188 results on '"Airway Obstruction metabolism"'
Search Results
2. Inflammatory imbalance in tracheal aspirate of very preterm newborns is associated with airway obstruction and lung function deficiencies at school age: a cohort study.
- Author
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Hagman C, Björklund L, Hansen Pupp I, and Tufvesson E
- Subjects
- Humans, Male, Female, Infant, Newborn, Child, Infant, Extremely Premature, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A analysis, Cytokines metabolism, Matrix Metalloproteinase 9 metabolism, Cohort Studies, Respiratory Function Tests, Trachea metabolism, Airway Obstruction metabolism, Uteroglobin metabolism, Uteroglobin analysis
- Abstract
Objective: A low expression of club cell secretory protein (CC16) and high levels of proinflammatory cytokines at preterm birth are associated with airway inflammation and more severe neonatal lung disease. The present study aimed to investigate if low levels of CC16, proinflammatory cytokines and vascular endothelial growth factors (VEGF) in tracheal aspirate early after birth were associated with lung function impairment at school age., Patients and Methods: Participants were 20 children, born very preterm (median gestational age 25+3 weeks+days, IQR: 24+1-27+0 weeks+days), who had tracheal aspirates collected during mechanical ventilation in their first day of life. CC16, cytokines, VEGF and matrix metalloproteinase-9 were measured in the tracheal aspirate and later correlated to results from advanced lung function measurements at 12 years of age., Results: Low levels of CC16 and high levels of the proinflammatory cytokines IL-1β and TNF-α in tracheal aspirate were associated with airway obstruction at school age but not with other lung function parameters. The correlation with airway obstruction was even stronger when the ratio between the respective proinflammatory cytokine and CC16 was used. In addition, low levels of VEGF and CC16 were associated with impaired diffusion capacity of the lung., Conclusions: An imbalance in inflammatory mediators and growth factors in the lungs at birth may have consequences for airway function and vasculature at school age in preterm born children., Competing Interests: Competing interests: CH has no conflict of interest. LB has received honoraria from Chiesi Pharma AB, Sweden, for being a member of the steering committee for the Nordic Neonatal Meetings and from AbbVie AB for lectures and for previously being a member of the steering committee for the NEOSPEX educational project. IHP holds stock/stock options in Premalux AB and has received honoraria from Baxter International for lectures. ET has received honoraria from Intramedic AB., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2024
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3. Recombinant Slit2 attenuates tracheal fibroblast activation in benign central airway obstruction by inhibiting the TGF-β1/Smad3 signaling pathway.
- Author
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He C, Gu L, Li A, Li Y, Xiao R, Liao J, Mu J, Gan Y, Peng M, Mohan G, Liu W, Xu L, and Guo S
- Subjects
- Animals, Humans, Rats, Fibroblasts metabolism, Fibrosis, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Receptors, Immunologic metabolism, Signal Transduction, Transforming Growth Factor beta1 pharmacology, Airway Obstruction metabolism, Pulmonary Fibrosis metabolism
- Abstract
Airway fibrosis is among the pathological manifestations of benign central airway obstruction noted in the absence of effective treatments and requires new drug targets to be developed. Slit guidance ligand 2-roundabout guidance receptor 1 (Slit2-Robo1) is involved in fibrosis and organ development. However, its significance in airway fibrosis has not yet been reported. The study explored how the recombinant protein Slit2 functions in transforming growth factor-β1 (TGF-β1)-mediated airway fibrosis in vivo and in vitro. In this study, Slit2 expression initially increased in the tracheal granulation tissues of patients with tracheobronchial stenosis but decreased in the fibrotic tissue. In primary rat tracheal fibroblasts (RTFs), recombinant Slit2 inhibited the expression of extracellular matrices such as Timp1, α-SMA, and COL1A2, whereas recombinant TGF-β1 promoted the expression of Robo1, α-SMA, and COL1A2. Slit2 and TGF-β1 played a mutual inhibitory role in RTFs. Slit2 supplementation and Robo1 downregulation inhibited excessive extracellular matrix (ECM) deposition induced by TGF-β1 in RTFs via the TGF-β1/Smad3 pathway. Ultimately, exogenous Slit2 and Robo1 knockdown-mediated attenuation of airway fibrosis were validated in a trauma-induced rat airway obstruction model. These findings demonstrate that recombinant Slit2 alleviated pathologic tracheobronchial healing by attenuating excessive ECM deposition. Slit2-Robo1 is an attractive target for further exploring the mechanisms and treatment of benign central airway obstruction., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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4. An inhibitor of RORγ for chronic pulmonary obstructive disease treatment.
- Author
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Desai H, Marathe M, Potdar V, Tiwari P, Joshi A, Kadam SR, Joshi AR, Kulkarni A, Bhosale V, Hadambar A, Lodhiya B, Udupa V, Behera D, Chaudhari SS, Das S, Bajpai M, Gowda N, and Iyer PS
- Subjects
- Animals, Dogs, Humans, Interleukin-17 metabolism, Lung metabolism, Mice, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, Th17 Cells, Airway Obstruction metabolism, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Emphysema metabolism
- Abstract
The role of RORγ as a transcription factor for Th17 cell differentiation and thereby regulation of IL-17 levels is well known. Increased RORγ expression along with IL-17A levels was observed in animal models, immune cells and BAL fluid of COPD patients. Increased IL-17A levels in severe COPD patients are positively correlated with decreased lung functions and increased severity symptoms and emphysema, supporting an urgency to develop novel therapies modulating IL-17 or RORγ for COPD treatment. We identified a potent RORγ inhibitor, PCCR-1 using hit to lead identification followed by extensive lead optimization by structure-activity relationship. PCCR-1 resulted in RORγ inhibition with a high degree of specificity in a biochemical assay, with > 300-fold selectivity over other isoforms of ROR. Our data suggest promising potency for IL-17A inhibition in human and canine PBMCs and mouse splenocytes with no significant impact on Th1 and Th2 cytokines. In vivo, PCCR-1 exhibited significant efficacy in the acute CS model with dose-dependent inhibition of the PD biomarkers that correlated well with the drug concentration in lung and BAL fluid, demonstrating an acceptable safety profile. This inhibitor effectively inhibited IL-17A release in whole blood and BALf samples from COPD patients. Overall, we identified a selective inhibitor of RORγ to pursue further development of novel scaffolds for COPD treatment., (© 2022. The Author(s).)
- Published
- 2022
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5. The affection of plasma exosomes on airway obstruction and endothelial function in OSA patients.
- Author
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Li L, Wang Q, Xin W, Wen K, and Hang YZ
- Subjects
- Endothelium, Vascular, Humans, Retrospective Studies, Airway Obstruction metabolism, Exosomes metabolism, MicroRNAs metabolism, Plaque, Atherosclerotic metabolism, Sleep Apnea, Obstructive
- Abstract
This study aimed to investigate the effects on airway obstruction and endothelial function by extracting and analyzing plasma exosomes with OSA patients. For this purpose, the clinical data and imaging data of 60 patients with OSA were retrospectively analyzed, who were admitted to the Central Hospital from Apr.2018 to Jul.2021.By using an electron microscope for the observation of exosomes, the degree of airway obstruction was compared by pulmonary function instrument, and HE staining was performed to analyze them. The results showed that the diameter of exosome particles was concentrated at 80.5 ~ 158.6 nm, the diameter of OSA exosomes was concentrated at about 121.9 nm, and the diameter of exosomes in the control group was concentrated at about 145.0 nm. Compared with the patients in the control group, the level of miRNA-33b-3p in the control group was significantly different (P < 0.05). The content of exosomal miRNA-33b-3p in OSA patients decreased significantly, and the corresponding airway obstruction increased. The results of HE staining showed that there were obvious atherosclerotic plaques in the arterial endothelium of the OSA group, and the atherosclerotic plaques were significantly reduced after miRNA-33b-3p injection (P < 0.05). In general, OSA patients can regulate airway obstruction and endothelial cell function by controlling the expression of Plasma exosomes and miRNA-33b-3p, resulting in increased airway obstruction and endothelial cell atherosclerosis.
- Published
- 2022
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6. Elevated CXCL14 in Induced Sputum Was Associated with Eosinophilic Inflammation and Airway Obstruction in Patients with Asthma.
- Author
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Du L, Xu C, Shi J, Tang L, Xiao L, Lei C, Liu H, Liang Y, Guo Y, and Tang K
- Subjects
- Humans, Sputum, Interleukin-13 metabolism, Interleukin-33 metabolism, Interleukin-10 metabolism, Interleukin-5, Pilot Projects, Interleukin-4 metabolism, Cytokines metabolism, Inflammation genetics, Inflammation metabolism, Chemokines, CXC metabolism, Asthma metabolism, Eosinophilia metabolism, Airway Obstruction metabolism
- Abstract
Introduction: CXCL14 involved in inflammatory processes was upregulated in the asthma expression profile datasets in our pilot study. However, the expression of CXCL14 in induced sputum and its potential clinical role in asthma were poorly reported., Objective: We sought to detect CXCL14 expression in airway epithelium and induced sputum cells of asthma and explore its potential clinical implications., Methods: The expression of CXCL14 in asthma was analyzed using R software based on multiple microarray datasets, including GSE43696, GSE63142, GSE67940, and GSE76262. Subsequent verification of the CXCL14 expression pattern in induced sputum and bronchial epithelium cells was performed by qRT-PCR and ELISA. Besides, the correlations between CXCL14 and eosinophilic inflammation indicators (FeNO, EOS#, and IgE), Th2 signature genes (SERPINB2, POSTN, and CLCA1), inflammatory cytokines (IL-4, IL-5, IL-10, IL-13, IL-25, IL-33, TSLP, IL-8, IL-17A, IFN-γ, and IL-2), and airway obstruction indicators (pulmonary function and mucin secretion) were further explored., Results: The expression of CXCL14 in epithelium and sputum cells was upregulated in asthma and positively correlated with clinical eosinophilic indicators. The protein levels of CXCL14 were positively associated with Th2 signature genes (SERPINB2, POSTN, and CLCA1) and Th2 cytokines (IL-4, IL-5, IL-10, IL-13, IL-25, IL-33, and TSLP). Increased expression of CXCL14 was also observed in BEAS-2B cells stimulated by the cytokine IL-4. Furthermore, the expression of CXCL14 was positively correlated with MUC5AC secretion and negatively associated with pulmonary function., Conclusions: Upregulated CXCL14 in asthma was positively correlated with inflammatory indicators and negatively correlated with pulmonary function, which indicated that upregulated CXCL14 might act as a pathogenic gene through involvement in Th2 inflammation in asthma., (© 2022 S. Karger AG, Basel.)
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- 2022
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7. Eosinophil Extracellular Traps in the Casts of Plastic Bronchitis Associated With Influenza Virus Infection.
- Author
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Yoshida M, Miyahara Y, Orimo K, Kono N, Narita M, Ohya Y, Matsumoto K, Nakagawa S, Ueki S, Morita H, and Miyairi I
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- Asthma diagnosis, Asthma immunology, Cell Aggregation immunology, Cell Death, Child, Chromatin metabolism, Glycoproteins isolation & purification, Humans, Hypersensitivity diagnosis, Hypersensitivity immunology, Influenza A Virus, H1N2 Subtype isolation & purification, Lysophospholipase isolation & purification, Male, Neutrophils immunology, Risk Factors, Airway Obstruction immunology, Airway Obstruction metabolism, Airway Obstruction pathology, Bronchitis complications, Bronchitis etiology, Bronchitis immunology, Bronchitis pathology, Eosinophils immunology, Extracellular Traps immunology, Extracellular Traps metabolism, Granulocytes immunology, Influenza, Human complications, Influenza, Human diagnosis, Influenza, Human immunology, Influenza, Human therapy, Mucus diagnostic imaging, Mucus enzymology, Mucus immunology
- Published
- 2021
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8. VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway.
- Author
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Jiang M, Fang Y, Li Y, Huang H, Wei Z, Gao X, Sung HK, Hu J, Qiang L, Ruan J, Chen Q, Jiang D, Whitsett JA, Ai X, and Que J
- Subjects
- Airway Obstruction metabolism, Airway Obstruction pathology, Animals, Cell Transdifferentiation genetics, Disease Models, Animal, Gene Expression Regulation genetics, Goblet Cells metabolism, Goblet Cells pathology, Humans, Interleukin-13 genetics, MAP Kinase Signaling System genetics, Metaplasia pathology, Mice, Mucus metabolism, Single-Cell Analysis, Airway Obstruction genetics, Metaplasia genetics, SOX9 Transcription Factor genetics, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor Receptor-2 genetics
- Abstract
Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology., Competing Interests: Declaration of interests A patent application (CU21016, “SUPPRESSION OF KDR, VEGF OR THE DOWNSTREAM MEK/ERK KINASE PATHWAY”) related to this work has been filed by Columbia Technology Ventures. M.J. and J.Q. are listed as co-inventors on this application., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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9. Neutrophil Extracellular Traps Increase Airway Mucus Viscoelasticity and Slow Mucus Particle Transit.
