Published ahead of print on November 15, 2007, doi:10.1164/rccm.200705-675OC Am. J. Respir. Crit. Care Med., Volume 177, Number 5, March 2008, 544-554 A more recent version of this article appeared on March 1, 2008
Submitted on May 7, 2007 Delayed Neutrophil Apoptosis in Sleep Apnea PatientsLarissa Dyugovskaya1,1 The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Lloyd Rigler Sleep Apnea Research Laboratory, Unit of Anatomy and Cell Biology, Haifa, Israel * To whom correspondence should be addressed. 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 PMNs/endothelium interactions. PMN apoptosis is a fundamental, injury-limiting mechanism, which prevents their destructive potential. Objective: 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 PMNs to IHR and to sustained hypoxia in-vitro. Results: This study demonstrates for the first time that in moderate-to-severe OSA patients' PMN apoptosis is delayed. Apoptosis was attenuated in patients with apnea-hypopnea index (AHI)>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 moderate-to-severe OSA patients having AHI>15. The percentage of apoptotic PMNs was negatively correlated with OSA severity, determined by AHI, and positively with CD15 expression. In nasal-Continues-Positive-Airway-Pressure (nCPAP) treated patients, CD15 expression was attenuated and "low-CD16" was increased, while omitting nCPAP 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. While adhesion molecules may facilitate increased PMNs/endothelum interactions, decreased apoptosis may further augment these interactions and facilitate free radical and proteolytic enzymes' release. Key words: obstructive sleep apnea, polymorphonuclear leukocytes, apoptosis, adhesion molecules, atherosclerosis.
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