[Show abstract][Hide abstract] ABSTRACT: Patients with precapillary pulmonary hypertension (PH) have been reported to suffer from poor sleep quality, however, if this is related to physical exercise performance has not yet been thoroughly investigated.
Clinically stable out-patients with idiopathic pulmonary arterial hypertension (IPAH, n = 52) and chronic thromboembolic PH (CTEPH, n = 64) in NYHA classes II and III were prospectively enrolled. 54 healthy volunteers matched for anthropometric variables served as a control group. The Pittsburgh Sleep Quality Index (PSQI) was used to rate subjective sleep quality. In the PH patients, six-minute walk tests (6MWT) were performed to assess exercise capacity.
Poor sleep quality (i.e. a PSQI score > 5) occurred more frequently in PH (IPAH: n = 25 [48.1%], CTEPH: n = 39 [60.9%], controls: n = 10 [18.5%]; p < 0.01 when compared to controls). In addition, poor vs. good sleepers had significantly higher average NYHA class (IPAH: 2.6 ± 0.1 vs. 2.3 ± 0.1, CTEPH: 2.8 ± 0.1 vs. 2.3 ± 0.2; p < 0.01) and shorter 6MWT distances (IPAH: 338 ± 23 vs. 441 ± 29 m, CTEPH: 355 ± 15 vs. 413 ± 26 m; p < 0.05).
Self-reported poor sleep quality is more common in PH than in healthy controls. Furthermore, it is related to reduced physical exercise capacity.
BMC Pulmonary Medicine 12/2015; 15(1):5. DOI:10.1186/s12890-015-0005-3 · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate whether NADPH oxidase 2 (NOX2), a major source of reactive oxygen species (ROS), contributes to the emergence of arterial hypertension in a murine model of sleep apnea.
Obstructive sleep apnea (OSA) is a risk factor for arterial hypertension and it is linked to oxidative stress.
C57BL/6J mice were exposed to chronic intermittent hypoxia (CIH) for 6 weeks (5 days/week, 8 h/day, alternating cycles of hypoxia and normoxia, each lasting 120 s, nadir FiO2: 7%). Blood pressure was monitored by telemetric catheters implanted into the abdominal aorta. Pharmacological inhibition of NOX by apocynin and NOX2-deficient mice were used to assess the role of NOX in CIH-induced arterial hypertension. NOX2 gene expression was measured by real-time PCR in different cardiovascular tissues.
When compared with room air conditions, wild-type mice showed significant blood pressure elevations after exposure to CIH. This response was attenuated after treating animals with apocynin and in NOX2 (=gp91) knockout mice, whereas NOX2 was not upregulated in the heart, aorta, and femoral/carotid arteries of CIH mice.
We suggest that the CIH-induced arterial hypertension is mediated by ROS derived from an activation of NOX2 within cells located outside the cardiovascular system.
Journal of Hypertension 11/2013; 32(2). DOI:10.1097/HJH.0000000000000016 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Obstructive sleep apnea (OSA) is an independent risk factor for cardiovascular (CV) diseases such as arterial hypertension, heart failure, and stroke. Based on human research, sympathetic activation, inflammation, and oxidative stress are thought to play major roles in the pathophysiology of OSA-related CV diseases. Animal models of OSA have shown that endothelial dysfunction, vascular remodelling, and systemic and pulmonary arterial hypertension as well as heart failure can develop in response to chronic intermittent hypoxia (CIH). The available animal data are clearly in favour of oxidative stress playing a key role in the development of all of these CV manifestations of OSA. Presumably, the oxidative stress is due to an activation of NADPH oxidase and other free oxygen radicals producing enzymes within the CV system as evidenced by data from knockout mice and pharmacological interventions. It is hoped that animal models of OSA-related CV disease will continue to contribute to a deeper understanding of their underlying pathophysiology and will foster the way for the development of cardioprotective treatment options other than conventional CPAP therapy.
