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Respiratory Medicine Jun 2023Welders are exposed to gas and particle emissions that can cause severe lung disease, such as chronic obstructive pulmonary disease (COPD), a leading cause of mortality...
BACKGROUND
Welders are exposed to gas and particle emissions that can cause severe lung disease, such as chronic obstructive pulmonary disease (COPD), a leading cause of mortality and morbidity worldwide. It is difficult to detect COPD early and therefore mitigating measures may be delayed. The aim of this study was to investigate lung health in welders and evaluate new sensitive methods with potential to assess early onset pulmonary changes in occupational settings.
METHODS
This study assessed the lung health and symptoms in active welders (n = 28) and controls (n = 17). Lung measurements were performed with standard spirometry and new methods: airspace dimension assessment (AiDA), oscillometry, blood serum biomarkers (club cell secretory protein 16, surfactant protein D, matrix metalloproteinases, fibroblast, hepatocyte growth factor, interleukins), and one urine biomarker (desmosine).
RESULTS
According to spirometry measurements, all participants had normal lung function. However, prevalence of cough was significantly higher among welders compared with controls and lung changes were found in welders with the novel methods. Welders had significantly higher respiratory system resistance assessed with oscillometry, serum levels of metalloproteinases 9 and hepatocyte growth factor, compared with controls. Airspace dimensions were on average higher among welders compared with controls, but the difference was not significant. The number of welding years correlated with decreased respiratory system reactance and increased serum levels of matrix metalloproteinases 9, interleukin 6, and hepatocyte growth factor. Airspace dimension assessment indices were correlated with increasing levels of inflammatory markers and matrix metalloproteinases.
CONCLUSIONS
This study indicated the potential to use new and more sensitive methods for identification of changes in lungs when standard spirometry failed to do so.
Topics: Humans; Hepatocyte Growth Factor; Metal Workers; Respiratory Function Tests; Lung; Pulmonary Disease, Chronic Obstructive; Occupational Diseases; Occupational Exposure
PubMed: 37062499
DOI: 10.1016/j.rmed.2023.107244 -
American Journal of Physiology. Lung... Apr 2019Deterioration of lung functions and degradation of elastin fibers with age are accelerated during chronic obstructive pulmonary disease (COPD). Excessive genesis of...
Deterioration of lung functions and degradation of elastin fibers with age are accelerated during chronic obstructive pulmonary disease (COPD). Excessive genesis of soluble elastin peptides (EP) is a key factor in the pathophysiology of COPD. We have previously demonstrated that 6-wk-old mice exhibited emphysematous structural changes associated with proinflammatory immune response after EP instillation. In this study, we investigated the consequences of aging on inflammatory, immune, and histological criteria associated with murine emphysema progression after EP exposure. Young (6 wk old) and elderly (15 mo old) C57BL/6J mice were endotracheally instilled with EP, and, at various time points after treatment, the inflammatory cell profiles from bronchoalveolar lavage fluids (BALF) and the T-lymphocyte phenotypes, at local and systemic levels, were analyzed by flow cytometry. Lungs were also prepared to allow morphological and histological analysis by confocal microscopy. Elderly mice exhibited an earlier development of pulmonary emphysema, characterized by an increase of the inflammatory and lymphocytic infiltrates, extracellular matrix breakdown, and airspace enlargement compared with young mice. This age-dependent parenchymal tissue remodeling was associated with an increase of the matrix metalloproteinase expressions and desmosine levels in BALF and/or sera of EP-treated mice. In addition, both the proportion of CD4CD28 and CD8CD28 T cells in the tissues of EP-treated mice and the interferon-γ levels in the EP-specific memory T-cell clones were significantly higher in elderly versus younger mice. This study demonstrates that aging accelerates emphysema development and that this effect is linked to increased EP production and their effects on inflammatory and immune response.
Topics: Aging; Animals; Bronchoalveolar Lavage Fluid; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Desmosine; Disease Models, Animal; Elastin; Female; Inflammation; Lung; Macrophages, Alveolar; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Neutrophils; Proteolysis; Pulmonary Emphysema
PubMed: 30675803
DOI: 10.1152/ajplung.00402.2018 -
Respiratory Research Jan 2018There are urgent needs for clinically relevant biomarkers to identify children with cystic fibrosis (CF) at risk for more progressive lung disease and to serve as...
BACKGROUND
There are urgent needs for clinically relevant biomarkers to identify children with cystic fibrosis (CF) at risk for more progressive lung disease and to serve as outcome measures for clinical trials. Our objective was to investigate three targeted biomarkers in a population of asymptomatic CF infants.
