This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200705-675OCv1 177/5/544    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Dyugovskaya, L. Articles by Lavie, L. PubMed PubMed Citation Articles by Dyugovskaya, L. Articles by Lavie, L.

Delayed Neutrophil Apoptosis in Patients with Sleep Apnea

¹ Lloyd Rigler Sleep Apnea Research Laboratory, Unit of Anatomy and Cell Biology, The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

Correspondence and requests for reprints should be addressed to Dr. Lena Lavie, Ph.D., Unit of Anatomy and Cell Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion, POB 9649, 31096 Haifa, Israel. E-mail: lenal{at}tx.technion.ac.il

Rationale: Obstructive sleep apnea (OSA), characterized by intermittent hypoxia/reoxygenation (IHR), is associated with atherosclerosis. Polymorphonuclear leukocytes (PMNs) are implicated in atherogenesis by producing oxidizing radicals and proteolytic enzymes during PMN–endothelium interactions. PMN apoptosis is a fundamental, injury-limiting mechanism, which prevents their destructive potential.

Objectives: To determine whether PMN apoptosis and expression of adhesion molecules are affected by OSA and IHR in vitro.

Methods: Apoptosis and expression of adhesion molecules were assessed in whole blood PMNs by flow cytometry, verified by various culture conditions, and morphology. These were complemented by exposing whole blood and purified PMNs to IHR and to sustained hypoxia in vitro.

Measurements and Main Results: This study demonstrates for the first time that, in patients with moderate to severe OSA, PMN apoptosis is delayed. Apoptosis was attenuated in patients with an apnea–hypopnea index (AHI) of more than 15, determined by decreased expression of low-CD16/annexin-V–positive PMNs, by lowered caspase-3 activity and nuclear condensation. Concomitantly, selectin-CD15 expression was increased in a severity-dependent manner in patients with moderate to severe OSA having an AHI greater than 15. The percentage of apoptotic PMNs was negatively correlated with OSA severity, determined by AHI, and positively with CD15 expression. In nasal continuous positive airway pressure–treated patients, CD15 expression was attenuated and low CD16 was increased, whereas omitting nasal continuous positive airway pressure for a single night increased CD15 expression and decreased the percentage of low CD16. IHR in vitro delayed PMN apoptosis as well.

Conclusions: Decreased apoptosis and increased expression of adhesion molecules were noted in OSA PMNs. Although adhesion molecules may facilitate increased PMN–endothelium interactions, decreased apoptosis may further augment these interactions and facilitate free radical and proteolytic enzyme release.

Key Words: obstructive sleep apnea • polymorphonuclear leukocytes • apoptosis • adhesion molecules • atherosclerosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Sleep apnea is associated with increased vascular risk. Inflammatory cells participate in vascular morbidity and are also activated by sleep apnea. Yet, the mechanisms by which neutrophils mediate atherogenesis in this syndrome are currently unknown. What This Study Adds to the Field Neutrophil apoptosis decreases and expression of selectins increases in sleep apnea. Treatment with positive pressure reverses both measures, whereas neutrophils of healthy subjects exposed to intermittent hypoxia in vitro show delayed apoptosis.