- Author
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Linssen RS, Chai G, Ma J, Kummarapurugu AB, van Woensel JBM, Bem RA, Kaler L, Duncan GA, Zhou L, Rubin BK, and Xu Q
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- Adult, Airway Obstruction immunology, Airway Obstruction metabolism, Extracellular Traps metabolism, Humans, Mucus metabolism, Neutrophils metabolism, Oxidative Stress immunology, Peroxidase immunology, Peroxidase metabolism, Reactive Oxygen Species immunology, Reactive Oxygen Species metabolism, Respiratory System metabolism, Extracellular Traps immunology, Mucus immunology, Neutrophils immunology, Respiratory System immunology
- Abstract
Mucus obstruction is a key feature of many inflammatory airway diseases. Neutrophil extracellular traps (NETs) are released upon neutrophil stimulation and consist of extracellular chromatin networks studded with cytotoxic proteins. When released in the airways, these NETs can become part of the airway mucus. We hypothesized that the extracellular DNA and/or oxidative stress (e.g., by the release of reactive oxygen species and myeloperoxidase during NETs formation in the airways) would increase mucus viscoelasticity. We collected human airway mucus from endotracheal tubes of healthy patients admitted for elective surgery and coincubated these samples with NETs from phorbol 12-myristate 13-acetate-stimulated neutrophils. Unstimulated neutrophils served as controls, and blocking experiments were performed with dornase alfa for extracellular DNA and the free radical scavenger dimethylthiourea for oxidation. Compared with controls, the coincubation of mucus with NETs resulted in 1 ) significantly increased mucus viscoelasticity (macrorheology) and 2 ) significantly decreased mesh pore size of the mucus and decreased movement of muco-inert nanoparticles through the mucus (microrheology), but 3 ) NETs did not cause visible changes in the microstructure of the mucus by scanning EM. Incubation with either dornase alfa or dimethylthiourea attenuated the observed changes in macrorheology and microrheology. This suggests that the release of NETs may contribute to airway mucus obstruction by increasing mucus viscoelasticity and that this effect is not solely due to the release of DNA but may in part be due to oxidative stress.
- Published
- 2021
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10. Laryngeal Chemoreflex in Health and Disease: A Review.
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Pathak S, Slovarp L, Clary MS, and Jetté ME
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- Animals, Apnea metabolism, Brain Stem metabolism, Chemoreceptor Cells metabolism, Cough metabolism, Humans, Laryngeal Nerves metabolism, Larynx metabolism, Reflex, Airway Obstruction metabolism, Respiration Disorders metabolism
- Abstract
The larynx plays a key role in airway protection via the laryngeal chemoreflex (LCR). This involuntary reflex can be evoked when hazardous substances activate mucosal receptors, which send signals to be processed within the brainstem. Although the LCR is meant to be protective, the reflex can become hyperstimulated, even to benign stimuli, which can result in pathological disorders, such as chronic cough and inducible laryngeal obstruction. In this review, we will outline the mechanism of the LCR and its associated pathological disorders., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2020
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11. Oil red O staining for lipid-laden macrophage index of bronchoalveolar lavage: interobserver agreement and challenges to interpretation.
- Author
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Torous VF, Brackett D, Brown P, Edwin N, Heidarian A, Lobuono C, Sun T, Pitman MB, and Ly A
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- Adolescent, Adult, Aged, Airway Obstruction metabolism, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Lung Transplantation, Male, Middle Aged, Observer Variation, Young Adult, Azo Compounds, Bronchoalveolar Lavage Fluid cytology, Coloring Agents, Foam Cells metabolism, Lipid Metabolism, Macrophages, Alveolar metabolism, Pathologists psychology, Staining and Labeling methods
- Abstract
Introduction: Oil Red O (ORO) staining on cytologic specimens with calculation of the lipid-laden macrophage index (LLMI) is used as a part of the workup in a number of clinical settings, particularly when aspiration is of concern. As a part of ongoing internal quality improvement measures, the objective of the present study was to evaluate the interobserver agreement of the LLMI calculation and to identify factors that affect the variability of the calculation., Materials and Methods: There were 9 study participants, which included 3 trainees, 3 cytotechnologists, and 3 cytopathologists. Each participant reviewed 100 ORO-stained bronchoalveolar lavage slides and assigned an LLMI score to each case. The scores were categorized into 3 groups according to the associated aspiration risk: low, LLMI <40; intermediate, LLMI 40 to 90; and high, LLMI >90. The participants were also requested to note any challenges to the calculation for each case., Results: The interobserver agreement among all participants was fair (κ = 0.23). Stratified by participant group, the interobserver agreement among the trainees was fair (κ = 0.24), among cytotechnologists was fair (κ = 0.32), and among cytopathologists was moderate (κ = 0.60). In 70 cases, at least one participant scored the case at least one category higher than the other participants; in 47 cases there was a two category difference. A primary diagnostic challenge reported by participants was macrophage pigmentation (hemosiderin, anthracosis)., Conclusions: We found only fair interobserver agreement among all 9 participants in the study. Hemosiderin and anthracotic pigmentation was a major factor impeding LLMI calculation resulting in overestimation of the LLMI., (Copyright © 2020 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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12. TcCO 2 changes correlate with partial obstruction in children suspected of sleep disordered breathing.
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D'Souza B, Norman M, Sullivan CE, and Waters KA
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- Adolescent, Airway Obstruction metabolism, Child, Child, Preschool, Female, Humans, Male, Polysomnography, Retrospective Studies, Sleep physiology, Sleep Apnea Syndromes metabolism, Snoring metabolism, Airway Obstruction diagnosis, Carbon Dioxide metabolism, Sleep Apnea Syndromes diagnosis
- Abstract
Introduction: Pediatric sleep disordered breathing (SDB) is characterized by long periods of partial upper airway obstruction (UAO) with low apnea-hypopnea indices (AHI). By measuring snoring and stertor, Sonomat studies allow quantification of these periods of partial UAO., Aim: To determine whether transcutaneous CO
2 (TcCO2 ) levels correlate with increasing levels of partial UAO and to examine patterns of ΔTcCo2 in the transitions from (a) wakefulness to sleep and (b) non-rapid eye movement (NREM) to rapid eye movement (REM) sleep., Methods: This was a retrospective review of sleep studies in seven asymptomatic controls aged 7 to 12 years and 62 symptomatic children with suspected SDB and no comorbidities, aged 2 to 13 years. Both groups underwent overnight polysomnography, including continuous TcCO2 , at one of two pediatric hospitals in Sydney. Changes in carbon dioxide levels between wake to NREM (sleep onset) and NREM to REM sleep were evaluated using an all-night TcCO2 trace time-linked to a hypnogram. Paired Sonomat recordings were used to quantify periods of UAO in the symptomatic group., Results: The ΔTcCO2 at sleep onset was greater in SDB children than controls and ΔTcCO2 with sleep onset correlated with the duration of partial obstruction (r = .60; P < .0001). Children with an increase in TcCO2 from NREM to REM had a higher number of snoring and stertor events compared to those in whom TcCO2 decreased from NREM to REM (91 vs 30 events/h; P = < .0001)., Conclusions: In children without comorbidities, the measurement of TcCO2 during sleep correlates with indicators of partial obstruction., (© 2020 Wiley Periodicals LLC.)- Published
- 2020
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13. Optical Coherence Tomography Intensity Correlates with Extracellular Matrix Components in the Airway Wall.
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Carpaij OA, Goorsenberg AWM, d'Hooghe JNS, de Bruin DM, van den Elzen RM, Nawijn MC, Annema JT, van den Berge M, Bonta PI, and Burgess JK
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- Airway Obstruction metabolism, Biomarkers metabolism, Humans, Respiratory System metabolism, Airway Obstruction diagnosis, Extracellular Matrix metabolism, Respiratory System diagnostic imaging, Tomography, Optical Coherence methods
- Published
- 2020
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14. Acid exposure disrupts mucus secretion and impairs mucociliary transport in neonatal piglet airways.
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Liao YSJ, Kuan SP, Guevara MV, Collins EN, Atanasova KR, Dadural JS, Vogt K, Schurmann V, Bravo L, Eken E, Sponchiado M, and Reznikov LR
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- Acid Sensing Ion Channels metabolism, Airway Obstruction drug therapy, Airway Obstruction metabolism, Airway Obstruction pathology, Animals, Animals, Newborn, Bicarbonates metabolism, Bronchi drug effects, Bronchi metabolism, Bronchi pathology, Bronchoalveolar Lavage Fluid chemistry, Chlorides metabolism, Cystic Fibrosis drug therapy, Cystic Fibrosis metabolism, Cystic Fibrosis pathology, Diminazene pharmacology, Disease Models, Animal, Female, Gene Expression, Humans, Hydrogen-Ion Concentration, Male, Mucin 5AC genetics, Mucin 5AC metabolism, Mucin-5B genetics, Mucin-5B metabolism, Mucociliary Clearance drug effects, Mucus metabolism, Respiratory Mucosa drug effects, Respiratory Mucosa metabolism, Respiratory Mucosa pathology, Swine, Trachea drug effects, Trachea metabolism, Trachea pathology, Acetic Acid administration & dosage, Acid Sensing Ion Channel Blockers pharmacology, Acid Sensing Ion Channels genetics, Airway Obstruction chemically induced, Cystic Fibrosis chemically induced, Diminazene analogs & derivatives
- Abstract
Tenacious mucus produced by tracheal and bronchial submucosal glands is a defining feature of several airway diseases, including cystic fibrosis (CF). Airway acidification as a driving force of CF airway pathology has been controversial. Here we tested the hypothesis that transient airway acidification produces pathologic mucus and impairs mucociliary transport. We studied pigs challenged with intra-airway acid. Acid had a minimal effect on mucus properties under basal conditions. However, cholinergic stimulation in acid-challenged pigs revealed retention of mucin 5B (MUC5B) in the submucosal glands, decreased concentrations of MUC5B in the lung lavage fluid, and airway obstruction. To more closely mimic a CF-like environment, we also examined mucus secretion and transport following cholinergic stimulation under diminished bicarbonate and chloride transport conditions ex vivo. Under these conditions, airways from acid-challenged pigs displayed extensive mucus films and decreased mucociliary transport. Pretreatment with diminazene aceturate, a small molecule with ability to inhibit acid detection through blockade of the acid-sensing ion channel (ASIC) at the doses provided, did not prevent acid-induced pathologic mucus or transport defects but did mitigate airway obstruction. These findings suggest that transient airway acidification early in life has significant impacts on mucus secretion and transport properties. Furthermore, they highlight diminazene aceturate as an agent that might be beneficial in alleviating airway obstruction.
- Published
- 2020
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15. Evaluation of metabolic profile and C-reactive protein concentrations in brachycephalic dogs with upper airway obstructive syndrome.
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Gianella P, Caccamo R, Bellino C, Bottero E, Fietta F, Roncone S, Ostanello F, Pietra M, and Buracco P
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- Airway Obstruction genetics, Airway Obstruction metabolism, Animals, Craniosynostoses genetics, Craniosynostoses veterinary, Dog Diseases blood, Dog Diseases genetics, Dogs, Female, Gastrointestinal Diseases veterinary, Inflammation veterinary, Male, Prospective Studies, Airway Obstruction veterinary, C-Reactive Protein metabolism, Dog Diseases metabolism, Metabolome
- Abstract
Background: Brachycephalic dogs have abnormal breathing patterns similar to those in humans with obstructive sleep apnea syndrome. Obstructive sleep apnea syndrome is associated with dyslipidemia, hyperglycemia, and insulin resistance. Despite the fact that anatomic and functional alterations are well described in brachycephalic dogs, little is known about the consequences of upper airway obstruction on systemic inflammatory response and metabolic profile., Objectives: To describe history, clinical presentation, and anatomic abnormalities; to evaluate systemic inflammatory response and metabolic profile; and to identify possible associations among clinical signs, anatomic abnormalities, inflammatory response, and metabolic profile in brachycephalic dogs with airway obstruction., Animals: Thirty purebred brachycephalic dogs with brachycephalic airway obstructive syndrome (BAOS)., Methods: Prospective study. The following information was recorded and studied: respiratory and digestive signs, airway and digestive endoscopic anomalies, presence or absence of tracheal hypoplasia, histologic evaluation of gastrointestinal tract biopsy specimens, serum concentrations of C-reactive protein (CRP), fructosamine, insulin, glucose, triglyceride, cholesterol, and plasma concentrations of lipoprotein classes., Results: A high proportion of dogs (76.7%) had gastrointestinal signs. Esophageal deviation, atony of the cardia of the stomach, and distal esophagitis were the most common endoscopic anomalies detected. Twenty-six (86.6%) dogs had different degrees of laryngeal collapse. Gastrointestinal histologic evaluation identified mostly chronic inflammation. Glucose, fructosamine, triglycerides, cholesterol, CRP, pre-beta, beta lipoproteins, and chylomicrons were increased to a variable extent. Significant associations among clinical signs, anatomic abnormalities, CRP, and metabolic profile were not found., Conclusion and Clinical Importance: Despite the presence of inflammation and some mild metabolic derangements, the clinicopathological variables evaluated did not offer valuable information in dogs with BAOS., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)
- Published
- 2019
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16. Immunopathology of Airway Surface Liquid Dehydration Disease.
