Effects of 10 days of modest intermittent hypoxia on circulating measures of inflammation in healthy humans.

PURPOSE: Obstructive sleep apnea (OSA) is a common disease which is associated with elevated inflammatory markers and adhesion molecules, possibly due to nightly intermittent hypoxia (IH). The purpose of this study was to test the hypothesis that IH would increase systemic inflammatory markers in healthy human males. METHODS: Healthy, young male subjects (n = 9; 24 ± 2 years) were exposed to a single daily isocapnic hypoxia exposure (oxyhemoglobin saturation = 80%, 1 h/day) for 10 consecutive days. Serum granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1ß, interleukin-6, interleukin-8, leptin, monocyte chemotactic protein-1, vascular endothelial growth factor, intracellular adhesion molecule-1, and vascular cell adhesion molecule-1 were measured before and following the 10 days of IH using Luminex. RESULTS: Nine subjects completed the study (24 ± 2 years; 24 ± 2 kg/m(2)). The mean oxyhemoglobin saturation was 80.8 ± 1.6% during the hypoxia exposures. There was no significant change in any of the markers of inflammation (paired t test, P > 0.2 all cytokines). CONCLUSIONS: These findings suggest that (1) a more substantial or a different pattern of hypoxemia might be necessary to activate systemic inflammation, (2) the system may need to be primed before hypoxic exposure, or (3) increases in inflammatory markers in patients with OSA may be more related to other factors such as obesity or nocturnal arousal.

Residual sleep apnea on polysomnography after 3 months of CPAP therapy: clinical implications, predictors and patterns.

OBJECTIVE: We sought to determine the clinical implications, predictors and patterns of residual sleep apnea on continuous positive airway pressure (CPAP) treatment in patients with moderate-to-severe obstructive sleep apnea (OSA). METHODS: We performed a post hoc secondary analysis of data from a previously reported randomized trial. Sleepy patients with a high risk of moderate-to-severe OSA identified by a diagnostic algorithm were randomly assigned to standard CPAP titration during polysomnography (PSG) or ambulatory titration using auto-CPAP and home sleep testing. We observed them for 3 months and measured apnea-hypopnea index (AHI) on CPAP, Epworth sleepiness scale (ESS), sleep apnea quality of life index (SAQLI), CPAP pressure and objective CPAP compliance. RESULTS: Sixty-one patients were randomized, 30 to the PSG group and 31 to the ambulatory group. Fifteen patients (25%) had residual sleep apnea (AHI > 10/h on CPAP) with similar proportions in the PSG (7/30) and ambulatory (8/31) groups. Baseline variables including age, body mass index (BMI), ESS, SAQLI, respiratory disturbance index (RDI) and CPAP pressure did not differ between the groups. Outcomes including compliance were worse in patients with residual sleep apnea. Periodic breathing was prevalent among patients with residual sleep apnea. CONCLUSIONS: Residual sleep apnea is common in patients with moderate-to-severe OSA, despite careful CPAP titration, and is associated with worse outcomes.

Alpha-1-antitrypsin deficiency: current concepts.

Since the condition was first described four decades ago, alpha-1-antitrypsin (A1AT) deficiency has served as a model for other disease processes. A1AT is the archetypal serpin designed to ensnare proteases, a process that involves significant conformational change within the molecule. Mutations in the A1AT gene lead to misfolding of the protein and accumulation within the endoplasmic reticulum of hepatocytes resulting in two different pathologic processes. First, the accumulation of mutant A1AT protein has a directly toxic effect on the liver, resulting in hepatitis and cirrhosis. Second, the resultant decrease in circulating A1AT results in protease-antiprotease imbalance at the lung surface and emphysema ensues. A1AT deficiency therefore can be seen as two distinct disease processes: a conformational disease of the liver and a protease-antiprotease imbalance of the lung. This two-stage model of disease in A1AT deficiency is elegant in its simplicity and goes a long way to explaining the clinical manifestations that occur in patients with the condition. However, some aspects of the disease are not readily explained. Recent findings suggest that there is more to the lung damage in A1AT deficiency than simple proteolytic insult and that the presence of the mutant protein itself is proinflammatory and may indeed cause chronic injury to the cells that produce it. This review discusses some of the emerging concepts in alpha-1-antitrypsin research and outlines the implications these new ideas may have for treatment of this condition.

