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Delayed neutrophil apoptosis in patients with sleep apnea
Larissa Dyugovskaya1, Andrey Polyakov, Peretz Lavie
1Unit of Anatomy and Cell Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion, POB 9649, 31096 Haifa, Israel.
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.
Insights
Obstructive sleep apnea (OSA) delays polymorphonuclear leukocyte (PMN) apoptosis and increases adhesion molecule expression, contributing to atherosclerosis. This suggests PMNs may cause more damage in OSA patients.
Area of Science:
- Cardiovascular Research
- Immunology
- Sleep Medicine
Background:
- Obstructive sleep apnea (OSA) is linked to atherosclerosis, with polymorphonuclear leukocytes (PMNs) playing a role in atherogenesis.
- PMN apoptosis is a critical mechanism to limit tissue damage from PMN-derived factors.
Purpose of the Study:
- To investigate the impact of OSA and intermittent hypoxia/reoxygenation (IHR) on PMN apoptosis and adhesion molecule expression.
- To determine if OSA severity correlates with changes in PMN apoptosis and adhesion molecule expression.
Main Methods:
- PMN apoptosis and adhesion molecule expression (CD15, CD16) were measured using flow cytometry in patients with OSA.
- Whole blood and purified PMNs were exposed to in vitro IHR and sustained hypoxia to mimic OSA conditions.
- Morphological analysis and caspase-3 activity assays complemented flow cytometry findings.
Main Results:
- PMN apoptosis was significantly delayed in patients with moderate to severe OSA (apnea-hypopnea index > 15).
- CD15 expression on PMNs increased with OSA severity, while low-CD16/annexin-V-positive PMNs (apoptotic markers) decreased.
- In vitro IHR also delayed PMN apoptosis, supporting the in vivo findings.
Conclusions:
- OSA is associated with reduced PMN apoptosis and increased expression of adhesion molecules like CD15.
- These alterations in PMNs may enhance PMN-endothelium interactions, potentially increasing the release of damaging free radicals and enzymes in OSA.
- Continuous positive airway pressure (CPAP) treatment appeared to mitigate these PMN changes.
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