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Lewis BW, Patial S, and Saini Y
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- Airway Obstruction metabolism, Airway Obstruction microbiology, Animals, Cystic Fibrosis genetics, Cystic Fibrosis microbiology, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Dehydration metabolism, Dehydration physiopathology, Ion Channels deficiency, Ion Channels genetics, Leukocytes immunology, Lung immunology, Lung physiopathology, Macrophages immunology, Mice, Mice, Transgenic, Mucociliary Clearance genetics, Mucociliary Clearance immunology, Respiratory Tract Infections immunology, Respiratory Tract Infections physiopathology, Airway Obstruction immunology, Airway Obstruction physiopathology, Cystic Fibrosis immunology, Cystic Fibrosis physiopathology, Disease Models, Animal, Epithelial Sodium Channels genetics
- Abstract
The primary purpose of pulmonary ventilation is to supply oxygen (O
2 ) for sustained aerobic respiration in multicellular organisms. However, a plethora of abiotic insults and airborne pathogens present in the environment are occasionally introduced into the airspaces during inhalation, which could be detrimental to the structural integrity and functioning of the respiratory system. Multiple layers of host defense act in concert to eliminate unwanted constituents from the airspaces. In particular, the mucociliary escalator provides an effective mechanism for the continuous removal of inhaled insults including pathogens. Defects in the functioning of the mucociliary escalator compromise the mucociliary clearance (MCC) of inhaled pathogens, which favors microbial lung infection. Defective MCC is often associated with airway mucoobstruction, increased occurrence of respiratory infections, and progressive decrease in lung function in mucoobstructive lung diseases including cystic fibrosis (CF). In this disease, a mutation in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene results in dehydration of the airway surface liquid (ASL) layer. Several mice models of Cftr mutation have been developed; however, none of these models recapitulate human CF-like mucoobstructive lung disease. As an alternative, the Scnn1b transgenic ( Scnn1b -Tg+) mouse model overexpressing a transgene encoding sodium channel nonvoltage-gated 1 , beta subunit ( Scnn1b ) in airway club cells is available. The Scnn1b -Tg+ mouse model exhibits airway surface liquid (ASL) dehydration, impaired MCC, increased mucus production, and early spontaneous pulmonary bacterial infections. High morbidity and mortality among mucoobstructive disease patients, high economic and health burden, and lack of scientific understanding of the progression of mucoobstruction warrants in-depth investigation of the cause of mucoobstruction in mucoobstructive disease models. In this review, we will summarize published literature on the Scnn1b -Tg+ mouse and analyze various unanswered questions on the initiation and progression of mucobstruction and bacterial infections., Competing Interests: The authors declare that they have no competing interests.- Published
- 2019
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17. Heterogeneous Pulmonary Response After Tracheal Occlusion: Clues to Fetal Lung Growth.
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Dobrinskikh E, Al-Juboori SI, Shabeka U, Reisz JA, Zheng C, and Marwan AI
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- Airway Obstruction metabolism, Airway Obstruction pathology, Animals, Disease Models, Animal, Female, Fetus metabolism, Fetus pathology, Glycolysis physiology, Hernias, Diaphragmatic, Congenital etiology, Hernias, Diaphragmatic, Congenital metabolism, Humans, Lung metabolism, Lung pathology, Metabolomics, Organ Size physiology, Oxidative Phosphorylation, Pregnancy, Pulmonary Surfactants metabolism, Rabbits, Trachea surgery, Airway Obstruction complications, Fetus embryology, Hernias, Diaphragmatic, Congenital pathology, Lung embryology, Organogenesis physiology
- Abstract
Background: Understanding inconsistent clinical outcomes in infants with severe congenital diaphragmatic hernia (CDH) after tracheal occlusion (TO) is a crucial step for advancing neonatal care. The objective of this study is to explore the heterogeneous airspace morphometry and the metabolic landscape changes in fetal lungs after TO., Methods: Fetal lungs on days 1 and 4 after TO were examined using mass spectrometry-based metabolomics, fluorescence lifetime imaging microscopy (FLIM), the number of airspaces, and tissue-to-airspace ratio (TAR)., Results: Two morphometric areas were identified in TO lungs compared with controls (more small airspaces at day 1 and a higher number of enlarged airspaces at day 4). Global metabolomics analysis revealed a significant upregulation of glycolysis and a suppression of the tricarboxylic acid cycle in day 4 TO lungs compared with day 1 TO lungs. In addition, there was a significant increase in polyamines involved in cell growth and proliferation. Locally, FLIM analysis on day 1 TO lungs demonstrated two types of heterogeneous zones-similar to control and with increased oxidative phosphorylation. FLIM on day 4 TO lungs demonstrated appearance of zones with enlarged airspaces and a metabolic shift toward glycolysis, accompanied by a decrease in the FLIM "lipid-surfactant" signal., Conclusions: In normal fetal lungs, we report a novel temporal pattern of varied morphometric and metabolic changes. Initially, there is formation of zones with small airspaces, followed by airspace enlargement over time. Metabolically day 1 TO lungs have zones with increased oxidative phosphorylation, whereas day 4 TO lungs have a shift toward glycolysis in the enlarged airspaces. Based on our observations, we speculate that the "best responders" to tracheal occlusion should have bigger lungs with small airspaces and normal surfactant production., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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18. The effects of tracheal occlusion on Wnt signaling in a rabbit model of congenital diaphragmatic hernia.
- Author
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Mudri M, Smith SA, Vanderboor C, Davidson J, Regnault TRH, and Bütter A
- Subjects
- Airway Obstruction complications, Animals, DNA Topoisomerases, Type I genetics, Electron Transport Complex II genetics, Fetus, Gene Expression, Glycoproteins genetics, Hernias, Diaphragmatic, Congenital complications, Lung embryology, MicroRNAs genetics, Organ Size, Prenatal Care, Prospective Studies, Rabbits, Trachea, Airway Obstruction metabolism, Bronchioles pathology, Disease Models, Animal, Hernias, Diaphragmatic, Congenital metabolism, Lung pathology, Wnt Signaling Pathway
- Abstract
Purpose: Tracheal occlusion (TO) reverses pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH), but its mechanism of action remains poorly understood. Wnt signaling plays a critical role in lung development, but few studies exist. The purpose of our study was to a) confirm that our CDH rabbit model produced PH which was reversed by TO and b) determine the effects of CDH +/- TO on Wnt signaling., Methods: CDH was created in fetal rabbits at 23 days, TO at 28 days, and lung collection at 31 days. Lung body weight ratio (LBWR) and mean terminal bronchiole density (MTBD) were determined. mRNA and miRNA expression was determined in the left lower lobe using RT-qPCR., Results: Fifteen CDH, 15 CDH + TO, 6 sham CDH, and 15 controls survived and were included in the study. LBWR was low in CDH, while CDH + TO was similar to controls (p = 0.003). MTBD was higher in CDH fetuses and restored to control levels in CDH + TO (p < 0.001). Reference genes TOP1, SDHA, and ACTB were consistently expressed within and between treatment groups. miR-33 and MKI67 were increased, and Lgl1 was decreased in CDH + TO., Conclusion: TO reversed pulmonary hypoplasia and stimulated early Wnt signaling in CDH fetal rabbits., Type of Study: Basic science, prospective., Level of Evidence: II., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2019
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19. Targeting of cathepsin S reduces cystic fibrosis-like lung disease.
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Small DM, Brown RR, Doherty DF, Abladey A, Zhou-Suckow Z, Delaney RJ, Kerrigan L, Dougan CM, Borensztajn KS, Holsinger L, Booth R, Scott CJ, López-Campos G, Elborn JS, Mall MA, Weldon S, and Taggart CC
- Subjects
- Airway Obstruction metabolism, Animals, Cathepsins genetics, Disease Models, Animal, Epithelial Sodium Channels genetics, Lung pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Pneumonia etiology, Cathepsins metabolism, Cystic Fibrosis metabolism, Mucus metabolism, Pneumonia metabolism, Receptor, PAR-2 metabolism
- Abstract
Cathepsin S (CatS) is upregulated in the lungs of patients with cystic fibrosis (CF). However, its role in CF lung disease pathogenesis remains unclear.In this study, β-epithelial Na
+ channel-overexpressing transgenic (βENaC-Tg) mice, a model of CF-like lung disease, were crossed with CatS null (CatS-/- ) mice or treated with the CatS inhibitor VBY-999.Levels of active CatS were elevated in the lungs of βENaC-Tg mice compared with wild-type (WT) littermates. CatS-/- βENaC-Tg mice exhibited decreased pulmonary inflammation, mucus obstruction and structural lung damage compared with βENaC-Tg mice. Pharmacological inhibition of CatS resulted in a significant decrease in pulmonary inflammation, lung damage and mucus plugging in the lungs of βENaC-Tg mice. In addition, instillation of CatS into the lungs of WT mice resulted in inflammation, lung remodelling and upregulation of mucin expression. Inhibition of the CatS target, protease-activated receptor 2 (PAR2), in βENaC-Tg mice resulted in a reduction in airway inflammation and mucin expression, indicating a role for this receptor in CatS-induced lung pathology.Our data indicate an important role for CatS in the pathogenesis of CF-like lung disease mediated in part by PAR2 and highlight CatS as a therapeutic target., Competing Interests: Conflict of interest: D.M. Small has nothing to disclose. Conflict of interest: R.R. Brown has nothing to disclose. Conflict of interest: D.F. Doherty has nothing to disclose. Conflict of interest: A. Abladey has nothing to disclose. Conflict of interest: Z. Zhou-Suckow has nothing to disclose. Conflict of interest: R.J. Delaney has nothing to disclose. Conflict of interest: L. Kerrigan has nothing to disclose. Conflict of interest: C.M. Dougan has nothing to disclose. Conflict of interest: K.S. Borensztajn has nothing to disclose. Conflict of interest: L. Holsinger is an employee of Virobay. Conflict of interest: R. Booth has a patent US 7,547,701 issued. Conflict of interest: C.J. Scott is a consultant for Fusion Antibodies PLC, outside the submitted work; and is named inventor on various patents on antibodies to cathepsin S for treatment of cancer, many of which have now lapsed as not a current research direction for the company (Fusion Antibodies PLC). Conflict of interest: G. López-Campos has nothing to disclose. Conflict of interest: J.S. Elborn reports personal fees for advisory board work from Bayer, grants and personal fees for advisory board work from Horizion, during the conduct of the study; personal fees for advisory board work from Chiesi and Polyphor, outside the submitted work. Conflict of interest: M.A. Mall reports grants from German Federal Ministry of Education and Research (contract numbers 82DZL00401 and 82DZL004A1), during the conduct of the study; personal fees for advisory board and consultancy work from Spyryx Biosciences, Boehringer Ingelheim and Polyphor, personal fees for advisory board work from ProQR, PTC Pharmaceuticals, Arrowhead and Pro Axis, personal fees for consultancy and lecturing from Bayer, personal fees for consultancy from Enterprise Therapeutics and Sterna Biologicals, personal fees for advisory board work, consultancy and lecturing from Vertex Pharmaceuticals, outside the submitted work; and has a patent on the Scnn1b-transgenic mouse with royalties paid. Conflict of interest: S. Weldon reports grants from Randox and Pfizer UK, outside the submitted work. Conflict of interest: C.C. Taggart reports personal fees for consultancy from Albumedix, and grants from Randox and Pfizer UK, outside the submitted work., (Copyright ©ERS 2019.)- Published
- 2019
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20. Upregulated P-Rex1 exacerbates human airway smooth muscle hyperplasia in asthma.
- Author
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Huang Y, Xie Y, Jiang H, Abel PW, Panettieri RA Jr, Casale TB, and Tu Y
- Subjects
- Airway Obstruction genetics, Airway Remodeling genetics, Asthma genetics, Cells, Cultured, Guanine Nucleotide Exchange Factors genetics, Humans, Hyperplasia, Myocytes, Smooth Muscle pathology, Neoplasm Metastasis genetics, Receptor, Platelet-Derived Growth Factor beta metabolism, Up-Regulation, rac1 GTP-Binding Protein genetics, Airway Obstruction metabolism, Asthma metabolism, Guanine Nucleotide Exchange Factors metabolism, Myocytes, Smooth Muscle metabolism, Respiratory System pathology, rac1 GTP-Binding Protein metabolism
- Published
- 2019
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21. Proteomic profiling of tracheal fluid in an ovine model of congenital diaphragmatic hernia and fetal tracheal occlusion.
