TY - THES A1 - Rector, Michael V. T1 - The acute effect of exercise on flow-mediated dilation in young people with cystic fibrosis T1 - Der akute Effekt des Trainings auf den Fluss vermittelte Dilatation bei jungen Menschen mit Mukoviszidose N2 - Introduction: Cystic fibrosis (CF) is a genetic disease which disrupts the function of an epithelial surface anion channel, CFTR (cystic fibrosis transmembrane conductance regulator). Impairment to this channel leads to inflammation and infection in the lung causing the majority of morbidity and mortality. However, CF is a multiorgan disease affecting many tissues, including vascular smooth muscle. Studies have revealed young people with cystic fibrosis lacking inflammation and infection still demonstrate vascular endothelial dysfunction, measured per flow-mediated dilation (FMD). In other disease cohorts, i.e. diabetic and obese, endurance exercise interventions have been shown improve or taper this impairment. However, long-term exercise interventions are risky, as well as costly in terms of time and resources. Nevertheless, emerging research has correlated the acute effects of exercise with its long-term benefits and advocates the study of acute exercise effects on FMD prior to longitudinal studies. The acute effects of exercise on FMD have previously not been examined in young people with CF, but could yield insights on the potential benefits of long-term exercise interventions. The aims of these studies were to 1) develop and test the reliability of the FMD method and its applicability to study acute exercise effects; 2) compare baseline FMD and the acute exercise effect on FMD between young people with and without CF; and 3) explore associations between the acute effects of exercise on FMD and demographic characteristics, physical activity levels, lung function, maximal exercise capacity or inflammatory hsCRP levels. Methods: Thirty young volunteers (10 people with CF, 10 non-CF and 10 non-CF active matched controls) between the ages of 10 and 30 years old completed blood draws, pulmonary function tests, maximal exercise capacity tests and baseline FMD measurements, before returning approximately 1 week later and performing a 30-min constant load training at 75% HRmax. FMD measurements were taken prior, immediately after, 30 minutes after and 1 hour after constant load training. ANOVAs and repeated measures ANOVAs were employed to explore differences between groups and timepoints, respectively. Linear regression was implemented and evaluated to assess correlations between FMD and demographic characteristics, physical activity levels, lung function, maximal exercise capacity or inflammatory hsCRP levels. For all comparisons, statistical significance was set at a p-value of α < 0.05. Results: Young people with CF presented with decreased lung function and maximal exercise capacity compared to matched controls. Baseline FMD was also significantly decreased in the CF group (CF: 5.23% v non-CF: 8.27% v non-CF active: 9.12%). Immediately post-training, FMD was significantly attenuated (approximately 40%) in all groups with CF still demonstrating the most minimal FMD. Follow-up measurements of FMD revealed a slow recovery towards baseline values 30 min post-training and improvements in the CF and non-CF active groups 60 min post-training. Linear regression exposed significant correlations between maximal exercise capacity (VO2 peak), BMI and FMD immediately post-training. Conclusion: These new findings confirm that CF vascular endothelial dysfunction can be acutely modified by exercise and will aid in underlining the importance of exercise in CF populations. The potential benefits of long-term exercise interventions on vascular endothelial dysfunction in young people with CF warrants further investigation. N2 - Einleitung: Mukoviszidose (CF) ist eine genetische Erkrankung, die die Funktion eines Epithelien Oberflächenanionenkanals, CFTR (cystic fibrosis transmembrane conductance regulator), stört. Eine Beeinträchtigung dieses Kanals führt zu Entzündungen und Infektionen in der Lunge, die den Großteil der Morbidität und Mortalität verursachen. CF ist jedoch eine Multiorganerkrankung, die viele Gewebe einschließlich vaskulärer glatter Muskeln betrifft. Studien haben gezeigt, dass junge Menschen mit Mukoviszidose, die keine Entzündung und Infektion aufweisen, immer noch