Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation.

Acute intestinal inflammation involves early accumulation of neutrophils (PMNs) followed by either resolution or progression to chronic inflammation. Based on recent evidence that mucosal metabolism influences disease outcomes, we hypothesized that transmigrating PMNs influence the transcriptional profile of the surrounding mucosa. Microarray studies revealed a cohort of hypoxia-responsive genes regulated by PMN-epithelial crosstalk. Transmigrating PMNs rapidly depleted microenvironmental O2 sufficiently to stabilize intestinal epithelial cell hypoxia-inducible factor (HIF). By utilizing HIF reporter mice in an acute colitis model, we investigated the relative contribution of PMNs and the respiratory burst to "inflammatory hypoxia" in vivo. CGD mice, lacking a respiratory burst, developed accentuated colitis compared to control, with exaggerated PMN infiltration and diminished inflammatory hypoxia. Finally, pharmacological HIF stabilization within the mucosa protected CGD mice from severe colitis. In conclusion, transcriptional imprinting by infiltrating neutrophils modulates the host response to inflammation, via localized O2 depletion, resulting in microenvironmental hypoxia and effective inflammatory resolution.

Obesity and sleep: a growing concern.

PURPOSE OF REVIEW: The 'obesity epidemic' is a growing concern globally, and obesity trends are projected to continue increasing in both prevalence and overall mean BMI. Cardiovascular and metabolic comorbidities have historically been well described; however, obesity-related respiratory disease is now increasingly prevalent, in particular, sleep disordered breathing. The surge in clinically significant obstructive sleep apnoea and obesity hypoventilation syndrome is associated with increased cardiopulmonary morbidity, quality-of-life impairment, and a potential rise in the frequency of road traffic accidents. RECENT FINDINGS: We discuss recent trends in obesity and obesity-related sleep disordered breathing. We also discuss recently published international guidelines regarding the diagnosis and management of sleep disordered breathing, and in particular, the role of weight management interventions, such as bariatric surgery, in this area. We discuss possible approaches to meet the growing demand for sleep assessment and management in the future. SUMMARY: Obesity-related respiratory disease reflects an increasing proportion of patients in both inpatient and outpatient settings. It is important to recognize the impact of obesity on pulmonary physiology in order to appropriately care for this population, as well as plan for the future.

Severity of obstructive sleep apnoea predicts coronary artery plaque burden: a coronary computed tomographic angiography study.

Obstructive sleep apnoea (OSA) is associated with significantly increased risk of cardiovascular disease. Carotid ultrasonography and retrospective, uncontrolled, coronary imaging studies have suggested an association of OSA with subclinical atherosclerosis, but there is a lack of prospective, controlled studies directly evaluating the relationship of OSA with occult coronary artery disease. We performed coronary computed tomographic angiography and inpatient-attended sleep studies on a cohort of otherwise healthy males attending our sleep laboratory, and compared coronary artery plaque volume between subjects with low and high apnoea/hypopnoea index (AHI) scores. 29 subjects participated. The median AHI was 15.5 events · h(-1), with subjects who scored above this classified as high AHI. No significant differences were observed in demographic, anthropometric and clinical variables between the high- and low-AHI groups. Coronary plaque volume was significantly greater in the high-AHI group (mean plaque volume 2.6 ± 0.7 mm(2) versus 0.8 ± 0.2 mm(2); p=0.017) and, furthermore, correlated significantly with AHI (Spearman's r=0.433; p=0.019). Following adjustment for dyslipidaemia and fasting plasma glucose levels, AHI remained a significant predictor of plaque volume (standardised ß=0.424; p=0.027). In this prospective case-control study, we found that severity of OSA may predict occult coronary atherosclerosis in otherwise healthy overweight or obese male subjects.

An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia.

Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-κB. Recent studies have revealed a high degree of interdependence between HIF and NF-κB signaling; however, the relative contribution of each to hypoxia-induced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-κB to demonstrate that hypoxia activates NF-κB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-κB, we confirm a unidirectional dependence of hypoxic HIF-1α accumulation upon an intact canonical NF-κB pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptionally induced by hypoxia in a manner that is both HIF-1 and NF-κB dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-κB pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1α and the p65 subunit of NF-κB directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-κB signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression.

PGC-1alpha is coupled to HIF-1alpha-dependent gene expression by increasing mitochondrial oxygen consumption in skeletal muscle cells.

Mitochondrial biogenesis occurs in response to increased cellular ATP demand. The mitochondrial electron transport chain requires molecular oxygen to produce ATP. Thus, increased ATP generation after mitochondrial biogenesis results in increased oxygen demand that must be matched by a corresponding increase in oxygen supply. We found that overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which increases mitochondrial biogenesis in primary skeletal muscle cells, leads to increased expression of a cohort of genes known to be regulated by the dimeric hypoxia-inducible factor (HIF), a master regulator of the adaptive response to hypoxia. PGC-1alpha-dependent induction of HIF target genes under physiologic oxygen concentrations is not through transcriptional coactivation of HIF or up-regulation of HIF-1alpha mRNA but through HIF-1alpha protein stabilization. It occurs because of intracellular hypoxia as a result of increased oxygen consumption after mitochondrial biogenesis. Thus, we propose that at physiologic oxygen concentrations, PGC-1alpha is coupled to HIF signaling through the regulation of intracellular oxygen availability, allowing cells and tissues to match increased oxygen demand after mitochondrial biogenesis with increased oxygen supply.

A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury.

Nitric oxide (NO(*)) competitively inhibits oxygen consumption by mitochondria at cytochrome c oxidase and S-nitrosates thiol proteins. We developed mitochondria-targeted S-nitrosothiols (MitoSNOs) that selectively modulate and protect mitochondrial function. The exemplar MitoSNO1, produced by covalently linking an S-nitrosothiol to the lipophilic triphenylphosphonium cation, was rapidly and extensively accumulated within mitochondria, driven by the membrane potential, where it generated NO(*) and S-nitrosated thiol proteins. MitoSNO1-induced NO(*) production reversibly inhibited respiration at cytochrome c oxidase and increased extracellular oxygen concentration under hypoxic conditions. MitoSNO1 also caused vasorelaxation due to its NO(*) generation. Infusion of MitoSNO1 during reperfusion was protective against heart ischemia-reperfusion injury, consistent with a functional modification of mitochondrial proteins, such as complex I, following S-nitrosation. These results support the idea that selectively targeting NO(*) donors to mitochondria is an effective strategy to reversibly modulate respiration and to protect mitochondria against ischemia-reperfusion injury.

Nasal pillows as an alternative interface in patients with obstructive sleep apnoea syndrome initiating continuous positive airway pressure therapy.

Side-effects directly due to the nasal mask are common in patients with obstructive sleep apnoea syndrome (OSAS) commencing continuous positive airway pressure (CPAP). Recently, nasal pillows have been designed to overcome these issues. Limited evidence exists of the benefits and effectiveness of these devices. Twenty-one patients (19 male, 49±10years) with the established diagnosis of OSAS [apnoea/hypopnoea index (AHI): 52±22] and who had a successful CPAP titration were commenced on CPAP therapy (10±2cmH2O), and randomized to 4weeks of a nasal pillow (P) and a standard nasal mask (M) in a crossover design. Outcome measures were objective compliance, AHI, quality of life, Epworth Sleepiness Score (ESS) and CPAP side-effects. There was no difference in compliance (M versus P: 5.1±1.9h versus 5.0±1.7h; P=0.701) and AHI (2.6±2.7 versus 3.0±2.9; P=0.509). Quality of life and ESS improved with CPAP, but there was no difference in the extent of improvement between both devices. Usage of nasal pillows resulted in less reported pressure on the face and more subjects found the nasal pillow the more comfortable device. However, there was no clear overall preference for either device at the end of the study (mask=57%, pillow=43%; P=0.513). The applied CPAP pressure did not correlate with compliance, AHI and ESS. Furthermore, no differences in outcome parameters were noted comparing groups with CPAP pressure <10 and ≥10cm H(2) O. Nasal pillows are equally effective in CPAP therapy, but do not generally lead to improved compliance.