- Author
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Peiro JL, Oria M, Aydin E, Joshi R, Cabanas N, Schmidt R, Schroeder C, Marotta M, and Varisco BM
- Subjects
- Animals, Disease Models, Animal, Female, Gene Expression Profiling methods, Lung metabolism, Pregnancy, Prenatal Care methods, Proteomics methods, Tubulin metabolism, Airway Obstruction metabolism, Body Fluids metabolism, Fetus metabolism, Hernias, Diaphragmatic, Congenital metabolism, Sheep metabolism, Trachea metabolism
- Abstract
Congenital diaphragmatic hernia (CDH) occurs in ~1:2,000 pregnancies and is associated with substantial morbidity and mortality. Fetal tracheal occlusion (TO) is an emerging therapy that improves lung growth and reduces mortality, although substantial respiratory compromise persists in survivors. In this study, we used tracheal fluid in a fetal sheep model of CDH with TO for proteomic analysis with subsequent validation of findings in sheep lung tissue. We found that the proteomic profiles of CDH tracheal fluid was most similar to control lung and CDH/TO lung most similar to TO lung. Among 118 proteins altered in CDH, only 11 were reciprocally regulated in CDH/TO. The most significantly altered pathways and processes were cell proliferation, phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling, inflammation, and microtubule dynamics. CDH suppressed and TO promoted cell proliferation and AKT-related signaling cascades. By Western blot analysis and immunohistochemistry, epithelial PCNA and phosphorylated AKT were decreased in CDH and increased in TO and CDH/TO lungs. The Wnt target Axin2 was decreased threefold in CDH lung compared with control without a significant increase in CDH/TO lung. Cilia-related pathways were among the most dysregulated with CDH lung having a nearly twofold increase in acetylated α-tubulin and a relative increase in the number of ciliated cells. While TO improves lung growth and patient survival in CDH, the procedure substantially alters many processes important in lung development and cell differentiation. Further elucidation of these changes will be critical to improving lung health in infants with CDH treated with TO.
- Published
- 2018
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22. Mucin Concentrations and Peripheral Airway Obstruction in Chronic Obstructive Pulmonary Disease.
- Author
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Kesimer M, Smith BM, Ceppe A, Ford AA, Anderson WH, Barr RG, O'Neal WK, and Boucher RC
- Subjects
- Airway Obstruction physiopathology, Humans, Lung diagnostic imaging, Lung metabolism, Lung physiopathology, Pulmonary Disease, Chronic Obstructive physiopathology, Spirometry, Tomography, X-Ray Computed, Airway Obstruction complications, Airway Obstruction metabolism, Mucins metabolism, Pulmonary Disease, Chronic Obstructive complications, Pulmonary Disease, Chronic Obstructive metabolism
- Published
- 2018
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23. Changes in surface tension of saliva in Down syndrome.
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Kawai M, Ito N, and Ayuse T
- Subjects
- Adult, Age Factors, Airway Obstruction etiology, Airway Obstruction metabolism, Airway Obstruction physiopathology, Case-Control Studies, Down Syndrome complications, Down Syndrome physiopathology, Humans, Male, Middle Aged, Risk Factors, Salivation, Surface Tension, Young Adult, Down Syndrome metabolism, Saliva chemistry
- Abstract
Objective: Surface tension in saliva might contribute to the maintenance of upper airway patency. The present study aimed to determine whether salivary surface tension is altered in patients with Down syndrome who are predisposed to upper airway collapse., Patients and Methods: We used the pull-off force technique to measure surface tension in samples (100 μL) of saliva collected from twenty-three male patients with Down syndrome and twenty-three healthy males (controls). p < 0.05 was considered to indicate significance., Results: Salivary surface tension was significantly lower in the patients than in the controls (57.3 ± 4.9 vs. 60.3 ± 4.7 mN/m; p = 0.039). Age and surface tension positively correlated in the patients (p = 0.001)., Conclusions: The lower surface tension of saliva in patients with Down syndrome might compensate for an anatomical predisposition towards upper airway collapsibility and other risk factors. The function of surface tension in saliva might be altered due to aging in such patients.
- Published
- 2018
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24. Evaluation of the severity of small airways obstruction and alveolar destruction in chronic obstructive pulmonary disease.
- Author
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Kawamoto T, Kanazawa H, Tochino Y, and Kawaguchi T
- Subjects
- Aged, Airway Obstruction complications, Airway Obstruction physiopathology, Arginine metabolism, Female, Humans, Lysine metabolism, Male, Middle Aged, Nitrogen metabolism, Pulmonary Disease, Chronic Obstructive diagnostic imaging, Pulmonary Disease, Chronic Obstructive pathology, Pulmonary Disease, Chronic Obstructive physiopathology, Severity of Illness Index, Smoking metabolism, Sputum metabolism, Tomography, X-Ray Computed methods, Airway Obstruction metabolism, Arginine analogs & derivatives, Lysine analogs & derivatives, Pulmonary Alveoli pathology, Pulmonary Disease, Chronic Obstructive metabolism, Vascular Endothelial Growth Factor A metabolism
- Abstract
Background: Airflow limitation in COPD is caused by a mixture of small airways obstruction and alveolar destruction., Objective: To evaluate the contributions of these factors to airflow limitation through measurement of two biomarkers, pentosidine and vascular endothelial growth factor (VEGF), which reflect pathology or function of the lower respiratory tract of COPD., Methods: We measured pentosidine and VEGF levels in induced sputum from 23 non-smokers, 26 smokers without COPD, and 43 smokers with COPD. We evaluated the correlations of two biomarkers levels with the grade of low attenuation area (LAA) in high-resolution computed tomographic scans and the Δ N
2 from the nitrogen washout curve., Results: Pentosidine levels were significantly higher in smokers with COPD than in non-smokers and smokers without COPD. In contrast, VEGF levels were significantly lower in smokers without COPD than in non-smokers, and further decreased in smokers with COPD. In the four-stage classification of LAA grading, pentosidine levels steeply increased from grade I to Ⅳ, while VEGF levels decreased with increasing severity of LAA grade. Pentosidine levels were positively correlated with Δ N2 in COPD patients with mild emphysema. In contrast, VEGF levels were inversely correlated with Δ N2 in COPD patients with severe emphysema., Conclusion: Pentosidine level is responsible for the severity of small airways obstruction, while VEGF level reflects the magnitude of alveolar destruction. Thus, simultaneous measurement of pentosidine and VEGF levels may be a promising approach to discriminate the severity of small airways obstruction and alveolar destruction in the lower respiratory tract of COPD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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25. Airway stenting for patients with airway stenosis because of small cell lung cancer.
- Author
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Oki M and Saka H
- Subjects
- Aged, Aged, 80 and over, Airway Obstruction etiology, Airway Obstruction metabolism, Constriction, Pathologic, Drug-Eluting Stents, Female, Humans, L-Lactate Dehydrogenase blood, Lung Neoplasms complications, Lung Neoplasms metabolism, Male, Middle Aged, Retrospective Studies, Small Cell Lung Carcinoma complications, Small Cell Lung Carcinoma metabolism, Survival Analysis, Treatment Outcome, Airway Obstruction surgery, Bronchoscopy instrumentation, Lung Neoplasms therapy, Small Cell Lung Carcinoma therapy
- Abstract
Background: Airway stenting has been reported to be useful for patients with malignant airway stenosis as a bridge to tumour-specific therapy, such as chemotherapy and radiation therapy, as well as palliative therapy. However, its role in patients with small-cell lung cancer (SCLC), the most aggressive lung cancer subtype, is unclear. We investigated the efficacy of airway stenting for patients with airway stenosis resulting from SCLC., Methods: All stenting procedures were performed using both rigid and flexible bronchoscopes under general anaesthesia. Among 512 patients who underwent rigid bronchoscopy during a 9-year period at a single centre, those who underwent airway stenting for airway stenosis because of SCLC were retrospectively reviewed., Results: Twenty-one SCLC patients with airway stenosis who underwent stenting were eligible for analysis. Twelve patients (57%) were chemoradiotherapy-naïve. Supplemental oxygen was reduced after the procedure in 11 out of 12 patients (92%) who had previously required it. Fourteen patients (67%) received tumour-specific therapy after the procedure. The median post-procedural survival was 47 days (range, 5-617 days). Longer survival was associated with the performance of post-procedural tumour-specific therapy, low serum lactate dehydrogenase levels and either tracheal or bronchial stenosis., Conclusions: SCLC patients with airway stenting experienced longer survival when post-procedural tumour-specific therapy was performed, when they showed low serum lactate dehydrogenase levels, and when they had either tracheal or bronchial stenosis., (© 2018 John Wiley & Sons Ltd.)
- Published
- 2018
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26. Caveolin-3 differentially orchestrates cholinergic and serotonergic constriction of murine airways.
- Author
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Keshavarz M, Skill M, Hollenhorst MI, Maxeiner S, Walecki M, Pfeil U, Kummer W, and Krasteva-Christ G
- Subjects
- Airway Obstruction metabolism, Animals, Constriction, Pathologic, Male, Mice, Mice, Knockout, Muscarine pharmacology, Muscle Contraction drug effects, Muscle, Smooth metabolism, Receptors, Cholinergic metabolism, Receptors, Serotonin metabolism, Serotonin pharmacology, Airway Obstruction genetics, Bronchi metabolism, Caveolin 3 genetics, Caveolin 3 metabolism, Trachea metabolism
- Abstract
The mechanisms of controlling airway smooth muscle (ASM) tone are of utmost clinical importance as inappropriate constriction is a hallmark in asthma and chronic obstructive pulmonary disease. Receptors for acetylcholine and serotonin, two relevant mediators in this context, appear to be incorporated in specialized, cholesterol-rich domains of the plasma membrane, termed caveolae due to their invaginated shape. The structural protein caveolin-1 partly accounts for anchoring of these receptors. We here determined the role of the other major caveolar protein, caveolin-3 (cav-3), in orchestrating cholinergic and serotonergic ASM responses, utilizing newly generated cav-3 deficient mice. Cav-3 deficiency fully abrogated serotonin-induced constriction of extrapulmonary airways in organ baths while leaving intrapulmonary airways unaffected, as assessed in precision cut lung slices. The selective expression of cav-3 in tracheal, but not intrapulmonary bronchial epithelial cells, revealed by immunohistochemistry, might explain the differential effects of cav-3 deficiency on serotonergic ASM constriction. The cholinergic response of extrapulmonary airways was not altered, whereas a considerable increase was observed in cav-3
-/- intrapulmonary bronchi. Thus, cav-3 differentially organizes serotonergic and cholinergic signaling in ASM through mechanisms that are specific for airways of certain caliber and anatomical position. This may allow for selective and site-specific intervention in hyperreactive states.- Published
- 2018
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27. A simple method to reconstruct the molar mass signal of respiratory gas to assess small airways with a double-tracer gas single-breath washout.
- Author
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Port J, Tao Z, Junger A, Joppek C, Tempel P, Husemann K, Singer F, Latzin P, Yammine S, Nagel JH, and Kohlhäufl M
- Subjects
- Adult, Airway Obstruction metabolism, Child, Helium metabolism, Humans, Pulmonary Disease, Chronic Obstructive metabolism, Reproducibility of Results, Respiration, Sulfur Hexafluoride metabolism, Tidal Volume physiology, Airway Obstruction diagnosis, Lung metabolism, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Ventilation physiology
- Abstract
For the assessment of small airway diseases, a noninvasive double-tracer gas single-breath washout (DTG-SBW) with sulfur hexafluoride (SF
6 ) and helium (He) as tracer components has been proposed. It is assumed that small airway diseases may produce typical ventilation inhomogeneities which can be detected within one single tidal breath, when using two tracer components. Characteristic parameters calculated from a relative molar mass (MM) signal of the airflow during the washout expiration phase are analyzed. The DTG-SBW signal is acquired by subtracting a reconstructed MM signal without tracer gas from the signal measured with an ultrasonic sensor during in- and exhalation of the double-tracer gas for one tidal breath. In this paper, a simple method to determine the reconstructed MM signal is presented. Measurements on subjects with and without obstructive lung diseases including the small airways have shown high reliability and reproducibility of this method.- Published
- 2017
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28. Increased production of TGF-β1 from sputum cells of COPD: Relationship with airway obstruction.
