122 research outputs found
CHI3L1 polymorphisms, cord blood YKL-40 levels and later asthma development
No full textSingle nucleotide polymorphisms (SNPs) in chitinase 3-like 1 (CHI3L1), the gene encoding YKL-40, and increased serum YKL-40 levels are associated with severe forms of asthma. It has never been addressed whether SNPs in CHI3L1 and cord blood YKL-40 levels could already serve as potential biomarkers for milder forms of asthma. We assessed in an unselected population whether SNPs in CHI3L1 and cord blood YKL-40 levels at birth are associated with respiratory symptoms, lung function changes, asthma, and atopy.; In a prospective birth cohort of healthy term-born neonates (n = 260), we studied CHI3L1 polymorphisms, and measured cord blood YKL-40 levels by ELISA in (n = 170) infants. Lung function was performed at 5 weeks and 6 years. Respiratory health during the first year of life was assessed weekly by telephone interviews. Diagnosis of asthma and allergic sensitisation was assessed at 6 years (n = 142).; The SNP rs10399805 was significantly associated with asthma at 6 years. The odds ratio for asthma was 4.5 (95 % CI 1.59-12.94) per T-allele. This finding was unchanged when adjusting for cord blood YKL-40 levels. There was no significant association for cord blood YKL-40 levels and asthma. SNPs in CHI3L1 and cord blood YKL-40 were not associated with lung function measurements at 5 weeks and 6 years, respiratory symptoms in the first year, and allergic sensitisation at 6 years.; Genetic variation in CHI3L1 might be related to the development of milder forms of asthma. Larger studies are warranted to establish the role of YKL-40 in that pathway
A big step forward in understanding global differences in respiratory health: first lung function data in African infants.
No full textInert gas washout: background and application in various lung diseases
No full textMultiple breath inert gas washout (MBW) is a lung function technique to measure ventilation inhomogeneity. The technique was developed more than 60 years ago, but not much used for many decades. Technical improvements, easy protocols and higher sensitivity compared with standard lung function tests in some disease groups have led to a recent renaissance of MBW. The lung clearance index (LCI) is a common measure derived from MBW tests, and offers information on lung pathology complementary to that from conventional lung function tests such as spirometry. The LCI measures the overall degree of pulmonary ventilation inhomogeneity. There are other MBW-derived parameters, which describe more regional airway ventilation and enable specific information on conductive or acinar ventilation inhomogeneity. How this specific ventilation distribution is exactly related to different disease processes has not entirely been examined yet. MBW measurements are performed during tidal breathing, making this technique attractive for children, even young children and infants. These benefits and the additional physiological information on ventilation inhomogeneity early in the course of lung diseases have led to increasing research activities and clinical application of MBW, especially in paediatric lung diseases such as cystic fibrosis (CF). In these patients, LCI detects early airway damage and enables monitoring of disease progression and treatment response. Guidelines for the standardisation of the MBW technique were recently published. These guidelines will, hopefully, increase comparability of LCI data obtained in different centres or intervention trials in children and adults. In this non-systematic review article, we provide an overview of recent developments in MBW, with a special focus on children. We first explain the physiological and technical background to this technique with a short explanation of several methodological aspects that are important for understanding the principle behind the technique and enable high quality measurements. We then provide examples of MBW application in different lung diseases of children and adults, with regards to both clinical application and research activities. Lastly, we report on ongoing clinical trials using MBW as outcome and give an outlook on possible future developments
Diesel exposure increases susceptibility of primary human nasal epithelial cells to rhinovirus infection
No full textAbstract Nasal epithelial cells (NECs) are among the first cells to be exposed to air pollutants and respiratory viruses. Although it is known that air pollution exposure and rhinovirus infections increase the risk for asthma development independently, it is unclear how these risk factors interact on a cellular level. Therefore, we aimed to investigate how exposure to diesel particulate matter (DPM) modifies the response of primary NECs to rhinovirus (RV) infection in vitro. Exposure of re‐differentiated, primary NECs (49 healthy children [0–7 years], 12 adults) to DPM modified the mRNA expression of viral cell‐surface receptors, pattern recognition receptors, and pro‐inflammatory response (also protein levels). After exposure to DPM, we additionally infected the NECs with RV‐1b and RV‐16. Viral loads (assessed by titration assays) were significantly higher in DPM‐exposed compared with non‐exposed NECs. Exposure to DPM prior to RV infection resulted in a significant upregulation of pro‐inflammatory cytokines (mRNA and protein level) and β‐defensins mRNA, and significant downregulation of pattern recognition receptors mRNA and CXCL10 (mRNA and protein levels). There was no difference between all outcomes of NECs from children and adults. We can conclude that exposure to DPM prior to RV infection increases viral loads by downregulation of viral defense receptors and upregulation of pro‐inflammatory cytokines. Our findings indicate a strong interaction between air pollution and the antiviral response to RV infection in NECs. We provide mechanistic evidence that exposure to air pollution increases susceptibility to RV infection
