameliorate morbidity associated with three different types of pathology in the sickle cell patient: renal dysfunction; retinopathy, which leads to loss of vision; and pulmonary dysfunction which leads to acute chest. We will examine Ss vaso-occlusion in three organs using two animal models: I) Using betaS transgenic mice we will: Establish the natural history of kidney, retinal, and lung pathology by documenting the development of organ damage by determining the presence of edema and the appearance of infarcts with non-invasive MRI techniques. We will also conduct functional tests in the kidney and lung and descriptive studies of neovascularization in the retina on control and transgenic animals before and after subjecting them to pro-sickling and pro-occlusive stresses in collaboration with investigators experienced in the study of each individual organ. II) Using rat organ preparations perfused either in vivo or ex vivo with human red cells in which we will: Determine if deformable SS discocytes (SS2) and SS dense cells (SS4) adhere or obstruct the microcirculation and to which vessels. What are the consequences of simultaneous perfusion of deformable disocytes (SS2) and dense cells (SS4)? What are the functional consequences of vaso- occlusion by sickle cells for various organs. What is the role of endogenous vaso-active substances such as prostaglandins, EDRF, and endothelin which may be released in response to hypoxia or red cell adhesion.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Comprehensive Center (P60)
Project #
5P60HL038655-09
Application #
5213667
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
1996
Total Cost
Indirect Cost
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