Diagnosis and initial management of obstructive sleep apnea without polysomnography: a randomized validation study.

BACKGROUND: Polysomnography (PSG), despite limited availability and high cost, is currently recommended for diagnosis of obstructive sleep apnea and titration of effective continuous positive airway pressure (CPAP). OBJECTIVE: To test the utility of a diagnostic algorithm in conjunction with ambulatory CPAP titration in initial management of obstructive sleep apnea. DESIGN: A randomized, controlled, open-label trial that compared standard PSG with ambulatory CPAP titration in high-risk patients identified by a diagnostic algorithm. SETTING: A tertiary referral sleep disorders program in Vancouver, British Columbia, Canada. PATIENTS: 68 patients with a high pretest probability of moderate to severe obstructive sleep apnea (apnea-hypopnea index [AHI] >15 episodes/h) identified by sequential application of the Epworth Sleepiness Scale (ESS) score, Sleep Apnea Clinical Score, and overnight oximetry. INTERVENTION: Patients were randomly assigned to PSG or ambulatory titration by using a combination of auto-CPAP and overnight oximetry. They were observed for 3 months. MEASUREMENTS: Apnea-hypopnea index on CPAP, ESS score, quality of life, and CPAP adherence. RESULTS: The PSG and ambulatory groups had similar median BMI (38 kg/m2), age (55 years), ESS score (14 points), and respiratory disturbance index (31 episodes of respiratory disturbance/h). Each episode is determined by a computer algorithm based on analysis of oxygen saturation measured by pulse oximetry. After 3 months, there were no differences in the primary outcome, AHI on CPAP (median, 3.2 vs. 2.5; difference, 0.8/h [95% CI, -0.9 to 2.3]) (P = 0.31), between the PSG and ambulatory groups, or in the secondary outcomes, ESS score, Sleep Apnea Quality of Life Index, and CPAP. Adherence to CPAP therapy was better in the ambulatory group than in the PSG group (median, 5.4 vs. 6.0; difference, -1.12 h/night [CI, -2.0 to 0.2]) (P = 0.021). CONCLUSIONS: In the initial management of patients with a high probability of obstructive sleep apnea, PSG confers no advantage over the ambulatory approach in terms of diagnosis and CPAP titration. The ambulatory approach may improve adherence to treatment. When access to PSG is inadequate, the ambulatory approach can be used to expedite management of patients most in need of treatment.

Z alpha1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant.

BACKGROUND: Alpha1-antitrypsin (A1AT) is an abundant protein that is synthesized in the liver and is secreted into the plasma. From the plasma, A1AT diffuses into various body compartments, including the lung where it provides much of the antiprotease protection. The current understanding of the pathogenesis of emphysema in A1AT-deficient individuals focuses on the polymerization of mutant protein within the liver, which results in a deficiency of circulating A1AT and a protease-antiprotease imbalance in the lungs. METHODS AND RESULTS: In this study, we evaluated BAL fluid samples from five healthy volunteers, five individuals with ZA1AT deficiency, and an individual with the PiZZ phenotype who had received a liver transplant. We show that the lung itself is a source of A1AT. In addition, the Z protein formed in the lung polymerizes, and these polymers are detectable in lung epithelial lining fluid by enzyme-linked immunosorbent assay and Western blot analysis. Finally, we show that polymeric ZA1AT is a potent neutrophil chemoattractant that is similar to polymerized MA1AT. CONCLUSIONS: Our findings suggest that the polymerization of locally produced ZA1AT is a contributory factor to the lung inflammation experienced by those with A1AT deficiency and that standard antiprotease therapies may not address this problem.