- Author
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Godinas L, Corhay JL, Henket M, Guiot J, Louis R, and Moermans C
- Subjects
- Adult, Body Mass Index, Case-Control Studies, Cell Count, Demography, Female, Humans, Kinetics, Luciferases metabolism, Male, Reproducibility of Results, Smoking, Tumor Necrosis Factor-alpha metabolism, Airway Obstruction metabolism, Airway Obstruction pathology, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive pathology, Sputum metabolism, Transforming Growth Factor beta1 biosynthesis
- Abstract
Chronic obstructive pulmonary disease (COPD) is a chronic airway disease characterized by a profound airway remodelling that leads to airway obstruction. A role for transforming growth factor-β1 (TGF-β1) has been proposed in airway remodelling of COPD. Regarding the TGF-β1 production at local level, the results seemed to be controversial. In this study, an original model of sputum cell culture thought to maintain important cells interactions, was used. We investigated the production of TGF-β1 from sputum cell culture in 33 COPD encompassing the whole severity spectrum and compared the results with those found in 39 healthy controls. Sputum was induced by inhalation of saline, the cellular fraction cultured for 24 h and the spontaneous production of total TGF-β1 was assessed by ELISA. Using, a TGF-β1 reporter cell assay, we also compared the levels of active and total TGF-β1 in the sputum cell culture supernatants of COPD and controls. Moreover, as a combination of tumor necrosis factor-α (TNF-α) and TGF-β1 have been shown to have a cumulative impact on the severity of airflow limitation in COPD, the TNF-α release was also measured in a representative subgroup of patients. Our results indicated that the use of sputum cell culture was a reliable and reproducible method to assess TGF-β1 production at airway level. Sputum cells from COPD produced greater amount of total TGF-β1 than those of healthy controls (p<0.001). This result was confirmed using the cell reporter assay which also showed a higher level of active TGF-β1 in the COPD group compared to controls. In addition, total TGF-β1 production was increased according to GOLD stage and was inversely related to FEV1/FVC ratio (p<0.05). By contrast, the production of this growth factor was not correlated with the functional markers of emphysema nor with demographic characteristics such as age, BMI or smoking status. Interestingly, the production of total TGF-β1 was inversely related to that of TNF-α (r=-0.53, p<0.05) which was decreased in COPD. In summary, COPD patients displayed a raised production of total and active TGF-β1 from their airway cells. Total TGF-β1 correlates with the severity of airway obstruction without evidence of a link with emphysema. ., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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29. Are pulmonary hemostasis and fibrinolysis out of balance in equine chronic pneumopathies?
- Author
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Barton AK, Wirth C, Bondzio A, Einspanier R, and Gehlen H
- Subjects
- Acute-Phase Proteins analysis, Airway Obstruction metabolism, Airway Obstruction physiopathology, Airway Obstruction veterinary, Animals, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid cytology, Fibrin Fibrinogen Degradation Products analysis, Fibrinogen analysis, Horse Diseases metabolism, Horses, Lung Diseases metabolism, Lung Diseases physiopathology, Serum Amyloid A Protein analysis, Fibrinolysis physiology, Hemostasis physiology, Horse Diseases physiopathology, Lung Diseases veterinary
- Abstract
Clinical examination, bronchoalveolar lavage fluid (BALF) cytology, acute-phase protein, and pulmonary hemostasis and fibrinolysis marker (fibrinogen, serum amyloid A [SAA], and D-dimer) results were compared between control and respiratory disease-affected horses. Using a clinical scoring system, horses (n = 58) were classified as respiratory disease-free (Controls, n = 15) or with recurrent airway obstruction (RAO; n = 18), inflammatory airway disease (n = 14) or chronic interstitial pneumopathy (n = 11). There were no significant differences in fibrinogen concentrations among groups, but there was a trend toward a lower value in controls (median 0.0024 g/L) than in horses with chronic pneumopathies (median 0.0052 g/L), in particular, those with RAO (median 0.0062 g/L). Fibrinogen concentration was positively correlated with percentage of neutrophils in BALF ( r
s = 0.377, p = 0.004). SAA concentrations were low; 65.5% of samples were below the detection limit. D-dimer concentrations were also low and quantifiable concentrations were only obtained after ultrafiltration and only in RAO (median 0.1 mg/L). In conclusion, there was limited evidence of increased coagulatory activity in chronic pneumopathies, apart from RAO. It is uncertain whether fibrinogen and D-dimer concentrations increased due to their role as acute-phase proteins or as a misbalance of coagulation and fibrinolysis.- Published
- 2017
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30. PAI-1 gain-of-function genotype, factors increasing PAI-1 levels, and airway obstruction: The GALA II Cohort.
- Author
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Sherenian MG, Cho SH, Levin A, Min JY, Oh SS, Hu D, Galanter J, Sen S, Huntsman S, Eng C, Rodriguez-Santana JR, Serebrisky D, Avila PC, Kalhan R, Smith LJ, Borrell LN, Seibold MA, Keoki Williams L, Burchard EG, and Kumar R
- Subjects
- Adolescent, Adult, Airway Obstruction epidemiology, Airway Obstruction physiopathology, Alleles, Asthma, Occupational epidemiology, Asthma, Occupational genetics, Asthma, Occupational metabolism, Asthma, Occupational physiopathology, Child, Cohort Studies, Ethnicity, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Male, Odds Ratio, Polymorphism, Single Nucleotide, Respiratory Function Tests, Young Adult, Airway Obstruction genetics, Airway Obstruction metabolism, Gain of Function Mutation, Plasminogen Activator Inhibitor 1 genetics, Plasminogen Activator Inhibitor 1 metabolism
- Abstract
Background: PAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma., Objective: We sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level., Methods: We studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function., Results: There was an interaction between asthma status and the PAI-1 polymorphism on FEV
1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1 /FVC in subjects with asthma (β=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P<.001). In asthmatics, the risk genotype (AA/AG) was associated with a 39% increase in risk of clinically relevant airway obstruction (OR=1.39, CI: 1.01, 1.92, P=.04). These associations persisted after exclusion of factors that increase PAI-1 including tobacco exposure and obesity., Conclusions and Clinical Relevance: The decrease in the FEV1 /FVC ratio associated with the risk genotype was modified by asthma status. The genotype increased the odds of airway obstruction by 75% within asthmatics only. As exposures known to increase PAI-1 levels did not mitigate this association, PAI-1 may contribute to airway obstruction in the context of chronic asthmatic airway inflammation., (© 2017 John Wiley & Sons Ltd.)- Published
- 2017
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31. IL-17RB + granulocytes are associated with airflow obstruction in asthma.
- Author
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Li L, Lukacs NW, Schaller MA, Petersen B, and Baptist AP
- Subjects
- Adult, Airway Obstruction immunology, Asthma immunology, Asthma physiopathology, Biomarkers, Case-Control Studies, Eosinophils, Female, Fluorescent Antibody Technique, Forced Expiratory Volume, Granulocytes immunology, Humans, Immunophenotyping, Leukocyte Count, Male, Middle Aged, Phenotype, Receptors, Interleukin-17, Respiratory Function Tests, Airway Obstruction metabolism, Airway Obstruction pathology, Asthma metabolism, Asthma pathology, Granulocytes metabolism, Receptors, Interleukin metabolism
- Abstract
Background: Interleukin (IL)-25 (IL-17E) is a proinflammatory cytokine that plays an important role in the T-helper type 2 cell pathway. The effects of IL-25 are mediated by its specific receptor, IL-17RB. Previous studies have defined an IL-17RB
+ granulocyte population known as type 2 myeloid (T2M) cells that express T-helper type 2 cell cytokines. The correlation of IL-17RB+ granulocytes, T2M cells, and asthma parameters is unknown., Objective: To investigate the relation of IL-17RB+ granulocytes (and its subset, T2M cells) in patients with asthma with clinical parameters including spirometric values and the Asthma Control Test (ACT)., Methods: Peripheral blood from subjects with asthma and healthy controls was collected and analyzed by flow cytometry. Granulocytes were gated for IL-17RB+ , T2M (CD11b+ CD16+ CD177+ IL-17RB+ ), and eosinophil (CD16- ) populations. Spirometry testing was performed on subjects with asthma. ACT scores and medical histories were collected by questionnaire and chart review. Correlations of IL-17RB+ cells and T2M cells with spirometry and ACT score were analyzed., Results: Percentages of IL-17RB+ granulocytes and T2M cells were larger in subjects with asthma than in controls. Furthermore, percentages of the 2 cell populations were negatively correlated with degree of airway obstruction as measured by the ratio of percentage-predicted forced expiratory volume in 1 second to force vital capacity (r = -0.17, P = .043 for IL-17RB+ granulocytes; r = -0.32, P = .03 for T2M cells). There was no correlation with ACT score. The percentage of eosinophils was increased in subjects with asthma. However, IL-17RB+ eosinophil percentages were similar between subjects with asthma and controls and did not correlate with any clinical parameter., Conclusion: IL-17RB+ granulocytes and T2M cells from peripheral blood were increased in subjects with asthma, and the 2 cell types correlated with degree of airflow obstruction., Competing Interests: None, (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2016
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32. Evaluation of serum cytokine levels in recurrent airway obstruction.
- Author
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Niedźwiedź A, Borowicz H, Kubiak K, Nicpoń J, Skrzypczak P, Jaworski Z, Cegielski M, and Nicpoń J
- Subjects
- Airway Obstruction metabolism, Airway Obstruction pathology, Animals, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid cytology, Cytokines genetics, Female, Gene Expression Regulation, Horses, Male, Airway Obstruction veterinary, Cytokines metabolism, Horse Diseases metabolism
- Abstract
Recurrent airway obstruction (RAO) represents a serious health problem and is traditionally classified as an allergic disease, where contact with an antigen can induce clinical airway inflammation, bronchial hyper-responsiveness and reversible airway obstruction. Previous studies have demonstrated the presence of the Th2 response in the lungs of human patients with asthma and horses with heaves. These cells are involved in the production of cytokines which regulate the synthesis of immunoglobulins. 40 horses were evaluated: 30 horses with RAO and 10 healthy animals. The expression levels of interferon-alpha 1 (IFN-α1), interferon-gamma (IFN-γ), interleukin-1β, (IL-1β), IL-2, IL-4, IL-13 and tumor necrosis factor alpha (TNF-α) were measured in the serum obtained from control and RAO-susceptible horses during crisis. In all the patients, serum cytokine levels were detected. Serum median IL-13 and IFN-γ levels were significantly higher in RAO-affected horses than in the healthy group (p < 0.001). The serum median IFN-α1, IL-1β, IL-2, IL-4, and TNF-α levels were similar in both groups. These results indicate a low variability of the levels of cytokines and a high frequency of their detection in serum samples from horses with RAO. Immune mechanisms involved in equine RAO are more complex than those defined by a simple Th1/Th2 dichotomy.
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- 2016
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33. A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation.
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Chillappagari S, Müller C, Mahavadi P, Guenther A, Nährlich L, Rosenblum J, Rubin BK, and Henke MO
- Subjects
- Airway Obstruction metabolism, Airway Obstruction physiopathology, Humans, Mucociliary Clearance, Spectrophotometry methods, Sputum metabolism, Sputum microbiology, Benzoxazines metabolism, Cystic Fibrosis complications, Cystic Fibrosis metabolism, Leukocyte Elastase antagonists & inhibitors, Leukocyte Elastase metabolism, Mucins analysis, Mucins metabolism, Pseudomonas Infections diagnosis, Pseudomonas Infections etiology, Pseudomonas aeruginosa isolation & purification, Pseudomonas aeruginosa physiology, Pyrrolidines metabolism, Respiratory Tract Infections diagnosis, Respiratory Tract Infections etiology
- Abstract
Background: Neutrophil elastase (NE) rapidly degrades gel-forming airway mucins in cystic fibrosis (CF) sputum. We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro., Methods: Sputa were collected from CF patients (n=5) chronically or intermittently infected with Pseudomonas aeruginosa (P.a.). Mucin degradation was analyzed using western blot. Protease inhibitor studies were performed using alpha1-proteinase inhibitor (A1-PI Prolastin®) and KRP-109. Elastase activity assays were performed using spectrophotometry., Results: There were significant differences in the amount of active NE in different CF sputum samples. KRP-109 decreased the NE driven mucin degradation in vitro. Pseudomonas elastases appeared to blunt elastase inhibition by A1-PI or KRP-109., Conclusion: Inhibitors of neutrophil and Pseudomonas-derived elastases might rescue mucus clearance and reverse airway obstruction in CF., (Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
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34. Exercise-Induced Changes in Exhaled NO Differentiates Asthma With or Without Fixed Airway Obstruction From COPD With Dynamic Hyperinflation.