Continuous positive airway pressure therapy: new generations.

Continuous positive airway pressure (CPAP) is the treatment of choice for obstructive sleep apnoea syndrome (OSAS). However, CPAP is not tolerated by all patients with OSAS and alternative modes of pressure delivery have been developed to overcome pressure intolerance, thereby improving patient comfort and adherence. Auto-adjustable positive airway pressure (APAP) devices may be utilised for the long-term management of OSAS and may also assist in the initial diagnosis of OSAS and titration of conventional CPAP therapy. Newer modalities such as C-Flex and A-Flex also show promise as treatment options in the future. However, the evidence supporting the use of these alternative modalities remains scant, in particular with regard to long-term cardiovascular outcomes. In addition, not all APAP devices use the same technological algorithms and data supporting individual APAP devices cannot be extrapolated to support all. Further studies are required to validate the roles of APAP, C-Flex and A-Flex. In the interim, standard CPAP therapy should continue as the mainstay of OSAS management.

Technologic advances in the assessment and management of obstructive sleep apnoea beyond the apnoea-hypopnoea index: a narrative review.

Obstructive sleep apnoea (OSA) is a growing and serious worldwide health problem with significant health and socioeconomic consequences. Current diagnostic testing strategies are limited by cost, access to resources and over reliance on one measure, namely the apnoea-hypopnoea frequency per hour (AHI). Recent evidence supports moving away from the AHI as the principle measure of OSA severity towards a more personalised approach to OSA diagnosis and treatment that includes phenotypic and biological traits. Novel advances in technology include the use of signals such as heart rate variability (HRV), oximetry and peripheral arterial tonometry (PAT) as alternative or additional measures. Ubiquitous use of smartphones and developments in wearable technology have also led to increased availability of applications and devices to facilitate home screening of at-risk populations, although current evidence indicates relatively poor accuracy in comparison with the traditional gold standard polysomnography (PSG). In this review, we evaluate the current strategies for diagnosing OSA in the context of their limitations, potential physiological targets as alternatives to AHI and the role of novel technology in OSA. We also evaluate the current evidence for using newer technologies in OSA diagnosis, the physiological targets such as smartphone applications and wearable technology. Future developments in OSA diagnosis and assessment will likely focus increasingly on systemic effects of sleep disordered breathing (SDB) such as changes in nocturnal oxygen and blood pressure (BP); and may also include other factors such as circulating biomarkers. These developments will likely require a re-evaluation of the diagnostic and grading criteria for clinically significant OSA.

A portable automated assessment tool for sleep apnea using a combined Holter-oximeter.

STUDY OBJECTIVES: Resource limitations have raised interest in portable monitoring systems that can be used by specialist sleep physicians as part of an overall strategy to improve access to the diagnosis of sleep apnea. This study validates a combined electrocardiogram and oximetry recorder (Holter-oximeter) against simultaneous polysomnography for detection of sleep apnea. DESIGN: Prospective study. SETTING: A dedicated sleep disorders unit. PARTICIPANTS: 59 adults presenting for evaluation of suspected sleep apnea. INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: An automated algorithm previously developed for sleep apnea detection was applied to the electrocardiogram and oximetry measurements. The algorithm provides (a) epoch-by-epoch estimates of apnea occurrence and (b) estimates of overall per-subject AHI. Using separate thresholds of AHI > or =15 and AHI <5 for defining clinically significant and insignificant sleep apnea, sensitivity, specificity, and likelihood ratios, conditional on positive or negative (but not indeterminate) test results were used to assess agreement between the proposed system and polysomnography. Sensitivity of 95.8% and specificity of 100% was achieved. Positive and negative likelihood ratios were >20 and 0.04 respectively, with 16.7% of subjects having intermediate test results (AHI 5-14/h). Regardless ofAHI, 85.3% of respiratory events were correctly annotated on an epoch-by-epoch basis. AHI underestimation bias was 0.9/h, and the antilogs of log-transformed limits of agreement were 0.3 and 2.7. Correlation between estimated and reference AHI was 0.95 (P <0.001). CONCLUSION: Combined Holter-oximeter monitoring compares well with polysomnography for identifying sleep apnea in an attended setting and is potentially suitable for home-based automated assessment of sleep apnea in a population suspected of having sleep apnea.