eine vaskuläre Dysfunktion aufweisen, gemessen anhand der durchflussbedingten Dilatation (FMD). In anderen Krankheitskohorten, u.a. Diabetes und Fettleibigkeit, wurde gezeigt, dass Ausdauersporteingriffe diese Beeinträchtigungen verbessern oder reduzieren. Langfristige Bewegungseingriffe sind jedoch riskant und kostenintensiv in Bezug auf Zeit und Ressourcen. Nichtsdestotrotz hat die aufkommende Forschung die akuten Auswirkungen von körperlicher Bewegung mit ihren langfristigen Vorteilen korreliert und befürwortet die Untersuchung akuter Bewegungseffekte auf FMD vor longitudinalen Studien. Die akuten Auswirkungen von körperlicher Bewegung auf FMD wurden bisher bei jungen Menschen mit Mukoviszidose nicht untersucht, konnten jedoch Erkenntnisse über die potenziellen Vorteile langfristiger Bewegungseingriffe liefern. Die Ziele dieser Studien waren, 1) die Zuverlässigkeit der FMD-Methode und ihre Anwendbarkeit zu entwickeln, um akute Übungseffekte zu untersuchen; 2) Vergleich der Grundlinien-FMD und der Akutübungswirkung bei FMD zwischen Jugendlichen mit und ohne CF; und 3) Zusammenhänge zwischen den akuten Auswirkungen von körperlicher Bewegung auf FMD und demographischen Merkmalen, der körperlichen Aktivität, der Lungenfunktion, der maximalen körperlichen Belastbarkeit oder den entzündlichen hsCRP-Spiegeln zu untersuchen. Methoden: Dreißig junge Freiwillige (10 CF-Patienten, 10 gesunde und 10 aktive, gesunde Kontrollpersonen) im Alter von 10 bis 30 Jahren führten zuvor Blutabnahmen, Lungenfunktionstests, maximale Belastungstests und Grundlinien-FMD-Messungen durch Rückkehr etwa 1 Woche später und Durchführung eines 30-minütigen Dauerlasttrainings bei 75% HFmax durch. FMD-Messungen wurden vor, unmittelbar nach, 30 Minuten nach und 1 Stunde nach konstantem Belastungstraining durchgeführt. ANOVAs und ANOVAs mit wiederholten Messungen wurden verwendet, um Unterschiede zwischen Gruppen bzw. Zeitpunkten zu untersuchen. Die lineare Regression wurde implementiert und evaluiert, um Korrelationen zwischen FMD und demographischen Merkmalen, körperlichen Aktivitätsniveaus, Lungenfunktion, maximaler Belastungskapazität oder inflammatorischen hsCRP-Spiegeln zu bestimmen. Für alle Vergleiche wurde die statistische Signifikanz auf einen p-Wert von α < 0,05 eingestellt. Ergebnisse: Jugendliche mit Mukoviszidose zeigten eine verminderte Lungenfunktion und maximale Belastbarkeit im Vergleich zu Kontrollpersonen. Baseline FMD (%) war auch in der CF-Gruppe (CF: 5.23% v nicht-CF: 8.27% v nicht-CF-aktive: 9.12%) signifikant verringert. Unmittelbar nach dem Training war die FMD in allen Gruppen mit CF, die immer noch die minimalste FMD aufwiesen, signifikant abgeschwächt (~40%). Follow-up-Messungen von FMD zeigte eine langsame Erholung in Richtung Baseline-Werte 30 Minuten nach dem Training und Verbesserungen in der CF-und nicht-CF-aktive Gruppen 60 Minuten nach dem Training. Die lineare Regression zeigte signifikante Korrelationen zwischen maximaler Belastungsfähigkeit (VO2-Peak), BMI und FMD unmittelbar nach dem Training. Feststellung: Diese neuen Ergebnisse bestätigen, dass die vaskuläre Dysfunktion der CF durch sportliche Betätigung akut verändert werden kann und dazu beitragen wird, die Bedeutung von Bewegung in CF-Populationen zu unterstreichen. Die potenziellen Vorteile von Langzeitübungsinterventionen bei vaskulärer Dysfunktion bei jungen CF-Patienten rechtfertigen weitere Untersuchungen. KW - cystic fibrosis KW - flow-mediated dilation KW - vascular dysfunction KW - exercise KW - Mukoviszidose KW - Fluss vermittelte Dilatation KW - vaskuläre Dysfunktion KW - Sporttraining Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-438938 ER - TY - JOUR A1 - Pewzner-Jung, Yael A1 - Tabazavareh, Shaghayegh Tavakoli A1 - Grassme, Heike A1 - Becker, Katrin Anne A1 - Japtok, Lukasz A1 - Steinmann, Joerg A1 - Joseph, Tammar A1 - Lang, Stephan A1 - Tuemmler, Burkhard A1 - Schuchman, Edward H. A1 - Lentsch, Alex B. A1 - Kleuser, Burkhard A1 - Edwards, Michael J. A1 - Futerman, Anthony H. A1 - Gulbins, Erich T1 - Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa JF - EMBO molecular medicine N2 - Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P.aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P.aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection. KW - cystic fibrosis KW - long chain base KW - lung infection KW - Pseudomonas