טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentMazor Rafi
SubjectA Role for Primed Polymorphonuclear Leukocytes in the
Development of Hypertension
DepartmentDepartment of Medicine
Supervisors Ms. Batya Kristal
Assistant Professor Shifra Sela
Full Thesis textFull thesis text - English Version


Abstract

Chronic inflammation and endothelial dysfunction are two pathologies involved in the initiation of the development of atherosclerosis. Previous studies have shown that in hypertension, diabetes, renal failure, all clinical situations associated with high risk for developing atherosclerosis and cardiovascular disease, the peripheral polymorphonuclear leukocytes (PMNLs) are primed concomitantly contributing to oxidative stress and chronic inflammation, thus can be involved the development of atherosclerosis. In this study we 1. Characterized the PMNLs in hyperlipidemic patients as a representative group of patients in high risk for developing cardiovascular complications. 2. Evaluated the contribution of the PMNLs to the development of hypertension in the Sabra rat model of salt sensitivity. 1. We found that in hyperlipidemic patients, the PMNLs are primed concomitantly with high levels of inflammatory markers in the circulation. In these patients the PMNLs undergo spontaneous degranulation and the priming state correlated with the severity of hyperlipidemia. 2. We found that PMNL priming, oxidative stress and inflammation antecede the rise in blood pressure. PMNL depletion with specific antibodies significantly attenuated the development of hypertension. Inhibition of the NADPH oxidase markedly inhibited the development of hypertension in the salt sensitive strain, as well as decreased oxidative stress and inflammation. We conclude that primed PMNLs contribute to oxidative stress and inflammation also in hyperlipidemia as in other diseases associated with high risk for developing cardiovascular complications. In the Sabra rat model of hypertension, PMNLs are directly involved in the mechanism responsible for blood pressure elevation. At present, when clinical studies utilizing antioxidants as a treatment modality have failed in reducing cardiovascular events in diseases associated with atherosclerosis, this study suggests new treatment strategy aimed toward reducing PMNL priming.