All trans retinoic acid recruits Smad3 to drive TGF beta signaling in lung fibroblasts : new insights for the management of bronchopulmonary dysplasia with retinoids
No full textThere is currently much interest in using retinoids such as all trans retinoic acid (ATRA), or retinoid analogs such as vitamin A (retinol), in the management of premature neonates at risk for the development of bronchopulmonary dysplasia (BPD). Current clinical evidence is contradictory, with some reports suggesting benefits, while other reports suggest no impact, or a deleterious effect of retinoid administration. In contrast, retinoids generally perform very well in animal models of BPD, and serve to stimulate lung development, particularly alveolarization. In this study, we attempted to evaluate the impact of retinoids on the activity of the transforming growth factor (TGF) beta signaling pathway, a pathway that has been credited with high importance in driving lung development and alveolarization.We employed NIH/3T3 mouse fibroblasts to study the impact of ATRA on TGF beta signaling. While the NIH/3T3 cell line differs in some important aspects to that of lung fibroblasts, it is reasonable to assume that NIH/3T3 have a similar biological behavior to that of airway fibroblasts in tissue. We observed that ATRA had a dramatic effect on TGF beta signaling in NIH/3T3 cells. Pre-treatment of NIH/3T3 cells with ATRA caused a strong increase in TGF beta signaling, as assessed by phosphorylation of Smad3, and by a luciferase-based promoter-reporter assay. Further studies revealed that this effect was caused by the ability of ATRA to strongly increase Smad3 expression levels in NIH/3T3 cells. Using plasmid-mediated overexpression of the smad3 gene, we confirmed these observations, and showed that increased Smad3 levels in NIH/3T3 cells can indeed make the NIH/3T3 cells more responsive to TGF beta. To further support these data, we also down-regulated smad3 gene expression using siRNA directed against Smad3, and demonstrated that by down-regulating smad3 expression, the pro-TGF beta signaling effect of ATRA was lost. We also demonstrated that the degree of change in smad3 gene expression caused by ATRA stimulation is sufficient to cause a significant change in the TGF beta signaling pathway.Together, these data demonstrate that ATRA administration can upregulate TGF beta signaling in NIH/3T3 cells. This may have important consequences for lung development, since TGF beta drives multiple fibroblast functions such as extracellular matrix (ECM) production, as well as ECM reshaping in developing organs. Future studies should address the cross-talk of TGF beta and retinoid signaling on other lung cell types, primary cells, and in animal models of BPD, in order to complete the picture of how retinoids may influence lung organogenesis. With a better understanding about the impact of retinoids on lung fibroblasts function and lung development one might be able to optimize the administration of retinoids in patients with BPD and thus improve clinical outcome.Aktuell besteht ein großes Forschungsinteresse in der Verwendung von Retinoiden wie Vitamin A Säure (englisch: all trans retinoic acid (ATRA)) oder Retinoid-Analoga wie Vitamin A (Retinol) bei der Behandlung von Frühgeborenen, welche an Bronchopulmonaler Dysplasie (BPD) erkrankt sind. Der klinische Effekt von Vitamin A bei der Behandlung von BPD ist sehr widersprüchlich. Manche Studien berichten Erfolge, wobei andere Studien keinen Effekt oder sogar schädliche Auswirkungen bei der Verwendung von Vitamin A berichten. Hierzu steht im Widerspruch, dass Retinoide meist eine sehr gute Wirksamkeit in BPD Tiermodellen zeigen, wo sie die Lungenentwicklung, insbesondere die Alveolarisierung fördern. In dieser Studie untersuchten wir die Auswirkung von Retinoiden auf die transformierende Wachstumsfaktor beta (englisch: transforming growth factor (TGF) beta) Signalkaskade. Der TGF beta Signalkaskade wird eine wichtige Bedeutung für die Lungenentwicklung und Alveolarisierung zugeschrieben.Zur Untersuchung des Einflusses von ATRA auf die TGF beta Signalkaskade verwendeten wir NIH/3T3 Maus-Fibroblasten. Diese unterscheiden sich in einigen wichtigen Aspekten von Lungenfibroblasten, jedoch wird angenommen, dass NIH/3T3 Zellen ähnliche biologische Funktionen wie Lungenfibroblasten erfüllen. Wir konnten zeigen, dass ATRA einen dramatischen Effekt auf die TGF beta Signalkaskade in NIH/3T3 Zellen hat. Die Vorbehandlung von NIH/3T3 Zellen mit ATRA resultierte in einer starken Zunahme der TGF beta Signaltransduktion, was durch die Bestimmung der Phosphorilisierung von Smad3 und in einem Luciferase Promoter-Assay untersucht wurde. Weiterhin konnte gezeigt werden, dass dieser Effekt durch ATRA hervorgerufen wurde, welches die Fähigkeit besitzt, die Smad3 Expression in NIH/3T3 Zellen zu erhöhen. Wir konnten mit Hilfe einer Plasmid-vermittelten Überexpression des smad3 Gens diese Beobachtung bestätigen und konnten zeigen, dass durch eine Erhöhung von Smad3 in NIH/3T3 Zellen diese Zellen gegenüber TGF beta sensibilisiert werden. Um diese Beobachtung zu bestätigen, unterdrückten wir die Smad3 Gen Expression unter der Verwendung von siRNA gegen smad3 und zeigten durch die Reduktion der smad3 Expression einen Verlust der ATRA-abhängigen TGF beta Stimulation. Des Weiteren konnte beobachtet werden, dass das Ausmaß der smad3 Gen