aeruginosa KW - sphingosine Y1 - 2014 U6 - https://doi.org/10.15252/emmm.201404075 SN - 1757-4676 SN - 1757-4684 VL - 6 IS - 9 SP - 1205 EP - 1214 PB - Wiley-Blackwell CY - Hoboken ER - TY - JOUR A1 - Halilbasic, Emina A1 - Fuerst, Elisabeth A1 - Heiden, Denise A1 - Japtok, Lukasz A1 - Diesner, Susanne C. A1 - Trauner, Michael A1 - Kulu, Askin A1 - Jaksch, Peter A1 - Hoetzenecker, Konrad A1 - Kleuser, Burkhard A1 - Kazemi-Shirazi, Lili A1 - Untersmayr, Eva T1 - Plasma levels of the bioactive sphingolipid metabolite S1P in adult cystic fibrosis patients BT - potential target for immunonutrition? JF - Nutrients N2 - Recent research has linked sphingolipid (SL) metabolism with cystic fibrosis transmembrane conductance regulator (CFTR) activity, affecting bioactive lipid mediator sphingosine-1-phosphate (S1P). We hypothesize that loss of CFTR function in cystic fibrosis (CF) patients influenced plasma S1P levels. Total and unbound plasma S1P levels were measured in 20 lung-transplanted adult CF patients and 20 healthy controls by mass spectrometry and enzyme-linked immunosorbent assay (ELISA). S1P levels were correlated with CFTR genotype, routine laboratory parameters, lung function and pathogen colonization, and clinical symptoms. Compared to controls, CF patients showed lower unbound plasma S1P, whereas total S1P levels did not differ. A positive correlation of total and unbound S1P levels was found in healthy controls, but not in CF patients. Higher unbound S1P levels were measured in Delta F508-homozygous compared to Delta F508-heterozygous CF patients (p = 0.038), accompanied by higher levels of HDL in Delta F508-heterozygous patients. Gastrointestinal symptoms were more common in Delta F508 heterozygotes compared to Delta F508 homozygotes. This is the first clinical study linking plasma S1P levels with CFTR function and clinical presentation in adult CF patients. Given the emerging role of immunonutrition in CF, our study might pave the way for using S1P as a novel biomarker and nutritional target in CF. KW - sphingolipids KW - sphingosine-1-phosphate KW - intestine KW - high density KW - lipoproteins KW - cystic fibrosis KW - Delta F508 mutation KW - immunonutrition Y1 - 2020 U6 - https://doi.org/10.3390/nu12030765 SN - 2072-6643 VL - 12 IS - 3 PB - MDPI CY - Basel ER - TY - JOUR A1 - Barucha, Anton A1 - Mauch, Renan Marrichi A1 - Duckstein, Franziska A1 - Zagoya, Carlos A1 - Mainz, Jochen G. T1 - The potential of volatile organic compound analysis for pathogen detection and disease monitoring in patients with cystic fibrosis JF - Expert review of respiratory medicine N2 - Introduction Airway infection with pathogens and its associated pulmonary exacerbations (PEX) are the major causes of morbidity and premature death in cystic fibrosis (CF). Preventing or postponing chronic infections requires early diagnosis. However, limitations of conventional microbiology-based methods can hamper identification of exacerbations and specific pathogen detection. Analyzing volatile organic compounds (VOCs) in breath samples may be an interesting tool in this regard, as VOC-biomarkers can characterize specific airway infections in CF. Areas covered We address the current achievements in VOC-analysis and discuss studies assessing VOC-biomarkers and fingerprints, i.e. a combination of multiple VOCs, in breath samples aiming at pathogen and PEX detection in people with CF (pwCF). We aim to provide bases for further research in this interesting field. Expert opinion Overall, VOC-based analysis is a promising tool for diagnosis of infection and inflammation with potential to monitor disease progression in pwCF. Advantages over conventional diagnostic methods, including easy and non-invasive sampling procedures, may help to drive prompt, suitable therapeutic approaches in the future. Our review shall encourage further research, including validation of VOC-based methods. Specifically, longitudinal validation under standardized conditions is of interest in order to ensure repeatability and enable inclusion in CF diagnostic routine. KW - Breath analysis KW - cystic fibrosis KW - pathogens KW - Pseudomonas aeruginosa KW - volatile organic compounds Y1 - 2022 U6 - https://doi.org/10.1080/17476348.2022.2104249 SN - 1747-6348 SN - 1747-6356 VL - 16 IS - 7 SP - 723 EP - 735 PB - Routledge, Taylor & Francis Group CY - Abingdon ER -