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Journal of Cystic Fibrosis : Official... May 2010In infected lungs of the cystic fibrosis (CF) patients, opportunistic pathogens and mutated cystic fibrosis transmembrane conductance regulator protein (CFTR) contribute...
BACKGROUND
In infected lungs of the cystic fibrosis (CF) patients, opportunistic pathogens and mutated cystic fibrosis transmembrane conductance regulator protein (CFTR) contribute to chronic airway inflammation that is characterized by neutrophil/macrophage infiltration, cytokine release and ceramide accumulation. We sought to investigate CF lung inflammation in the alveoli.
METHODS
Lung tissue from 14 CF patients and four healthy individuals was analyzed for numbers of effector cells, elastin and collagen concentrations, inflammatory markers and density of Pseudomonas aeruginosa. Additionally, desmosine and isodesmosine concentrations were determined in 52 urine specimens from CF patients to estimate the burden of elastase activities in respiratory secretions.
RESULTS
Elastin concentration was significantly decreased and collagen significantly increased in CF alveolar tissues as compared to age-matched, healthy individuals. Elastin split products were significantly increased in urine samples from patients with CF and correlated inversely with age, indicating local tissue remodelling due to elastin degradation by unopposed proteolytic enzymes. Alveolar inflammation was also characterized by a significant cell infiltration of neutrophils, macrophages and T cells, extensive nuclear factor-kappaB and insulin-like growth factor-1 activation in various cell types and increased intercellular adhesion molecule-1 expression, and increased numbers of myofibroblasts. Additionally, ceramide accumulated in type II alveolar epithelial cells, lacking CFTR. P. aeruginosa organisms were rarely present in inflamed alveoli.
CONCLUSIONS
Chronic inflammation and remodeling is present in alveolar tissues of the CF lung and needs to be addressed by anti-inflammatory therapies.
Topics: Adolescent; Adult; Case-Control Studies; Ceramides; Collagen; Cystic Fibrosis; Desmosine; Elastin; Female; Humans; Inflammation; Isodesmosine; Male; Pseudomonas aeruginosa; Pulmonary Alveoli; Young Adult
PubMed: 20347403
DOI: 10.1016/j.jcf.2010.03.001 -
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 -
The Journal of Investigative Dermatology Jan 1979The elastic fibers present in various connective tissues of the body are responsible for physiologic elasticity of the organs. These fibers consist of 2 distinct... (Review)
Review
The elastic fibers present in various connective tissues of the body are responsible for physiologic elasticity of the organs. These fibers consist of 2 distinct components, elastin and the elastic fiber microfibrils. Controlled synthesis and balanced interaction of these 2 components are essential for normal fibrillogenesis. The intracellular biosynthesis of elastin by connective tissue cells, such as smooth muscle cells, involves assembly of the polypeptide chains on the membrane-bound ribosomes, hydroxylation of some prolyl residues to hydroxyproline, and secretion of the polypeptides packaged in Golgi vacuoles. In the extracellular space the elastin molecules assemble into fiber structures which are stabilized by the synthesis of complex covalent cross-links, desmosines. Recently, aberrations in the structure or metabolism of elastin have been detected in a variety of heritable and acquired diseases affecting skin and other connective tissues. These conditions include pseudoxanthoma elasticum, cutis laxa, and elastosis perforans serpiginosa, as well as arteriosclerosis and other degenerative changes of the vascular connective tissues.
Topics: Amino Acids; Arteriosclerosis; Chemical Phenomena; Chemistry; Collagen Diseases; Connective Tissue; Contractile Proteins; Cutis Laxa; Desmosine; Ehlers-Danlos Syndrome; Elastic Tissue; Elastin; Female; Glycoproteins; Humans; Hydroxyproline; Marfan Syndrome; Menkes Kinky Hair Syndrome; Muscle Proteins; Pancreatic Elastase; Peptide Biosynthesis; Protein Precursors; Pseudoxanthoma Elasticum; X Chromosome
PubMed: 368254
DOI: 10.1111/1523-1747.ep12530093 -
Journal of Oleo Science 2010Desmosine (DES) and isodesmosine (IDES) are both pyridinium amino acid isomers that serve as cross-linking molecules binding the polymeric chains of amino acids into...