Oxidative Medicine and Cellular Longevity 03/2013; 2013(1):234631. DOI:10.1155/2013/234631 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives:
Pilot studies have described the occurrence of sleep apnea in patients with precapillary pulmonary hypertension (PH). However, there are no data on the prevalence of sleep-related breathing disorders in larger patient cohorts with PH.
169 patients with a diagnosis of PH confirmed by right heart catheterisation and clinically stable in NYHA classes II or III were prospectively investigated by polygraphy (n = 105 females, mean age: 61.3 years, mean body mass index: 27.2 kg/m(2)). Recruitment was independent of sleep-related symptoms and the use of vasodilator drugs or nasal oxygen.
45 patients (i.e. 26.6%) had an apnea-hypopnea-index (AHI) >10/h. Of these, 27 patients (i.e. 16%) had obstructive sleep apnea (OSA) and 18 patients (i.e. 10.6%) had central sleep apnea (CSA). The mean AHI was 20/hour. As a polygraphy had been performed with nasal oxygen in half of the patients without evidence for sleep apnea, the frequency of CSA was probably underestimated. Patients with OSA were characterized by male gender and higher body mass index whereas, those with CSA were older and hypocapnic.
At least every fourth patient with PH suffers from mild-to-moderate sleep apnea. Considering the anthropometric characteristics of the patients studied, the prevalence of both OSA and CSA seem to be higher in PH than in the general population.
Sleep Medicine 01/2013; 14(3). DOI:10.1016/j.sleep.2012.11.013 · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with cystic fibrosis (CF) may suffer from sleep disturbances and reduced health-related quality of life (HRQoL). However, the relationships of daytime sleepiness and sleep quality to HRQoL in CF have not yet been investigated.
55 adult CF out-patients free from a pulmonary exacerbation were prospectively enrolled in this study. Questionnaires were used to assess disease-specific HRQoL (German version of the revised Cystic Fibrosis Questionnaire for adults, CFQ18 + R), daytime sleepiness (Epworth Sleepiness Scale, ESS) and sleep quality (Pittsburgh Sleep Quality Index, PSQI). 30 age- and sex-matched healthy volunteers served as a control group.
The prevalence of daytime sleepiness was higher in the CF than in the control group (ESS > 10; n = 11 [20%] vs. n = 2 [6.7%]; p < 0.01) as was reduced sleep quality (PSQI > 5; n = 21 [38.2%] vs. n = 1 [3.3%]; p < 0.01). Multiple regression analysis including age, gender, body mass index, lung function and pseudomonas status showed that higher PSQI scores significantly correlated with lower CFQ18 + R scores for vitality, emotional functioning, social, role, eating disturbances and digestive symptoms.
In clinically stable adult CF out-patients self-reported daytime sleepiness and poor sleep quality are more common than in age and sex-matched healthy controls. In addition, impaired sleep quality is related to reduced disease-specific HRQoL in CF.
Respiratory medicine 07/2012; 106(9):1244-9. DOI:10.1016/j.rmed.2012.06.010 · 3.09 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sleep-disordered breathing (SDB) may trigger thromboembolic events by enhancing intravascular clot formation. The primary objective of the present nested case-control study was to investigate whether the prevalence of SDB is increased in patients with deep vein thrombosis (DVT) and/or acute pulmonary embolism (PE). 82 consecutive patients with DVT and/or PE (cases) were prospectively enrolled irrespective of SDB-related symptoms and formed matched pairs with patients without DVT and/or PE (controls) according to sex and pre-defined categories of age and body mass index. The prevalence of SDB (respiratory disturbance index assessed by polygraphy ≥15 events·h(-1)) was significantly greater in the cases with DVT and/or PE than in controls (40 versus 26%, p=0.046) and was predominantly obstructive in nature. Multiple regression analysis revealed that SDB was significantly associated with DVT and/or PE (OR 2.28, 95% CI 1.08-4.85; p=0.032) independent of established risk factors for thrombosis. In the sex-specific analyses this association was significant in females (OR 4.14, 95% CI 1.05-16.36; p=0.042), but not in males (OR 1.55, 95% CI 0.57-4.21; p=0.391). SDB occurs more frequently in females with DVT and/or PE than in controls matched for anthropometric variables, and is independently associated with the occurrence of these thromboembolic events.
