טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentTsabary Ziva
SubjectExpression of Adhesion Molecules, Cytokines and Activation
Markers in Plasma and Monocytes of Sleep Apnea
Patients
DepartmentDepartment of Medicine
Supervisors Dr. Lena Lavie
Professor Emeritus Peretz Lavie


Abstract

Background:  Obstructive sleep apnea syndrome (OSAS) is characterized by frequent episodes of cessation of breathing (apneas) and hypoxemic events during sleep. OSAS has emerged in recent years as an important risk factor for cardiovascular morbidity. It has been suggested, that repeated apnea-related hypoxic events, initiate oxidative stress, which increases free-radical production in OSAS patients. We hypothesized that apnea-induced free-radical generation increases oxidative stress, which initiates monocyte and endothelial cell activation. This activation process promotes cytokine production and secretion, expression of adhesion molecules, and facilitates increased expression of oxidized LDL receptor CD36 and Fcγ receptors on monocytes' membrane.

Methods: Blood samples were withdrawn from OSAS patients and a control matched   group matched for age, gender, and body mass index (BMI). None of the subjects had any history of known disease, and none were taking any medications. 

Plasma levels of adhesion molecules sE-selectin and sP-selectin, plasma cytokines Tumor necrosis factor α (TNF-α) and Interleukin-10 (IL-10), monocyte expression levels of adhesion molecules CD15 and CD11c, monocytes scavenger receptor CD36 and monocytes Fcγ receptors CD16, CD32 and CD64 were measured.

Additionally, the levels of reactive oxygen species (ROS) were measured within monocytes, lymphocytes and granulocytes using oxidized Dihydroethidium (DHE), before and after cell activation with phorbol myristate acetate (PMA).

Results: The plasma sE-selectin, sP-selectin and monocytes CD15 and CD11c adhesion molecules of OSAS patients were significantly higher compared to the   matched control group. Plasma levels of TNF-α were significantly higher and plasma levels of IL-10 were significantly lower in OSAS group. Additionally, the mean fluorescence intensity of the CD32 on monocytes was significantly higher, while   CD16 and CD36 were only borderline significantly higher is OSAS patients compared to the matched control group. Except for IL-10, all these markers were correlated with sleep apnea severity.

Basal ROS production, as measured by oxidized Dihydroethidium, was significantly higher is monocytes of OSAS patients, and borderline significantly higher in lymphocytes and granulocytes. PMA activation resulted in significantly higher ROS production in OSAS patients compared to the control group in all three cells' populations.

Conclusions: Our findings support the hypothesis that oxidative stress, endothelial cell and monocyte activation increase in OSAS patients. This was evident by the increase in plasma concentrations of sE-selectin and sP-selectin, TNF-α, monocytes CD15 and CD11c, monocytes CD36 and CD32, and ROS production by monocytes, granulocytes and lymphocytes. These processes most probably constitute some of the mechanisms which are responsible for the development of cardiovascular morbidity in patients with sleep apnea.