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Huang SY, Chou PC, Wang TY, Lo YL, Joa WC, Chen LF, Sheng TF, Chung KF, Wang CH, and Kuo HP
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Female, Forced Expiratory Volume, Humans, Inflammation metabolism, Male, Middle Aged, Prospective Studies, Respiratory Function Tests, Airway Obstruction metabolism, Asthma metabolism, Exercise physiology, Nitric Oxide metabolism, Pulmonary Disease, Chronic Obstructive metabolism
- Abstract
Asthmatic patients with fixed airway obstruction (FAO) and patients with chronic obstructive pulmonary disease (COPD) share similarities in terms of irreversible pulmonary function impairment. Exhaled nitric oxide (eNO) has been documented as a marker of airway inflammation in asthma, but not in COPD. To examine whether the basal eNO level and the change after exercise may differentiate asthmatics with FAO from COPD, 27 normal subjects, 60 stable asthmatics, and 62 stable COPD patients were studied. Asthmatics with FAO (n = 29) were defined as showing a postbronchodilator FEV1/forced vital capacity (FVC) ≤70% and FEV1 less than 80% predicted after inhaled salbutamol (400 μg). COPD with dynamic hyperinflation (n = 31) was defined as a decrease in inspiratory capacity (ΔIC%) after a 6 minute walk test (6MWT). Basal levels of eNO were significantly higher in asthmatics and COPD patients compared to normal subjects. The changes in eNO after 6MWT were negatively correlated with the percent change in IC (r = -0.380, n = 29, P = 0.042) in asthmatics with FAO. Their levels of basal eNO correlated with the maximum mid-expiratory flow (MMEF % predicted) before and after 6MWT. In COPD patients with air-trapping, the percent change of eNO was positively correlated to ΔIC% (rs = 0.404, n = 31, P = 0.024). We conclude that asthma with FAO may represent residual inflammation in the airways, while dynamic hyperinflation in COPD may retain NO in the distal airspace. eNO changes after 6MWT may differentiate the subgroups of asthma or COPD patients and will help toward delivery of individualized therapy for airflow obstruction.
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- 2016
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35. Airway factor XIII associates with type 2 inflammation and airway obstruction in asthmatic patients.
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Esnault S, Kelly EA, Sorkness RL, Evans MD, Busse WW, and Jarjour NN
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- Adult, Asthma diagnosis, Biomarkers, Bronchial Provocation Tests, Bronchoalveolar Lavage Fluid, Dendritic Cells immunology, Dendritic Cells metabolism, Factor XIII metabolism, Female, Gene Expression, Humans, Immunoglobulin E blood, Immunoglobulin E immunology, Male, Middle Aged, RNA, Messenger genetics, RNA, Messenger metabolism, Respiratory Function Tests, Severity of Illness Index, Skin Tests, Young Adult, Airway Obstruction metabolism, Airway Obstruction pathology, Asthma genetics, Asthma pathology, Factor XIII genetics
- Abstract
Background: Coagulation Factor XIII (FXIII) plays an important role in wound healing by stabilizing fibrin clots and cross-linking extracellular matrix proteins. FXIII is expressed in cells of the monocyte/macrophage and dendritic cell lineages in response to type 2 cytokines., Objective: We sought to determine the association between FXIII and asthma pathobiology., Methods: We analyzed the expression of FXIII mRNA and protein levels in bronchoalveolar lavage samples obtained before and after segmental allergen challenge from patients with mild asthma and in induced sputum samples collected from patients with mild-to-moderate and severe asthma., Results: FXIII mRNA and protein levels were highly upregulated in bronchoalveolar cells and fluid after allergen challenge and mRNA levels correlated with protein levels. In sputum of asthmatic patients, FXIII expression was positively correlated with type 2 immune response and dendritic cell markers (CD209 and CD207). FXIII expression was also associated with increased airflow limitation (FEV1/forced vital capacity and residual volume/total lung capacity ratios) and greater reversibility to β-agonists., Conclusions: FXIII expression was upregulated in the airways of asthmatic patients after allergen exposure. Expression in the sputum of asthmatic patients correlated with the type 2 immune response and airflow limitation. Excessive activity of FXIII could contribute to the pathophysiology of airway obstruction in asthmatic patients., Competing Interests: none, (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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36. Increased TGF-β: a drawback of tracheal occlusion in human and experimental congenital diaphragmatic hernia?
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Vuckovic A, Herber-Jonat S, Flemmer AW, Ruehl IM, Votino C, Segers V, Benachi A, Martinovic J, Nowakowska D, Dzieniecka M, and Jani JC
- Subjects
- Animals, Fetus metabolism, Humans, Pulmonary Alveoli metabolism, Rabbits, Respiration, Artificial methods, Trachea metabolism, rho-Associated Kinases metabolism, Airway Obstruction metabolism, Hernias, Diaphragmatic, Congenital genetics, Hernias, Diaphragmatic, Congenital metabolism, Lung metabolism, Transforming Growth Factor beta metabolism
- Abstract
Survivors of severe congenital diaphragmatic hernia (CDH) present significant respiratory morbidity despite lung growth induced by fetal tracheal occlusion (TO). We hypothesized that the underlying mechanisms would involve changes in lung extracellular matrix and dysregulated transforming growth factor (TGF)-β pathway, a key player in lung development and repair. Pulmonary expression of TGF-β signaling components, downstream effectors, and extracellular matrix targets were evaluated in CDH neonates who died between birth and the first few weeks of life after prenatal conservative management or TO, and in rabbit pups that were prenatally randomized for surgical CDH and TO vs. sham operation. Before tissue harvesting, lung tissue mechanics in rabbits was measured using the constant-phase model during the first 30 min of life. Human CDH and control fetal lungs were also collected from midterm onwards. Human and experimental CDH did not affect TGF-β/Smad2/3 expression and activity. In human and rabbit CDH lungs, TO upregulated TGF-β transcripts. Analysis of downstream pathways indicated increased Rho-associated kinases to the detriment of Smad2/3 activation. After TO, subtle accumulation of collagen and α-smooth muscle actin within alveolar walls was detected in rabbit pups and human CDH lungs with short-term mechanical ventilation. Despite TO-induced lung growth, mediocre lung tissue mechanics in the rabbit model was associated with increased transcription of extracellular matrix components. These results suggest that prenatal TO increases TGF-β/Rho kinase pathway, myofibroblast differentiation, and matrix deposition in neonatal rabbit and human CDH lungs. Whether this might influence postnatal development of sustainably ventilated lungs remains to be determined., (Copyright © 2016 the American Physiological Society.)
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- 2016
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37. Airway and alveolar nitric oxide production, lung function, and pulmonary blood flow in sickle cell disease.
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Lunt A, Ahmed N, Rafferty GF, Dick M, Rees D, Height S, Thein SL, and Greenough A
- Subjects
- Adolescent, Airway Obstruction diagnosis, Airway Obstruction metabolism, Airway Obstruction physiopathology, Anemia, Sickle Cell diagnosis, Biomarkers metabolism, Blood Flow Velocity, Breath Tests, Case-Control Studies, Child, Female, Humans, Lung blood supply, Lung physiopathology, Male, Respiratory Function Tests, Risk Factors, Airway Obstruction etiology, Airway Resistance, Anemia, Sickle Cell complications, Lung metabolism, Nitric Oxide metabolism, Pulmonary Circulation
- Abstract
Background: Children with sickle cell disease (SCD) often have obstructive lung function abnormalities which could be due to asthma or increased pulmonary blood volume; it is important to determine the underlying mechanism to direct appropriate treatment. In asthmatics, exhaled nitric oxide (FeNO) is elevated. FeNO, however, can also be raised due to increased alveolar production. Our aim, therefore, was to determine if airway or alveolar NO production differed between SCD children and ethnic and age-matched controls., Methods: Lung function, airway NO flux and alveolar NO production, and effective pulmonary blood flow were assessed in 18 SCD children and 18 ethnic and age-matched controls., Results: The SCD children compared to the controls had a higher respiratory system resistance (P = 0.0008), alveolar NO production (P = 0.0224), and pulmonary blood flow (P < 0.0001), but not airway NO flux. There was no significant correlation between FeNO and respiratory system resistance in either group, but in the SCD children, there were correlations between alveolar NO production (P = 0.0006) and concentration (P < 0.0001) and pulmonary blood flow., Conclusion: Airway NO flux was not elevated in the SCD children nor correlated with airways obstruction, suggesting that airways obstruction, at least in some SCD children, is not due to asthma.
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- 2016
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38. Recombinant human deoxyribonuclease therapy improves airway resistance and reduces DNA extracellular traps in a murine acute asthma model.
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da Cunha AA, Nuñez NK, de Souza RG, Moraes Vargas MH, Silveira JS, Antunes GL, Durante Lda S, Porto BN, Marczak ES, Jones MH, and Pitrez PM
- Subjects
- Administration, Intranasal methods, Airway Obstruction drug therapy, Airway Obstruction metabolism, Allergens pharmacology, Animals, Asthma metabolism, Bronchial Hyperreactivity drug therapy, Bronchial Hyperreactivity metabolism, Bronchoalveolar Lavage Fluid, Disease Models, Animal, Extracellular Traps metabolism, Female, Humans, Lung drug effects, Lung metabolism, Mice, Mice, Inbred BALB C, Mucus drug effects, Mucus metabolism, Ovalbumin pharmacology, Airway Resistance drug effects, Asthma drug therapy, DNA metabolism, Deoxyribonucleases pharmacology, Extracellular Traps drug effects, Recombinant Proteins pharmacology
- Abstract
Purpose: Asthma is a highly prevalent chronic inflammatory lung disease characterized by airway hyperresponsiveness to allergens, airway edema, and increased mucus secretion. Such mucus can be liquefied by recombinant human deoxyribonuclease (rhDNase), in which efficacy of rhDNase has been well documented in patients with cystic fibrosis, but little studied in asthma. In the present study, we investigated whether rhDNase intranasal administration improved inflammation and pulmonary function in an experimental model of asthma., Methods: Mice were sensitized by two subcutaneous injections of ovalbumin (OVA), on days 0 and 7, followed by three intranasal challenges with OVA on days 14, 15, and 16. A control group, replacing OVA by DPBS, was included. On days 15 and 16, after 2 hours of OVA challenge, mice received 1 mg/mL of intranasal rhDNase., Results: We showed that rhDNase decreased significantly the airway resistance and reduced EETs formation and globet cells hyperplasia., Conclusions: Our results suggest that extracellular DNA in mucus play a role in lower airways obstruction in OVA asthma protocol and that the treatment with rhDNase improved lung function and DNA extracellular traps, with no direct cellular anti-inflammatory effects.
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- 2016
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39. Blood lipid levels associate with childhood asthma, airway obstruction, bronchial hyperresponsiveness, and aeroallergen sensitization.
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Vinding RK, Stokholm J, Chawes BLK, and Bisgaard H
- Subjects
- Airway Obstruction epidemiology, Airway Obstruction metabolism, Airway Obstruction physiopathology, Allergens immunology, Asthma metabolism, Asthma physiopathology, Bronchial Hyperreactivity epidemiology, Bronchial Hyperreactivity metabolism, Bronchial Hyperreactivity physiopathology, Child, Child, Preschool, Cohort Studies, Denmark epidemiology, Female, Forced Expiratory Volume, Humans, Immunoglobulin E blood, Infant, Male, Nitric Oxide metabolism, Rhinitis, Allergic epidemiology, Rhinitis, Allergic metabolism, Rhinitis, Allergic physiopathology, Spirometry, Airway Obstruction blood, Asthma blood, Bronchial Hyperreactivity blood, Rhinitis, Allergic blood
- Abstract
Background: Studies of children's blood lipid profiles in relation to asthma are few, and the results are ambiguous., Objective: We sought to examine whether the lipid profile is associated with concurrent asthma, altered lung function, and allergic sensitization in children., Methods: High-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were measured at ages 5 to 7 years in the Copenhagen Prospective Studies on Asthma in Childhood2000 at-risk birth cohort. Asthma and allergic rhinitis were diagnosed based on predefined algorithms at age 7 years along with assessments of lung function, bronchial responsiveness, fraction of exhaled nitric oxide (Feno), and allergic sensitization. Associations between lipid levels and clinical outcomes were adjusted for sex, passive smoking, and body mass index., Results: High levels of low-density lipoprotein cholesterol were associated with concurrent asthma (adjusted odds ratio [aOR], 1.93; 95% CI, 1.06-3.55; P = .03) and airway obstruction: 50% of forced expiratory flow (aβ coefficient, -0.13 L/s; 95% CI, -0.24 to -0.03 L/s; P = .01) and specific airway resistance (aβ coefficient, 0.06 kPa/s; 95% CI, 0.00-0.11 kPa/s; P = .05). High levels of high-density lipoprotein cholesterol were associated with improved specific airway resistance (aβ coefficient, -0.11 kPa/s; 95% CI, -0.21 to -0.02; P = .02), decreased bronchial responsiveness (aβ coefficient, 0.53 log-μmol; 95% CI, 0.00-1.60 log-μmol; P = .05), decreased risk of aeroallergen sensitization (aOR, 0.27; 95% CI, 0.01-0.70; P = .01), and a trend of reduced Feno levels (aβ coefficient, -0.22 log-ppb; 95% CI, -0.50 to 0.01 log-ppb; P = .06). High triglyceride levels were associated with aeroallergen sensitization (aOR, 2.01; 95% CI, 1.14-3.56; P = .02) and a trend of increased Feno levels (aβ coefficient, 0.14 log-ppb; 95% CI, -0.02 to 0.30 log-ppb; P = .08)., Conclusion: The blood lipid profile is associated with asthma, airway obstruction, bronchial responsiveness, and aeroallergen sensitization in 7-year-old children. These findings suggest that asthma and allergy are systemic disorders with commonalities with other chronic inflammatory disorders., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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40. COPD Exacerbations Are Associated With Proinflammatory Degradation of Hyaluronic Acid.