European Respiratory Journal 02/2012; 40(4):919-924. DOI:10.1183/09031936.00176711 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. We report in an emphysema model of mice chronically exposed to tobacco smoke that pulmonary vascular dysfunction, vascular remodeling, and pulmonary hypertension (PH) precede development of alveolar destruction. We provide evidence for a causative role of inducible nitric oxide synthase (iNOS) and peroxynitrite in this context. Mice lacking iNOS were protected against emphysema and PH. Treatment of wild-type mice with the iNOS inhibitor N(6)-(1-iminoethyl)-L-lysine (L-NIL) prevented structural and functional alterations of both the lung vasculature and alveoli and also reversed established disease. In chimeric mice lacking iNOS in bone marrow (BM)-derived cells, PH was dependent on iNOS from BM-derived cells, whereas emphysema development was dependent on iNOS from non-BM-derived cells. Similar regulatory and structural alterations as seen in mouse lungs were found in lung tissue from humans with end-stage COPD.
[Show abstract][Hide abstract] ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive, dysregulated response to alveolar injury that culminates in compromised lung function from excess extracellular matrix production. Associated with high morbidity and mortality, IPF is generally refractory to current pharmacological therapies. We examined fibrotic lungs from mice and from patients with IPF and detected increased expression of dimethylarginine dimethylaminohydrolases (DDAHs)--key enzymes that metabolize asymmetric dimethylarginine (ADMA), which is an endogenous inhibitor of nitric oxide synthase, to form l-citrulline and dimethylamine. DDAHs are up-regulated in primary alveolar epithelial type II cells from these mice and patients where they are colocalized with inducible nitric oxide synthase. In cultured alveolar epithelial type II cells from bleomycin-induced fibrotic mouse lungs, inhibition of DDAH suppressed proliferation and induced apoptosis in an ADMA-dependent manner. In addition, DDAH inhibition reduced collagen production by fibroblasts in an ADMA-independent but transforming growth factor/SMAD-dependent manner. In mice with bleomycin-induced pulmonary fibrosis, the DDAH inhibitor L-291 reduced collagen deposition and normalized lung function. In bleomycin-induced fibrosis, inducible nitric oxide synthase inhibition decreased fibrosis, but an even stronger reduction was observed after inhibition of DDAH. Thus, DDAH inhibition reduces fibroblast-induced collagen deposition in an ADMA-independent manner and reduces abnormal epithelial proliferation in an ADMA-dependent manner, offering a possible therapeutic avenue for attenuation of pulmonary fibrosis.
Science translational medicine 06/2011; 3(87):87ra53. DOI:10.1126/scitranslmed.3001725 · 15.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by vasoconstriction and remodelling of the pulmonary vasculature. The serotonin (5-hydroxytryptamine (5-HT)) pathway has been shown to play a major role in the pathogenesis of PAH, but pharmacological modulation of this pathway for treatment of PAH is, to date, at a pre-clinical level. Terguride is a 5-HT receptor (5-HTR) antagonist that is well tolerated and clinically approved for ovulation disorders. Immunohistochemistry against 5-HTR(₂A/B) on human lungs revealed their localisation to the vascular smooth muscle layer and quantitative RT-PCR showed 5-HTR(₂B) upregulation in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients. Proliferation and migration of cultured primary human PASMC were dose-dependently blocked by terguride. Therapeutic 5-HT signalling inhibition was 1) demonstrated in isolated, ventilated and perfused rat lungs and 2) by chronic terguride treatment of rats with monocrotaline (MCT)-induced pulmonary hypertension in a preventive or curative approach. Terguride inhibited proliferation of PASMCs and abolished 5-HT-induced pulmonary vasoconstriction. Chronic terguride treatment prevented dose-dependently the development and progression of MCT-induced PAH in rats. Thus, terguride represents a valuable novel therapeutic approach in PAH.