METHODS
Urine, blood and lung function data were collected for 2 years from clinically stable infants diagnosed with CF by newborn screening. A subset of CF infants had bronchoscopy with lavage performed at 6 months and 1 year. Urine was collected quarterly from healthy control infants. Expectorated sputum and urine were collected quarterly for 2 years from clinically stable CF adults. Desmosine, club cell secretory protein (CCSP) and cathepsin B concentrations were measured and compared. Mixed effects models were used to identify associations between biomarker concentrations and clinical characteristics. Receiver operator characteristic curves were generated to investigate the sensitivity and specificity of the biomarkers.
RESULTS
Urinary cathepsin B was significantly higher in CF infants compared to healthy infants (p = 0.005). CF infant airway and urinary cathepsin B concentrations were significantly lower compared to adult CF subjects (p = 0.002 & p = 0.022, respectively). CF infant airway CCSP was significantly higher than adult CF subjects (p < 0.001). There was a significant correlation between CF infant plasma CCSP and BALF CCSP (p = 0.046). BALF CCSP was negatively associated with IL-8 (p = 0.017). There was no correlation between biomarker concentration and FEV.
CONCLUSIONS
Cathepsin B and CCSP show promise as biomarkers of inflammation in CF infants. Further study is needed.
Topics: Biomarkers; Bronchoalveolar Lavage Fluid; Child, Preschool; Cohort Studies; Cystic Fibrosis; Female; Humans; Infant; Infant, Newborn; Inflammation; Longitudinal Studies; Male; Neonatal Screening; Neutrophils; Prospective Studies; Sputum
PubMed: 29310632
DOI: 10.1186/s12931-017-0713-8 -
ERJ Open Research Oct 2019Electronic cigarettes (e-cigs) were introduced as electronic nicotine delivery systems, and have become very popular in the USA and globally. There is a paucity of data...
BACKGROUND
Electronic cigarettes (e-cigs) were introduced as electronic nicotine delivery systems, and have become very popular in the USA and globally. There is a paucity of data on systemic injury biomarkers of vaping in e-cig users that can be used as a noninvasive assessment of vaping-associated lung injuries. We hypothesised that characterisation of systemic biomarkers of inflammation, anti-inflammatory, oxidative stress, vascular and lipid mediators, growth factors, and extracellular matrix breakdown may provide information regarding the toxicity of vaping in e-cig users.
METHODS
We collected various biological fluids, plasma, urine, saliva and exhaled breath condensate (EBC), measured pulmonary function and vaping characteristics, and assessed various biomarkers in e-cig users and nonusers.
RESULTS
The plasma samples of e-cig users showed a significant increase in biomarkers of inflammation (interleukin (IL)-1β, IL-6, IL-8, IL-13, interferon (IFN)-γ, matrix metalloproteinase-9, intercellular cell adhesion molecule-1) and extracellular matrix breakdown (desmosine), and decreased pro-resolving lipid mediators (resolvin D and resolvin D). There was a significant increase in growth factor (endothelial growth factor, vascular endothelial growth factor, β-nerve growth factor, platelet-derived growth factor-AA, stem cell factor, hepatocyte growth factor and placental growth factor) levels in plasma of e-cig users nonusers. E-cig users showed a significant increase in levels of inflammatory biomarker IFN-γ, oxidative stress biomarker 8-isoprostane and oxidative DNA damage biomarker 8-oxo-dG in urine samples, and of inflammatory biomarker IL-1β in saliva samples. EBC showed a slight increase in levels of triglycerides and 8-isoprostane in e-cig users compared with normal nonusers.
CONCLUSION
E-cig users have increased levels of biomarkers of inflammation and oxidative stress, reduced pro-resolving anti-inflammatory mediators, and endothelial dysfunction, which may act as risk factors for increasing susceptibility to systemic diseases. The identified noninvasive biomarkers can be used for determining e-cig vaping-associated lung injuries, and for regulatory and diagnostic aspects of vaping in humans.
PubMed: 31886159
DOI: 10.1183/23120541.00182-2019 -
Respiratory Research Jan 2021In chronic obstructive pulmonary disease (COPD), lung-infiltrating inflammatory cells secrete proteases and participate in elastin breakdown and genesis of... (Clinical Trial)
Clinical Trial
BACKGROUND
In chronic obstructive pulmonary disease (COPD), lung-infiltrating inflammatory cells secrete proteases and participate in elastin breakdown and genesis of elastin-derived peptides (EP). In the present study, we hypothesized that the pattern of T lymphocytes cytokine expression may be modulated by EP in COPD patients.
METHODS
CD4 and CD8 T-cells, sorted from peripheral blood mononuclear cells (PBMC) collected from COPD patients (n = 29) and controls (n = 13) were cultured with or without EP. Cytokine expression in T-cell phenotypes was analyzed by multicolor flow cytometry, whereas desmosine concentration, a specific marker of elastin degradation, was measured in sera.