Desmosine (DES) and isodesmosine (IDES) are both pyridinium amino acid isomers that serve as cross-linking molecules binding the polymeric chains of amino acids into elastin. Found in urine, they are markers for the degradation of elastin which occurs in chronic obstructive pulmonary disease (COPD). In this study, a robust method using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) with selected reaction monitoring (SRM) mode was developed for the analysis of DES and IDES in human urine. Pyridylethyl-cysteine (PE-Cys) as internal standard (I.S.) was employed for the quantification of DES and IDES. The analytes and I.S. were extracted by solid-phase extraction with Oasis MCX cartridges and separated on an AccQ-Tag Ultra column. The assay was accurate (-6.8% to 14.5%) and precise (2.8% to 13.8%) within the concentration range of 1 to 250 pmol/mL. Moreover, the recovery and stability (working/ I.S. solution, urine samples with added elastin, and pretreated sample) was investigated, and these parameters were found acceptable. The UPLC-MS/MS method was validated and had good reproducibility and stability for the quantification of DES and IDES, which requires only 100 mL of human urine. This assay will be a useful means for measuring DES and IDES levels in urine with robustness and characterizing patients with COPD.
Topics: Adult; Calibration; Case-Control Studies; Chromatography, Liquid; Desmosine; Drug Stability; Efficiency; Elastin; Female; Humans; Isodesmosine; Lung Neoplasms; Lymphangioleiomyomatosis; Male; Models, Biological; Reproducibility of Results; Sensitivity and Specificity; Specimen Handling; Tandem Mass Spectrometry; Urinalysis
PubMed: 20625235
DOI: 10.5650/jos.59.431 -
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 -
The European Respiratory Journal Oct 2012The aim of this study was to evaluate the safety and effect on clinical outcomes and biomarkers of inflammation and tissue damage of the neutrophil elastase inhibitor... (Randomized Controlled Trial)
Randomized Controlled Trial
The aim of this study was to evaluate the safety and effect on clinical outcomes and biomarkers of inflammation and tissue damage of the neutrophil elastase inhibitor AZD9668 (60 mg twice daily orally for 4 weeks) in cystic fibrosis. This was a randomised, double-blind, placebo-controlled study. Primary outcome measures were sputum neutrophil count, lung function, 24-h sputum weight, BronkoTest® diary card data and health-related quality-of-life (revised cystic fibrosis quality-of-life questionnaire). Secondary end-points included sputum neutrophil elastase activity, inflammatory biomarkers in sputum and blood, urine and plasma desmosine (an elastin degradation marker), AZD9668 levels and safety parameters (adverse events, routine haematology, biochemistry, electrocardiogram and sputum bacteriology). 56 patients were randomised, of which 27 received AZD9668. There was no effect for AZD9668 on sputum neutrophil counts, neutrophil elastase activity, lung function or clinical outcomes, including quality of life. In the AZD9668 group, there was a trend towards reduction in sputum inflammatory biomarkers with statistically significant changes in interleukin-6, RANTES and urinary desmosine. The pattern of adverse events was similar between groups. Consistent reductions in sputum inflammatory biomarkers were seen in the AZD9668 group, and reduction in urinary desmosine suggests that AZD9668 impacts elastin cleavage by neutrophil elastase.
Topics: Adolescent; Adult; Biomarkers; Cell Count; Cystic Fibrosis; Female; Humans; Inflammation Mediators; Leukocyte Elastase; Male; Neutrophils; Proteinase Inhibitory Proteins, Secretory; Pyridones; Quality of Life; Respiratory Function Tests; Sputum; Sulfones; Treatment Outcome
PubMed: 22267768
DOI: 10.1183/09031936.00194611 -
Journal of Cardiovascular Pharmacology Apr 2016This study was designed to determine whether vonapanitase (formerly PRT-201), a recombinant human elastase, treatment can fragment the protein elastin in elastic fibers...
