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International Journal of Chronic... 2019Current pharmacotherapy of chronic obstructive pulmonary disease (COPD) aims at reducing respiratory symptoms and exacerbation frequency. Effective therapies to reduce...
Current pharmacotherapy of chronic obstructive pulmonary disease (COPD) aims at reducing respiratory symptoms and exacerbation frequency. Effective therapies to reduce disease progression, however, are still lacking. Furthermore, COPD medications showed less favorable effects in emphysema than in other COPD phenotypes. Elastin fibers are reduced and disrupted, whereas collagen levels are increased in emphysematous lungs. Protease/antiprotease imbalance has historically been regarded as the sole cause of emphysema. However, it is nowadays appreciated that emphysema may also be provoked by perturbations in the sequential repair steps following elastolysis. Essentiality of fibulin-5 and lysyl oxidase-like 1 in the elastin restoration process is discussed, and it is argued that copper deficiency is a plausible reason for failing elastin repair in emphysema patients. Since copper-dependent lysyl oxidases crosslink elastin as well as collagen fibers, copper supplementation stimulates accumulation of both proteins in the extracellular matrix. Restoration of abnormal elastin fibers in emphysematous lungs is favorable, whereas stimulating pulmonary fibrosis formation by further increasing collagen concentrations and organization is detrimental. Heparin inhibits collagen crosslinking while stimulating elastin repair and might therefore be the ideal companion of copper for emphysema patients. Efficacy and safety considerations may lead to a preference of pulmonary administration of copper-heparin over systemic administration.
Topics: Animals; Copper; Disease Models, Animal; Heparin; Humans; Pulmonary Emphysema; Respiratory Therapy
PubMed: 32063701
DOI: 10.2147/COPD.S228411 -
Bioorganic & Medicinal Chemistry Mar 2023Ligamentum flavum (LF) pathologies often lead to severe myelopathy or radiculopathy characterized by reduced elasticity, obvious thickening, or worsened ossification....
Ligamentum flavum (LF) pathologies often lead to severe myelopathy or radiculopathy characterized by reduced elasticity, obvious thickening, or worsened ossification. Elastin endows critical mechanical properties to tissues and organs such as vertebrae and ligaments. Desmosine (DES) and isodesmosine (IDES) are crosslinkers of elastin monomers called tropoelastin. These crosslinkers are potential biomarkers of chronic obstructive pulmonary disease. As a biological diagnostic tool that supplements existing symptomatic, magnetic resonance imaging scanning or radiological imaging diagnostic measures for LF hypertrophy and associated pathologies, an isotope-dilution liquid chromatography-tandem mass spectrometry method with selected reaction monitoring mode for the quantitation of DESs in human plasma, urine, cerebrospinal fluid (CSF), and yellow ligamentum was investigated. Isotopically labeled IDES-C,N was used as an internal standard (ISTD) for DES quantitation for the first time. The samples plus ISTD were hydrolyzed with 6 N hydrochloric acid. Analytes and ISTD were extracted using a solid phase extraction cellulose cartridge column. The assays were repeatable, reproducible, and accurate with % CV ≤ 7.7, ISTD area % RSD of 7.6, and % AC ≤ (101.2 ± 3.90) of the calibrations. The ligamentum samples gave the highest average DES/IDES content (2.38 μg/mg) on a dry-weight basis. A high percentage of the CSF samples showed almost no DESs. Urine and plasma samples of patients showed no significant difference from the control (p-value = 0.0519 and 0.5707, respectively). Microscopy of the yellow ligamentum samples revealed dark or blue-colored zones of elastin fibers that retained the hematoxylin dye and highly red-colored zones of collagen after counterstaining with van Gieson solution. Thus, we successfully developed a method for DES/IDES quantitation in clinical samples.