- Author
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Papakonstantinou E, Roth M, Klagas I, Karakiulakis G, Tamm M, and Stolz D
- Subjects
- Adult, Aged, Airway Obstruction metabolism, Disease Progression, Extracellular Matrix metabolism, Female, Humans, Hyaluronan Synthases, Inflammation immunology, Male, Middle Aged, Patient Acuity, Predictive Value of Tests, Pulmonary Emphysema diagnosis, Pulmonary Emphysema metabolism, Respiratory Function Tests methods, Statistics as Topic, Bronchoalveolar Lavage Fluid immunology, Bronchoalveolar Lavage Fluid microbiology, Glucuronosyltransferase analysis, Glucuronosyltransferase metabolism, Hyaluronic Acid analysis, Hyaluronic Acid metabolism, Hyaluronoglucosaminidase analysis, Hyaluronoglucosaminidase metabolism, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Disease, Chronic Obstructive immunology, Pulmonary Disease, Chronic Obstructive physiopathology, Pulmonary Disease, Chronic Obstructive psychology, Quality of Life
- Abstract
Background: COPD is characterized by chronic airway inflammation and remodeling, with serious modifications of the extracellular matrix (ECM). Hyaluronic acid (HA) is an abundant ECM molecule in the lung with various biologic functions that depend on its molecular weight (MW). High-MW HA exhibits antiinflammatory and immunosuppressive effects, whereas low-MW HA is proinflammatory. In this study, we investigated whether acute exacerbations of COPD (AECOPDs), which affect patient quality of life and survival, are associated with altered HA turnover in BAL., Methods: We used BAL from patients with stable COPD (n = 53) or during AECOPD (n = 44) matched for demographics and clinical characteristics and BAL from control subjects (n = 15). HA, HA synthase-1 (HAS-1), and hyaluronidase (HYAL) values were determined by enzyme-linked immunosorbent assay, and HYAL activity was determined by HA zymography. The MW of HA was analyzed by agarose electrophoresis., Results: Levels of HA, HAS-1, and HYAL were significantly increased in BAL of patients with stable COPD and during exacerbations compared with control subjects. HYAL activity was significantly increased in BAL of patients with AECOPD, resulting in an increase of low-MW HA during exacerbations. In patients with AECOPD, we also observed a significant negative correlation of HA and HYAL levels with FEV1 % predicted but not with diffusing capacity of lung for carbon monoxide % predicted, indicating that increased HA degradation may be more associated with airway obstruction than with emphysema., Conclusions: AECOPDs are associated with increased HYAL activity in BAL and subsequent degradation of HA, which may contribute to airway inflammation and subsequent lung function decline during exacerbations.
- Published
- 2015
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41. Differential Gene Expression Profiles and Selected Cytokine Protein Analysis of Mediastinal Lymph Nodes of Horses with Chronic Recurrent Airway Obstruction (RAO) Support an Interleukin-17 Immune Response.
- Author
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Korn A, Miller D, Dong L, Buckles EL, Wagner B, and Ainsworth DM
- Subjects
- Airway Obstruction metabolism, Airway Obstruction veterinary, Animals, Bronchoalveolar Lavage Fluid cytology, Chronic Disease, Cytokines metabolism, Female, Horse Diseases metabolism, Horses, Immunohistochemistry, Interleukin-17 metabolism, Interleukin-4 genetics, Interleukin-4 metabolism, Male, Mediastinum, NF-kappa B genetics, NF-kappa B metabolism, Neutrophils metabolism, Oligonucleotide Array Sequence Analysis, Recurrence, Reverse Transcriptase Polymerase Chain Reaction, Airway Obstruction genetics, Cytokines genetics, Horse Diseases genetics, Interleukin-17 genetics, Lymph Nodes metabolism, Transcriptome
- Abstract
Recurrent airway obstruction (RAO) is a pulmonary inflammatory condition that afflicts certain mature horses exposed to organic dust particulates in hay. Its clinical and pathological features, manifested by reversible bronchoconstriction, excessive mucus production and airway neutrophilia, resemble the pulmonary alterations that occur in agricultural workers with occupational asthma. The immunological basis of RAO remains uncertain although its chronicity, its localization to a mucosal surface and its domination by a neutrophilic, non-septic inflammatory response, suggest involvement of Interleukin-17 (IL-17). We examined global gene expression profiles in mediastinal (pulmonary-draining) lymph nodes isolated from RAO-affected and control horses. Differential expression of > 200 genes, coupled with network analysis, supports an IL-17 response centered about NF-κB. Immunohistochemical analysis of mediastinal lymph node sections demonstrated increased IL-17 staining intensity in diseased horses. This result, along with the finding of increased IL-17 concentrations in lymph node homogenates from RAO-affected horses (P = 0.1) and a down-regulation of IL-4 gene and protein expression, provides additional evidence of the involvement of IL-17 in the chronic stages of RAO. Additional investigations are needed to ascertain the cellular source of IL-17 in this equine model of occupational asthma. Understanding the immunopathogenesis of this disorder likely will enhance the development of therapeutic interventions beneficial to human and animal pulmonary health.
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- 2015
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42. Influence of Tracheal Obstruction on the Efficacy of Superimposed High-frequency Jet Ventilation and Single-frequency Jet Ventilation.
- Author
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Sütterlin R, LoMauro A, Gandolfi S, Priori R, Aliverti A, Frykholm P, and Larsson A
- Subjects
- Airway Obstruction metabolism, Animals, Swine, Tracheal Stenosis metabolism, Treatment Outcome, Airway Obstruction pathology, Airway Obstruction therapy, High-Frequency Jet Ventilation methods, Tracheal Stenosis pathology, Tracheal Stenosis therapy
- Abstract
Background: Both superimposed high-frequency jet ventilation (SHFJV) and single-frequency (high-frequency) jet ventilation (HFJV) have been used with success for airway surgery, but SHFJV has been found to provide higher lung volumes and better gas exchange than HFJV in unobstructed airways. The authors systematically compared the ventilation efficacy of SHFJV and HFJV at different ventilation frequencies in a model of tracheal obstruction and describe the frequency and obstruction dependence of SHFJV efficacy., Methods: Ten anesthetized animals (weight 25 to 31.5 kg) were alternately ventilated with SHFJV and HFJV at a set of different fHF from 50 to 600 min. Obstruction was created by insertion of interchangeable stents with ID 2 to 8 mm into the trachea. Chest wall volume was measured using optoelectronic plethysmography, airway pressures were recorded, and blood gases were analyzed repeatedly., Results: SHFJV provided greater than 1.6 times higher end-expiratory chest wall volume than HFJV, and tidal volume (VT) was always greater than 200 ml with SHFJV. Increase of fHF from 50 to 600 min during HFJV resulted in a more than 30-fold VT decrease from 112 ml (97 to 130 ml) to negligible values and resulted in severe hypoxia and hypercapnia. During SHFJV, stent ID reduction from 8 to 2 mm increased end-expiratory chest wall volume by up to 3 times from approximately 100 to 300 ml and decreased VT by up to 4.2 times from approximately 470 to 110 ml. Oxygenation and ventilation were acceptable for 4 mm ID or more, but hypercapnia occurred with the 2 mm stent., Conclusion: In this in vivo porcine model of variable severe tracheal stenosis, SHFJV effectively increased lung volumes and maintained gas exchange and may be advantageous in severe airway obstruction.
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- 2015
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43. Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease?
- Author
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Gao W, Li L, Wang Y, Zhang S, Adcock IM, Barnes PJ, Huang M, and Yao X
- Subjects
- Airway Obstruction metabolism, Airway Obstruction physiopathology, Chemokines metabolism, Humans, Inflammation metabolism, Inflammation pathology, Lung pathology, Oxidative Stress drug effects, Epithelial Cells metabolism, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Disease, Chronic Obstructive pathology, Pulmonary Disease, Chronic Obstructive physiopathology, Pulmonary Disease, Chronic Obstructive therapy, Respiratory Mucosa drug effects, Respiratory Mucosa metabolism, Respiratory Mucosa pathology
- Abstract
The primary function of the bronchial epithelium is to act as a defensive barrier aiding the maintenance of normal airway function. Bronchial epithelial cells (BEC) form the interface between the external environment and the internal milieu, making it a major target of inhaled insults. However, BEC can also serve as effectors to initiate and orchestrate immune and inflammatory responses by releasing chemokines and cytokines, which recruit and activate inflammatory cells. They also produce excess reactive oxygen species as a result of an oxidant/antioxidant imbalance that contributes to chronic pulmonary inflammation and lung tissue damage. Accumulated mucus from hyperplastic BEC obstructs the lumen of small airways, whereas impaired cell repair, squamous metaplasia and increased extracellular matrix deposition underlying the epithelium is associated with airway remodelling particularly fibrosis and thickening of the airway wall. These alterations in small airway structure lead to airflow limitation, which is critical in the clinical diagnosis of chronic obstructive pulmonary disease (COPD). In this review, we discuss the abnormal function of BEC within a disturbed immune homeostatic environment consisting of ongoing inflammation, oxidative stress and small airway obstruction. We provide an overview of recent insights into the function of the bronchial epithelium in the pathogenesis of COPD and how this may provide novel therapeutic approaches for a number of chronic lung diseases., (© 2015 Asian Pacific Society of Respirology.)
- Published
- 2015
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44. Free DNA in cystic fibrosis airway fluids correlates with airflow obstruction.
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Marcos V, Zhou-Suckow Z, Önder Yildirim A, Bohla A, Hector A, Vitkov L, Krautgartner WD, Stoiber W, Griese M, Eickelberg O, Mall MA, and Hartl D
- Subjects
- Adolescent, Adult, Airway Obstruction metabolism, Animals, Bronchoalveolar Lavage Fluid chemistry, Chemokines, CXC metabolism, Child, Disease Models, Animal, Female, Humans, Inflammation metabolism, Ligands, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Neutrophils immunology, Young Adult, Cystic Fibrosis metabolism, DNA chemistry, Inflammation microbiology, Neutrophils metabolism, Pseudomonas aeruginosa immunology
- Abstract
Chronic obstructive lung disease determines morbidity and mortality of patients with cystic fibrosis (CF). CF airways are characterized by a nonresolving neutrophilic inflammation. After pathogen contact or prolonged activation, neutrophils release DNA fibres decorated with antimicrobial proteins, forming neutrophil extracellular traps (NETs). NETs have been described to act in a beneficial way for innate host defense by bactericidal, fungicidal, and virucidal actions. On the other hand, excessive NET formation has been linked to the pathogenesis of autoinflammatory and autoimmune disease conditions. We quantified free DNA structures characteristic of NETs in airway fluids of CF patients and a mouse model with CF-like lung disease. Free DNA levels correlated with airflow obstruction, fungal colonization, and CXC chemokine levels in CF patients and CF-like mice. When viewed in combination, our results demonstrate that neutrophilic inflammation in CF airways is associated with abundant free DNA characteristic for NETosis, and suggest that free DNA may be implicated in lung function decline in patients with CF.
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- 2015
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45. Oxidant-antioxidant status in the blood of horses with symptomatic recurrent airway obstruction (RAO).
- Author
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Niedzwiedz A and Jaworski Z
- Subjects
- Airway Obstruction blood, Airway Obstruction metabolism, Animals, Bronchoalveolar Lavage Fluid cytology, Case-Control Studies, Catalase blood, Female, Glutathione Peroxidase blood, Glutathione Reductase blood, Horse Diseases metabolism, Horses blood, Horses metabolism, Male, Oxidative Stress, Prospective Studies, Recurrence, Superoxide Dismutase blood, Airway Obstruction veterinary, Horse Diseases blood, Oxidation-Reduction
- Abstract
Background: Systemic oxidative stress in horses with recurrent airway obstruction (RAO) is poorly characterized., Objectives: The goal of this study was to investigate whether equine RAO is associated with systemic disturbances in the oxidant-antioxidant equilibrium., Animals: Seven healthy horses and 7 horses with symptomatic RAO., Methods: A prospective study. Healthy and RAO-affected horses were exposed to a 48-hour challenge with moldy hay and straw to induce clinical exacerbation of RAO. Venous blood was collected and the activities of the superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) in equine erythrocyte lysates were measured. The concentration of thiobarbituric acid-reactive substances (TBARSs) was assessed both in erythrocyte lysates and in plasma., Results: A significant increase in the activities of GPx and SOD was detected in RAO-affected horses compared with the control animals. There was no significant difference between groups in terms of the erythrocyte lysate activities of CAT, GR, or TBARs or the plasma concentration of TBARs., Conclusion and Clinical Importance: Our results support the hypothesis that RAO in horses is associated with systemic oxidative stress. Future studies are needed to assess whether horses suffering from RAO can benefit from antioxidant supplementation., (Copyright © 2014 by the American College of Veterinary Internal Medicine.)