RESULTS
Compared with control, the percentage of IL-4 (Th2) producing CD4 T-cells was decreased in COPD patients (35.3 ± 3.4% and 26.3 ± 2.4%, respectively, p < 0.05), whereas no significant differences were found with IFN-γ (Th1) and IL-17A (Th17). Among COPD patients, two subpopulations were observed based on the percentage of IL-4 (Th2) producing CD4 T-cells, of which only one expressed high IL-4 levels in association with high levels of desmosine and strong smoking exposure (n = 7). Upon stimulation with VGVAPG, a bioactive EP motif, the percentage of CD4 T cells expressing IL-4 significantly increased in COPD patients (p < 0.05), but not in controls. The VGVAPG-induced increase in IL-4 was inhibited in the presence of analogous peptide antagonizing VGVAPG/elastin receptor (S-gal) interactions.
CONCLUSIONS
The present study demonstrates that the VGVAPG elastin peptide modulates CD4 T-cells IL-4 production in COPD. Monitoring IL-4 in circulating CD4 T-cells may help to better characterize COPD phenotypes and could open a new pharmacologic opportunity through CD4 T-cells stimulation via the VGVAPG/S-gal receptor in order to favor an anti-inflammatory response in those COPD patients.
Topics: Adult; Aged; CD4-Positive T-Lymphocytes; Cells, Cultured; Female; Humans; Interleukin-4; Leukocytes, Mononuclear; Male; Middle Aged; Oligopeptides; Pulmonary Disease, Chronic Obstructive
PubMed: 33435988
DOI: 10.1186/s12931-020-01609-4 -
Respiratory Research Nov 2017Cardiovascular diseases are prevalent in patients with chronic obstructive pulmonary disease (COPD). Their coexistence implies that many COPD patients require... (Review)
Review
Cardiovascular diseases are prevalent in patients with chronic obstructive pulmonary disease (COPD). Their coexistence implies that many COPD patients require anticoagulation therapy. Although more and more replaced by direct oral anticoagulants, vitamin K antagonists (VKAs) are still widely used. VKAs induce profound deficiency of vitamin K, a key activator in the coagulation pathway. It is recognized however that vitamin K is also an essential cofactor in the activation of other extrahepatic proteins, such as matrix Gla protein (MGP), a potent inhibitor of arterial calcification. No or insufficient MGP activation by the use of VKAs is associated with a rapid progression of vascular calcification, which may enhance the risk for overt cardiovascular disease. Vitamin K consumption, on the other hand, seems to have a protective effect on the mineralization of arteries. Furthermore, vascular calcification mutually relates to elastin degradation, which is accelerated in patients with COPD associating with impaired survival. In this commentary, we hypothesize that vitamin K is a critical determinant to the rate of elastin degradation. We speculate on the potential link between poor vitamin K status and crucial mechanisms of COPD pathogenesis and raise concerns about the use of VKAs in patients with this disease. Future intervention studies are needed to explore if vitamin K supplementation is able to reduce elastin degradation and vascular calcification in COPD patients.
Topics: Animals; Cardiovascular Diseases; Dietary Supplements; Humans; Pulmonary Disease, Chronic Obstructive; Vascular Calcification; Vitamin K; Vitamin K Deficiency
PubMed: 29132356
DOI: 10.1186/s12931-017-0673-z -
Asian Journal of Andrology 2020This study aimed to explore whether and how anti-lysyl oxidase (anti-LOX) combined with a vacuum device (VD) could promote penile lengthening and to evaluate the effect...
This study aimed to explore whether and how anti-lysyl oxidase (anti-LOX) combined with a vacuum device (VD) could promote penile lengthening and to evaluate the effect on erectile function. This study was performed on four groups of adult rats: control, anti-LOX, VD (negative pressure value of -300 mmHg), and anti-LOX + VD. Penile length was measured by a modified VD method and verified on exposed length data. Intracavernous pressure (ICP) and maximum ICP/mean arterial pressure (MAP) ratio were recorded to assess erectile function. For corpus cavernosum, LOX activity and concentrations of pyridinoline, desmosine, hydroxyproline, and elastin were analyzed; transmission electron microscope and Hart's elastin staining were performed to monitor microstructural changes. Anti-LOX and VD significantly lengthened the penis by 10.8% (3.75 mm) and 8.2% (2.48 mm) compared with the control group, respectively, while anti-LOX + VD achieved the longest penile size (40.58 ± 0.40 mm) which was 17.4% longer than the control group (34.58 ± 0.54 mm). After 1-week washout, no penile retraction was observed. Meanwhile, exposed penile length data confirmed that the penis in the anti-LOX + VD group was also significantly longer. Anti-LOX inhibited LOX activity to reduce pyridinoline level, which led the penile tunica albuginea remodeling. However, it had no effect on hydroxyproline, desmosine, and elastin levels. Moreover, anti-LOX had no impact on erectile function, which was determined by ICP and ICP/MAP ratio. These results suggest that anti-LOX elongates the penis by reducing pyridinoline, which induces tunica albuginea remodeling. This lengthening effect was more obvious when combined with a VD. All procedures had no impact on erectile function.