PURPOSE
This study was designed to determine whether vonapanitase (formerly PRT-201), a recombinant human elastase, treatment can fragment the protein elastin in elastic fibers and cause dilation of atherosclerotic human peripheral arteries subjected to ex vivo balloon angioplasty.
MATERIALS AND METHODS
Seven patients undergoing lower limb amputation for peripheral artery disease or who died and donated their bodies to science donated 11 tibial arteries (5 anterior, 6 posterior) for this study. All arteries were atherosclerotic by visual inspection. The arteries underwent ex vivo balloon angioplasty and thereafter were cut into rings and studied on wire myographs where the rings were stretched and tension was recorded. After treatment with vonapanitase 2 mg/mL or vehicle control, myography was repeated and the rings were then subject to elastin content measurement using a desmosine radioimmunoassay and elastic fiber visualization by histology. The wire myography data were used to derive compliance, stress-strain, and incremental elastic modulus curves.
RESULTS
Vonapanitase treatment reduced elastin (desmosine) content by 60% and decreased elastic fiber histologic staining. Vonapanitase-treated rings experienced less tension at any level of stretch and as a result had shifts in the compliance and stress-strain curves relative to vehicle-treated rings. Vonapanitase treatment did not alter the incremental elastic modulus curve.
CONCLUSIONS
Vonapanitase treatment of atherosclerotic human peripheral arteries after ex vivo balloon angioplasty fragmented elastin in elastic fibers, decreased tension in the rings at any level of stretch, and altered the compliance and stress-strain curves in a manner predicting arterial dilation in vivo. Based on this result, local treatment of balloon angioplasty sites may increase blood vessel diameter and thereby improve the success of balloon angioplasty in peripheral artery disease.
Topics: Aged; Aged, 80 and over; Angioplasty, Balloon; Atherosclerosis; Carrier Proteins; Elastic Modulus; Elastic Tissue; Elastin; Female; Humans; Male; Middle Aged; Myography; Pancreatic Elastase; Peripheral Arterial Disease; Tibial Arteries; Vasodilation
PubMed: 26745001
DOI: 10.1097/FJC.0000000000000354 -
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 -
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 -
Analytical and Bioanalytical Chemistry Nov 2011Desmosine crosslinks are responsible for the elastic properties of connective tissues in lungs and cardiovascular system and are often compromised in disease states. We...
Desmosine crosslinks are responsible for the elastic properties of connective tissues in lungs and cardiovascular system and are often compromised in disease states. We developed a new, fast, and simple cation exchange HPLC assay for the analysis of desmosine and isodesmosine in animal elastin. The method was validated by determining linearity, accuracy, precision, and desmosines stability and was applied to measure levels of desmosines in porcine and murine organs. The detection and quantification limits were 2 and 4 pmol, respectively. The run-time was 8 min. Our cation exchange column does not separate desmosine and isodesmosine, but their level can be quantified from absorbance at different wavelengths. Using this assay, we found that desmosines levels were significantly lower in elastin isolated from various organs of immunodeficient severe combined immunodeficiency mice compared with wild-type animals. We also found that desmosines levels were lower in lung elastin isolated from hyperhomocysteinemic Pcft(-/-) mice deficient in intestinal folate transport compared with wild-type Pcft(+/+) animals.
Topics: Animals; Chromatography, High Pressure Liquid; Chromatography, Ion Exchange; Desmosine; Elastin; Hyperhomocysteinemia; Isodesmosine; Limit of Detection; Lung; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Severe Combined Immunodeficiency; Swine; Time Factors
PubMed: 21887606
DOI: 10.1007/s00216-011-5346-z