- Published
- 2014
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46. Airway mucus obstruction triggers macrophage activation and matrix metalloproteinase 12-dependent emphysema.
- Author
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Trojanek JB, Cobos-Correa A, Diemer S, Kormann M, Schubert SC, Zhou-Suckow Z, Agrawal R, Duerr J, Wagner CJ, Schatterny J, Hirtz S, Sommerburg O, Hartl D, Schultz C, and Mall MA
- Subjects
- Airway Obstruction metabolism, Animals, Bronchoalveolar Lavage Fluid immunology, Cystic Fibrosis genetics, Cystic Fibrosis immunology, Cystic Fibrosis metabolism, Dehydration immunology, Dehydration metabolism, Genomics, Macrophages, Alveolar metabolism, Matrix Metalloproteinase 12 genetics, Matrix Metalloproteinase 12 metabolism, Mice, Knockout, Mucus metabolism, Polymorphism, Single Nucleotide genetics, Pulmonary Disease, Chronic Obstructive immunology, Pulmonary Disease, Chronic Obstructive metabolism, Pulmonary Emphysema metabolism, STAT6 Transcription Factor genetics, STAT6 Transcription Factor immunology, STAT6 Transcription Factor metabolism, Signal Transduction immunology, Airway Obstruction immunology, Macrophage Activation immunology, Macrophages, Alveolar immunology, Matrix Metalloproteinase 12 immunology, Mucus immunology, Pulmonary Emphysema immunology
- Abstract
Whereas cigarette smoking remains the main risk factor for emphysema, recent studies in β-epithelial Na(+) channel-transgenic (βENaC-Tg) mice demonstrated that airway surface dehydration, a key pathophysiological mechanism in cystic fibrosis (CF), caused emphysema in the absence of cigarette smoke exposure. However, the underlying mechanisms remain unknown. The aim of this study was to elucidate mechanisms of emphysema formation triggered by airway surface dehydration. We therefore used expression profiling, genetic and pharmacological inhibition, Foerster resonance energy transfer (FRET)-based activity assays, and genetic association studies to identify and validate emphysema candidate genes in βENaC-Tg mice and patients with CF. We identified matrix metalloproteinase 12 (Mmp12) as a highly up-regulated gene in lungs from βENaC-Tg mice, and demonstrate that elevated Mmp12 expression was associated with progressive emphysema formation, which was reduced by genetic deletion and pharmacological inhibition of MMP12 in vivo. By using FRET reporters, we show that MMP12 activity was elevated on the surface of airway macrophages in bronchoalveolar lavage from βENaC-Tg mice and patients with CF. Furthermore, we demonstrate that a functional polymorphism in MMP12 (rs2276109) was associated with severity of lung disease in CF. Our results suggest that MMP12 released by macrophages activated on dehydrated airway surfaces may play an important role in emphysema formation in the absence of cigarette smoke exposure, and may serve as a therapeutic target in CF and potentially other chronic lung diseases associated with airway mucus dehydration and obstruction.
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- 2014
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47. Antifibrinolytic mechanisms in acute airway injury after sulfur mustard analog inhalation.
- Author
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Rancourt RC, Ahmad A, Veress LA, Rioux JS, Garlick RB, and White CW
- Subjects
- Acute Lung Injury metabolism, Acute Lung Injury pathology, Airway Obstruction chemically induced, Airway Obstruction metabolism, Airway Obstruction pathology, Animals, Blood-Air Barrier drug effects, Blood-Air Barrier metabolism, Bronchoalveolar Lavage Fluid chemistry, Capillary Permeability drug effects, Carboxypeptidase B2 metabolism, Lung metabolism, Lung pathology, Male, Mustard Gas toxicity, Plasminogen Activator Inhibitor 1 metabolism, Rats, Sprague-Dawley, Time Factors, alpha-2-Antiplasmin metabolism, Acute Lung Injury chemically induced, Antifibrinolytic Agents toxicity, Chemical Warfare Agents toxicity, Fibrinolysis drug effects, Inhalation Exposure, Lung drug effects, Mustard Gas analogs & derivatives
- Abstract
Acute lung injury in response to mustard gas (sulfur mustard [SM]) inhalation results in formation of fibrin casts, which obstruct the airway. The objective of this study was to identify fibrinolytic pathways that could be contributing to the persistence of airway casts after SM exposure. Rats were exposed to the SM analog, 2-chloroethyl ethyl sulfide, via nose-only aerosol inhalation. At 4 and 18 hours after exposure, animals were killed and airway-capillary leak estimated by measuring bronchoalveolar lavage fluid (BALF) protein and IgM content. The fibrin clot-degrading and plasminogen-activating capabilities of BALF were also assessed by activity assays, whereas Western blotting was used to determine the presence and activities of plasminogen activator inhibitor-1, thrombin activatable fibrinolytic inhibitor and α2-antiplasmin. Measurement of tissue-specific steady-state mRNA levels was also conducted for each fibrinolytic inhibitor to assess whether its synthesis occurs in lung or at extrapulmonary sites. The results of this study demonstrate that fibrin-degrading and plasminogen-activating capabilities of the airways become impaired during the onset of 2-chloroethyl ethyl sulfide-induced vascular leak. Findings of functionally active reservoirs of plasminogen activator inhibitor-1, thrombin activatable fibrinolysis inhibitor, and α2-antiplasmin in BALF indicate that airway fibrinolysis is inhibited at multiple levels in response to SM.
- Published
- 2014
- Full Text
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48. Irreversible airway obstruction assessed by high-resolution computed tomography (HRCT), exhaled nitric oxide (FENO), and biological markers in induced sputum in patients with asthma.
- Author
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Zhang L, Gang J, Zhigang C, Yali C, Baozhong S, Fangbiao Z, and Liu C
- Subjects
- Adolescent, Adult, Aged, Airway Obstruction etiology, Airway Obstruction metabolism, Asthma complications, Asthma metabolism, Biomarkers analysis, Breath Tests methods, Chronic Disease, Female, Humans, Male, Middle Aged, Reproducibility of Results, Sensitivity and Specificity, Young Adult, Airway Obstruction diagnosis, Asthma diagnosis, Nitric Oxide analysis, Pulmonary Gas Exchange, Sputum chemistry, Tomography, X-Ray Computed methods
- Abstract
Objective: The objective of this study was to explore the significance of assessing irreversible airway obstruction (IAO) in asthma patients by high-resolution computed tomography (HRCT), biological markers in induced sputum, and exhaled nitric oxide (FENO)., Methods: The study was conducted in 34 patients with IAO, 46 patients with reversible airway obstruction (RAO), 40 patients who did not have airway obstruction (NAO), and 40 healthy subjects serving as controls. These patients received a step therapy for at least 3 months based on the guidelines for the prevention and treatment of asthma. After achieving complete or partial control of asthma, HRCT, lung function, FENO, and chemokine levels in induced sputum were measured., Results: The airway wall area (WA; %) correlated with forced expiratory volume-1 (FEV-1(L); r = -0.67, p < 0.0001), and significant differences in bronchial wall thickening (BWT) of the LEVEL E generation airways were observed between the asthma and control groups (p < 0.01). FENO levels correlated with FEV-1 (%) in the IAO group (r = 0.49, p = 0.01). The levels of matrix metalloproteases-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in asthma patients with IAO, RAO, and NAO were significantly higher than those in the controls (p < 0.05). The level of neutrophilia in the sputum from the IAO group was higher than that from the RAO, NAO and control groups., Conclusion: Asthma patients with IAO have an increased BWT. Airway measurements with HRCT scans appear to be valuable in the evaluation of airway remodeling in asthma patients with IAO.
- Published
- 2014
- Full Text
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49. Airway collagen and elastic fiber content correlates with lung function in equine heaves.
- Author
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Setlakwe EL, Lemos KR, Lavoie-Lamoureux A, Duguay JD, and Lavoie JP
- Subjects
- Airway Obstruction metabolism, Airway Obstruction pathology, Animals, Asthma metabolism, Asthma pathology, Bronchoalveolar Lavage Fluid, Horse Diseases metabolism, Horse Diseases pathology, Horses metabolism, Inflammation metabolism, Inflammation pathology, Neutrophils metabolism, Neutrophils pathology, Oligopeptides metabolism, Proline analogs & derivatives, Proline metabolism, Prospective Studies, Collagen Type I metabolism, Collagen Type III metabolism, Elastic Tissue metabolism, Lung metabolism, Lung pathology
- Abstract
The consequences on lung function and inflammation of alterations in the extracellular matrix affecting the peripheral airway wall in asthma are largely unknown. We hypothesized that remodeling of collagen and elastic fibers in the peripheral airway wall leads to airway obstruction and contributes to neutrophilic airway inflammation. Animals used were six heaves-affected horses and five controls. Large peripheral lung biopsies were obtained from horses with heaves in clinical remission (Baseline) and during disease exacerbation and from age-matched controls. The area of collagen and elastic fiber content in the lamina propria was measured by histological staining techniques and corrected for airway size. Collagen type 1 and type 3 content was further assessed from additional horses after postmortem lung samples by immunohistochemistry. The collagen breakdown products proline-glycine-proline (PGP) and N-acetylated-PGP (N-α-PGP) were also measured in bronchoalveolar lavage fluids (BALF) by mass spectrometry. Compared with controls, heaves-affected horses had an increase in collagen (P = 0.05) and elastic fiber contents (P = 0.04) at baseline. Collagen types 1 and 3 content was also significantly increased in diseased horses (P = 0.015) when both collagen types were combined. No further change in collagen content was observed after a 30-day antigenic challenge. Airway collagen at baseline was positively correlated with pulmonary resistance in asthmatic horses (r(2) = 0.78, P = 0.03) and elastic fiber content was positively associated with pulmonary elastance in controls (r(2) = 0.95, P = 0.02). No difference between groups was appreciated in PGP and N-α-PGP peptides in BALF. Increased airway wall collagen and elastic fiber content may contribute to residual obstruction in the asthmatic airways., (Copyright © 2014 the American Physiological Society.)
- Published
- 2014
- Full Text
- View/download PDF
50. Reduced forced expiratory flow but not increased exhaled nitric oxide or airway responsiveness to methacholine characterises paediatric sickle cell airway disease.
- Author
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Chaudry RA, Rosenthal M, Bush A, and Crowley S
- Subjects
- Adolescent, Airway Obstruction metabolism, Airway Obstruction physiopathology, Anemia, Sickle Cell metabolism, Asthma diagnosis, Asthma metabolism, Breath Tests, Case-Control Studies, Child, Eosinophils, Female, Humans, Hypersensitivity metabolism, Hypersensitivity physiopathology, Leukocyte Count, Lung blood supply, Male, Nitric Oxide metabolism, Spirometry, Statistics, Nonparametric, Anemia, Sickle Cell physiopathology, Asthma physiopathology, Forced Expiratory Flow Rates physiology, Immunoglobulin E blood, Methacholine Chloride, Nitric Oxide analysis
- Abstract
Background: Asthma and airway hyper-responsiveness are reportedly more common in children with sickle cell disease (SCD)., Aim: To determine airway responsiveness, airway inflammation and clinical features of asthma in SCD., Methods: A prospective, single-centre study of 50 SCD children without overt pulmonary vascular disease and 50 controls. Exhaled nitric oxide (FeNO) and total serum IgE were measured and spirometry and methacholine challenge were performed. The methacholine dose-response slope (DRS) was calculated., Results: Doctor diagnosis of asthma was made in 7 (14%) SCD versus 12 (24%) control subjects (p=0.203). FeNO levels were similar in SCD and controls (p=0.250), and were higher in those with atopy and an asthma diagnosis (OR 4.33, 95% CI 1.7 to 11.1; p<0.05). zFEV1 (p=0.002) and zFEV1/FVC (p=0.003) but not zFVC (p=0.098) were lower in SCD versus controls. DRS was higher in those with asthma (p=0.006) but not in SCD versus controls (p=0.403). DRS correlated with FeNO and blood eosinophil count in controls but not SCD. In SCD, DRS was higher in those admitted to hospital with respiratory symptoms (n=27) versus those never admitted (n=23) (p=0.046). DRS was similar in those with at least one acute chest syndrome episode (n=12) versus those with none (n=35) (p=0.247)., Conclusions: SCD children have airflow obstruction despite having minimal evidence of pulmonary vascular disease. Airflow obstruction is not associated with increased methacholine sensitivity or eosinophilic inflammation, at least as judged by FeNO. Airflow obstruction in SCD does not appear to be related to childhood eosinophilic asthma, but its pathophysiology remains ill understood., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)
- Published
- 2014
- Full Text
- View/download PDF
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