Epidemiological aspects of obstructive sleep apnea.

Obstructive sleep apnea (OSA) is probably the most common respiratory disorder, with recent data from the United States and Europe suggesting that between 14% and 49% of middle-aged men have clinically significant OSA. The intimate relationship between OSA and obesity means that its prevalence will only increase as the global obesity epidemic evolves. At an individual level, OSA leads to a significant decrease in quality of life (QOL) and functional capacity, alongside a markedly increased risk of cardiovascular disease and death. Emerging data also suggest that the presence and severity of OSA and associated nocturnal hypoxemia are associated with an increased risk of diabetes and cancer. At a societal level, OSA not only leads to reduced economic productivity, but also constitutes a major treatable risk factor for hypertension, coronary artery disease (CAD) and stroke. This article addresses OSA from an epidemiological perspective, from prevalence studies to economic aspects to co-morbidity.

Combined pulmonary involvement in hereditary lysozyme amyloidosis with associated pulmonary sarcoidosis: a case report.

Sarcoidosis is a multisystem inflammatory disorder of unknown cause which can affect any organ system. Autosomal dominant lysozyme amyloidosis is a very rare form of hereditary amyloidosis. The Arg64 variant is extraordinarily rare with each family showing a particular pattern of organ involvement, however while Sicca syndrome, gastrointestinal involvement and renal failure are common, lymph node involvement is very rare. In this case report we describe the first reported case of sarcoidosis in association with hereditary lysozyme amyloidosis.

Hypoxia activates NF-kappaB-dependent gene expression through the canonical signaling pathway.

Hypoxia and inflammation are coincidental events in a diverse range of disease states including tumor growth, ischemia, and chronic inflammation. Hypoxia contributes to the development of inflammation, at least in part through the activation and/or potentiation of NF-kappaB, a master regulator of genes involved in innate immunity, inflammation, and apoptosis. NF-kappaB can be activated through two distinct signaling pathways termed the canonical and noncanonical pathways, respectively. The canonical pathway is activated through the IKKalpha/beta/gamma complex, while the noncanonical pathway involves NIK-mediated activation of IKKalpha homodimers. In the current study, we have investigated the relative roles of these two pathways in hypoxia-dependent NF-kappaB activation. Lymphotoxin alpha1beta2 (LTalpha1beta2) activated both the canonical and noncanonical NF-kappaB signaling pathways in HeLa cells. Sustained hypoxia enhanced basal and LTalpha1beta2-induced NF-kappaB activity in a manner that was dependent upon the canonical but not the noncanonical signaling pathway. Intermittent hypoxia activated NF-kappaB in a manner that was also primarily dependent upon the canonical pathway. Knockdown of the p65 subunit of the canonical NF-kappaB pathway was sufficient to abolish the effects of hypoxia on LTalpha1beta2-induced NF-kappaB activity. Furthermore, in synovial biopsies obtained at arthroscopy from patients with active inflammatory arthritis, the canonical pathway was preferentially activated in those patents with lower joint pO2 values. In summary, we hypothesize that hypoxia enhances NF-kappaB activity primarily through affecting the canonical pathway.