European Respiratory Journal 05/2011; 37(5):1104-18. DOI:10.1183/09031936.00126010 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: RATIONALE: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available. OBJECTIVES: To characterize WNT/beta-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice. METHODS: The expression, localization, and activity of WNT/beta-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative RT-PCR, immunohistochemistry, and Western blotting. The role of WNT/beta-catenin signaling was assessed in elastase- and cigarette smoke-induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild type mice in vivo. MEASUREMENTS AND MAIN RESULTS: No differences in the mRNA expression profile of the main WNT/beta-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear !-catenin-positive alveolar epithelial cells in COPD. Similarly, WNT/beta-catenin signaling was downregulated in both experimental emphysema models. Preventive, as well as therapeutic, WNT/beta-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers. CONCLUSION: Decreased WNT/beta-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/beta-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/beta-catenin activation as a future therapeutic approach for emphysema.
[Show abstract][Hide abstract] ABSTRACT: A unique subpopulation of peripheral blood mononuclear cells that exhibit a parallel expression of haematopoietic and mesenchymal markers has been described as "circulating fibrocytes". These cells were demonstrated to obtain a fibroblastic phenotype in tissues or cell culture and contribute to pulmonary fibrotic disorders and tissue remodelling processes. The aim of our study was to characterise the recruitment of circulating fibrocytes in vivo in the model of chronic hypoxic pulmonary hypertension in mice and to analyse the therapeutic effect of the stable prostacyclin analogue trepostinil with respect to this cell population. To track circulating fibrocytes in vivo, we transplanted wild-type mice with bone marrow from ubiquitously eGFP expressing mice and subjected them to chronic hypoxia. We observed significantly increased recruitment of circulating fibrocytes to the remodelled pulmonary resistance arteries in response to hypoxia. Treatment with treprostinil significantly reduced the recruitment of these cells compared to normoxic mice. Treprostinil also reduced right ventricular systolic pressure and slightly reduced the vascular remodelling but failed to reverse the right ventricular hypertrophy. In summary, we show that circulating fibrocytes contribute to hypoxic pulmonary vascular remodelling and may be specifically targeted by a prostacyclin analogue. Further investigations of cellular and paracrine mechanisms are warranted to decipher their role in pulmonary hypertension.
European Respiratory Journal 12/2010; 36(6):1302-14. DOI:10.1183/09031936.00028009 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited responsiveness to available treatments. It is characterised by epithelial cell injury, fibroblast activation and proliferation and extracellular matrix deposition. Serotonin (5-hydroxytryptamine; 5-HT) induces fibroblast proliferation via the 5-HTR(2A) and 5-HTR(2B) receptors, but its pathophysiological role in IPF remains unclear. A study was undertaken to determine the expression of 5-HT receptors in IPF and experimental lung fibrosis and to investigate the effects of therapeutic inhibition of 5-HTR(2A/B) signalling on lung fibrosis in vivo and in vitro.
Quantitative RT-PCR showed that the expression of 5-HTR(1A/B) and 5-HTR(2B) was significantly increased in the lungs of patients with IPF (n=12) and in those with non-specific interstitial pneumonia (NSIP, n=6) compared with transplant donors (n=12). The expression of 5-HTR(2A) was increased specifically in IPF lungs but not in NSIP lungs. While 5-HTR(2A) protein largely localised to fibroblasts, 5-HTR(2B) localised to the epithelium. To assess the effects of 5HTR(2A/B) inhibition on fibrogenesis in vivo, mice were subjected to bleomycin-induced lung fibrosis and treated with the 5-HTR(2A/B) antagonist terguride (or vehicle) in a therapeutic approach (days 14-28 after bleomycin). Terguride-treated mice had significantly improved lung function and histology and decreased collagen content compared with vehicle-treated mice. Functional in vitro studies showed that terguride is a potent inhibitor of transforming growth factor β(1)- or WNT3a-induced collagen production.