Topics: Amino Acids; Aminopropionitrile; Animals; Arterial Pressure; Collagen; Combined Modality Therapy; Desmosine; Elastin; Enzyme Inhibitors; Hydroxyproline; Male; Organ Size; Penile Erection; Penis; Protein-Lysine 6-Oxidase; Rats; Rats, Sprague-Dawley; Vacuum
PubMed: 31736474
DOI: 10.4103/aja.aja_120_19 -
Respiratory Medicine Jun 2021A previous 2-week clinical trial of aerosolized hyaluronan (HA) in COPD showed a rapid reduction in lung elastic fiber breakdown, as measured by sputum levels of the... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
A previous 2-week clinical trial of aerosolized hyaluronan (HA) in COPD showed a rapid reduction in lung elastic fiber breakdown, as measured by sputum levels of the unique elastin crosslinks, desmosine and isodesmosine (DID). To further assess the therapeutic efficacy of HA and the utility of DID as surrogate markers for the development of pulmonary emphysema, we have conducted a 28-day randomized, double-blind, placebo-controlled, phase 2 trial of HA involving 27 subjects with alpha-1 antiprotease deficiency COPD.
METHODS
The study drug consisted of a 3 ml inhalation solution containing 0.03% HA with an average molecular weight of 150 kDa that was self-administered twice daily. DID levels were measured in urine, sputum, and plasma using tandem mass spectrometry.
RESULTS
Free urine DID in the HA group showed a significant negative correlation with time between days 14 and 35 (r = -1.0, p = 0.023) and was statistically significantly decreased from baseline at day 35 (15.4 vs 14.2 ng/mg creatinine, p = 0.035). A marked decrease in sputum DID was also seen in the HA group between days 1 and 28 (0.96 vs 0.18 ng/mg protein), but the difference was not significant, possibly due to the small number of adequate specimens. Plasma DID remained unchanged following HA treatment and no significant reductions in urine, sputum, or plasma DID were seen in the placebo group.
CONCLUSIONS
The results support additional clinical trials to further evaluate the therapeutic effect of HA and the use of DID as a real-time marker of drug efficacy.
Topics: Administration, Inhalation; Adult; Aerosols; Aged; Biomarkers; Desmosine; Double-Blind Method; Female; Humans; Hyaluronic Acid; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Time Factors; Treatment Outcome; alpha 1-Antitrypsin Deficiency
PubMed: 33906126
DOI: 10.1016/j.rmed.2021.106402 -
ERJ Open Research Oct 2020Vitamin D supplementation lowers exacerbation frequency in severe vitamin D-deficient patients with COPD. Data regarding the effect of vitamin D on elastin degradation...
BACKGROUND
Vitamin D supplementation lowers exacerbation frequency in severe vitamin D-deficient patients with COPD. Data regarding the effect of vitamin D on elastin degradation are lacking. Based on the vitamin's anti-inflammatory properties, we hypothesised that vitamin D supplementation reduces elastin degradation, particularly in vitamin D-deficient COPD patients. We assessed the effect of vitamin D status and supplementation on elastin degradation by measuring plasma desmosine, a biomarker of elastin degradation.
METHODS
Desmosine was measured every 4 months in plasma of 142 vitamin D-naïve COPD patients from the Leuven vitamin D intervention trial (100 000 IU vitamin D3 supplementation every 4 weeks for 1 year).
RESULTS
No significant association was found between baseline 25-hydroxyvitamin D (25(OH)D) and desmosine levels. No significant difference in desmosine change over time was found between the placebo and intervention group during the course of the trial. In the intervention arm, an unexpected inverse association was found between desmosine change and baseline 25(OH)D levels (p=0.005).
CONCLUSIONS
Vitamin D supplementation did not have a significant overall effect on elastin degradation compared to placebo. Contrary to our hypothesis, the intervention decelerated elastin degradation in vitamin D-sufficient COPD patients and not in vitamin D-deficient subjects.
PubMed: 33043047
DOI: 10.1183/23120541.00128-2019 -
American Journal of Physiology. Lung... Jun 2015Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking...
Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor β-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, β-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia.
Topics: Aminopropionitrile; Animals; Bronchopulmonary Dysplasia; Collagen; Elastin; Extracellular Matrix; Hyperoxia; Lung; Mice; Protein Processing, Post-Translational; Protein-Lysine 6-Oxidase
PubMed: 25840994
DOI: 10.1152/ajplung.00039.2015