Expression durch ATRA intensiv genug ist, um signifikante Veränderungen in der TGF beta Signalkaskade zur Folge zu haben.Zusammenfassend konnte festgestellt werden, dass die Administration von ATRA die Aktivität der TGF beta Signalkaskade in NIH/3T3 Zellen erhöhen kann. Diese Beobachtung könnte wichtige Auswirkungen auf die Lungenentwicklung haben, da TGF beta verschiedene Funktionen von Fibroblasten reguliert. Hierzu zählt die Produktion von extrazellurärer Matrix (ECM), aber auch der Umbau der ECM bei sich entwickelnden Organen. Ergebnisse dieser Studie bilden eine Basis für zukünftige Studien, welche die Interaktion von TGF beta und Retinoiden in anderen Zelltypen wie z.B. primären Zellen, aber auch in BPD Tiermodellen untersuchen sollten, um den Einfluss von Retinoiden bei der Organentwicklung weiter zu verstehen. Mit einem besseren Verständnis über die Bedeutung von Retinoiden auf die Funktion von Fibroblasten und auf die Lungenentwicklung besteht das Potential, den therapeutischen Einsatz von Retinoiden bei BPD zu optimieren und den Verlauf der Erkrankung positiv zu beinflussen
Immunological and genetic determinants of pulmonary outcome in school aged children
No full textBackground: The prevalence of respiratory disorders in children has steadily increased over the past decades to such an extent that asthma is now the most common chronic disease of childhood. Childhood asthma resembles a complex syndrome rather than a single disease, and includes many wheeze phenotypes, making its diagnosis challenging. Most likely, it is not a single risk factor that determines whether a child develops asthma, but several risk factors (e.g. environmental, immunological, genetic, onset of respiratory symptoms) that each make small contributions to the development of the disease. Already infancy, lung function tests are available to assess airway disease. These tests are predominantly used in patients with Cystic Fibrosis (CF), for whom preservation of normal lung function is crucial. Despite recent advances in lung function testing, several methodological issues remain unanswered. Higher quality tests are required in order to effectively study the various risk factors involved in the development of complex airway diseases
Aim: The first aim was to describe methodological issues during infant lung function testing in order to improve their quality. The second aim was to study different risk factors for asthma development, and to investigate their association with respiratory diseases during childhood.
Methods: The study was conducted within the prospective Basel-Bern infant lung development (BILD) cohort, a population-based cohort of unselected infants of Central-European origin. The survey collects prenatal data via standardized interviews and cord blood samples for the assessment of immunological and genetic information. During the first year of life, research nurses call the parents weekly to assess the occurrence of respiratory symptoms. Pulmonary function tests, as well as measurement of fractional exhaled nitric oxide (FeNO) to assess airway inflammation, are completed at 5 weeks of age, and again at 6 years of age during follow-up.
Results: We provided specific recommendations on how to improve outcomes from infant lung measurements. Furthermore, we measured airway obstruction using the interrupter technique (Rint) in unsedated infants shortly after birth, and were able to show that measurements were feasible but had a high variability. We compared Rint between term and preterm infants, and found that Rint was higher, and variability of Rint lower, in term-born infants. We assessed FeNO in healthy newborn infants, and in infants with CF. FeNO at birth had no predictive value for asthma development at school age. In CF patients, FeNO at birth was lower compared to matched healthy controls.
We could also show that polymorphisms in the chitinase 3-like 1 (CHI3L1) gene encoding YKl-40 were associated with asthma at 6 years. There was some indication that increased YKL-40 levels at birth may also be involved in the development of airway disease. We also developed a novel method to characterize the time series of prospectively assessed respiratory symptom scores during infancy. This method assesses symptom dynamics in an observer-independent manner. Using this method, we were able to identify a high-risk phenotype, which was predominantly male, and contained more infants exposed to maternal asthma, and environmental tobacco smoke. This phenotype was also at increased risk for asthma and atopy at school age.
Conclusions: Infant lung function is useful to study airway disease at an early age, and outcomes can be improved by applying minimal changes in analyses algorithms. Assessment of airway obstruction in infants is feasible, but measurements require careful interpretation due to the high variability. We found some indication that FeNO levels early in life are determined by environmental factors and the child’s genetic profile. In CF patients, FeNO after birth was associated with the severity of the genetic mutation. In healthy infants, FeNO levels early in life seem to be influenced by environmental exposures.
Our findings contribute additional, relevant knowledge on asthma risk factors and their association with respiratory symptoms from birth through school age. We found associations between genetics and the immunological status at birth with asthma at school age. The development of asthma may also depend on respiratory symptoms early in life. We could show that the pattern of symptom deterioration and recovery during the first year of life determines whether or not a child has persistent wheezing until school age
- …