The studies revealed an increased expression of 5-HTR(2A) specifically in IPF. Blockade of 5-HTR(2A/B) signalling by terguride reversed lung fibrosis and is thus a promising therapeutic approach for IPF.
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) is a devastating disease, for which no causal therapy is available.
To characterize WNT/β-catenin signaling in COPD in humans and elucidate its potential role as a preventive and therapeutic target in experimental emphysema in mice.
The expression, localization, and activity of WNT/β-catenin signaling was assessed in 12 COPD and 12 transplant donor samples using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and Western blotting. The role of WNT/β-catenin signaling was assessed in elastase- and cigarette smoke-induced emphysema and therapeutic modulation thereof in elastase-induced emphysema in TOPGAL reporter and wild-type mice in vivo.
No differences in the mRNA expression profile of the main WNT/β-catenin signaling components were observed comparing COPD and donor lung homogenates. Immunohistochemical analysis revealed reduced numbers of nuclear β-catenin-positive alveolar epithelial cells in COPD. Similarly, WNT/β-catenin signaling was down-regulated in both experimental emphysema models. Preventive and therapeutic, WNT/β-catenin activation by lithium chloride attenuated experimental emphysema, as assessed by decreased airspace enlargement, improved lung function, reduced collagen content, and elevated expression of alveolar epithelial cell markers.
Decreased WNT/β-catenin signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema. These data indicate a crucial role of WNT/β-catenin signaling in lung repair mechanisms in vivo, and highlight WNT/β-catenin activation as a future therapeutic approach for emphysema.
American Journal of Respiratory and Critical Care Medicine 10/2010; 183(6):723-33. DOI:10.1164/rccm.200910-1560OC · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pulmonary fibrosis (PF) is a group of devastating and largely irreversible diseases. Phosphodiesterase (PDE) 4 is involved in the processes of remodeling and inflammation, which play key role in tissue fibrosis. The aim of the study was, therefore, to investigate the effect of PDE4 inhibition in experimental model of PF.
PF was induced in C57BL/6N mice by instillation of bleomycin. Pharmacological inhibition of PDE4 was achieved by using cilomilast, a selective PDE4 inhibitor. Changes in either lung inflammation or remodeling were evaluated at different stages of experimental PF. Lung inflammation was assessed by bronchoalveolar lavage fluid (BALF) differential cell count and reverse transcription quantitative polymerase chain reaction (RT-qPCR) for inflammatory cytokines. Changes in tissue remodeling were evaluated by pulmonary compliance measurement, quantified pathological examination, measurement of collagen deposition and RT-qPCR for late remodeling markers. Survival in all groups was analyzed as well.
PDE4 inhibition significantly reduced the total number of alveolar inflammatory cells in BALF of mice with bleomycin-induced PF at early fibrosis stage (days 4 and 7). Number of macrophages and lymphocytes, but not neutrophils, was significantly reduced as well. Treatment decreased lung tumor necrosis factor (TNF)-alpha mRNA level and increased mRNA level of interleukin (IL)-6 but did not influence IL-1 beta. At later stage (days 14 and 24) cilomilast improved lung function, which was shown by increase in lung compliance. It also lowered fibrosis degree, as was shown by quantified pathological examination of Hematoxilin-Eosin stained lung sections. Cilomilast had no significant effect on the expression of late remodeling markers such as transforming growth factor (TGF)-beta1 and collagen type Ia1 (COL(I)alpha1). However, it tended to restore the level of lung collagen, assessed by SIRCOL assay and Masson's trichrome staining, and to improve the overall survival.
Selective PDE4 inhibition suppresses early inflammatory stage and attenuates the late stage of experimental pulmonary fibrosis.
BMC Pulmonary Medicine 05/2010; 10(1):26. DOI:10.1186/1471-2466-10-26 · 2.40 Impact Factor