Topics: Humans; Chromatography, Liquid; Elastin; Desmosine; Tandem Mass Spectrometry; Ligamentum Flavum; Hypertrophy
PubMed: 36842401
DOI: 10.1016/j.bmc.2023.117216 -
Journal of Biomedical Materials... Jul 2019The failures of glutaraldehyde (GLUT) cross-linked bioprosthetic heart valves (BHVs) are mainly due to degeneration and calcification. In this study, we developed a new...
The failures of glutaraldehyde (GLUT) cross-linked bioprosthetic heart valves (BHVs) are mainly due to degeneration and calcification. In this study, we developed a new preparation strategy for BHVs named as "HPA/EDC/EGCG" that utilized 3,4-hydroxyphenylpropionic acid (HPA)-conjugated pericardium, epigallocatechin gallate (EGCG), and horseradish peroxidase (HRP)/hydrogen peroxide (H O ) enzymatic cross-linking. HPA-pericardium conjugation was done by carbodiimide coupling reaction using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and N-hydroxysuccinimide (NHS). Then HPA-conjugated pericardium was cross-linked by HRP/H O enzyme-catalyzed oxidation. The feeding ratios of HPA and EGCG were optimized. The consumption of amino groups, collagenase and elastase degradation in vitro, biomechanics, extracellular matrix stability, and calcification of HPA-/EDC-/EGCG-treated pericardiums were characterized. We demonstrated that HPA-/EDC-/EGCG-treated pericardiums had better elastin stabilization and less calcification. EGCG and enzymatic cross-linking treated pericardiums showed improved mechanical properties. This new EGCG and enzymatic cross-linking strategy would be a promising method to make BHVs with better elastin stability and anti-calcification property. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1551-1559, 2019.
Topics: Benzocaine; Biomechanical Phenomena; Bioprosthesis; Blood Coagulation; Calcification, Physiologic; Catechin; Chloramphenicol; Cross-Linking Reagents; Desmosine; Drug Combinations; Elastin; Ethyldimethylaminopropyl Carbodiimide; Extracellular Matrix; Glutaral; Heart Valve Prosthesis; Heart Valves; Horseradish Peroxidase; Humans; Hydrogen Peroxide; Nitrofurazone; Pericardium
PubMed: 30267643
DOI: 10.1002/jbm.b.34247 -
Acta Biomaterialia Mar 2020Intrinsically poor auto-regenerative repair of proteolytically-disrupted elastic matrix structures by resident SMCs in the wall of abdominal aortic aneurysms (AAAs)...
Intrinsically poor auto-regenerative repair of proteolytically-disrupted elastic matrix structures by resident SMCs in the wall of abdominal aortic aneurysms (AAAs) prevents growth arrest and regression of these wall expansions. Supporting their possible future use in a regenerative cell therapy for AAAs, in a prior study, we showed that bone marrow mesenchymal stem cell-derived Smooth Muscle Cells (BM-SMCs) secrete biological factors that have significant pro-elastogenic and anti-proteolytic effects on aneurysmal rat aortic SMCs (EaRASMCs) in non-contact co-cultures. We also identified one stable BM-SMC phenotype (cBM-SMC) generated by differentiating BM-MSCs on a 2D fibronectin substrate in the presence of PDGF (Platelet Derived Growth Factor) and TGF-β1 (Transforming Growth Factor-β1) that exhibited superior elastogenicity and pro-elastogenic/anti-proteolytic properties. In this study, we further investigated the ability of these cBM-SMCs to maintain these superior elastogenic properties in a 3D collagenous milieu alone and in co-culture with EaRASMC to evaluate their potential as an alternative cell source for cell therapy in AAA. Some of our key observations were higher contractility and greater amount of structurally intact elastin production in both standalone culture of cBM-SMCs as well as co-culture of cBM-SMCs with EaRASMCs as shown by VVG (Verhoeff-Van Gieson) staining and Pontamine Sky Blue labeling and lower MMP-9 protein expression in standalone culture in 3D collagenous environment. Our overall result indicates that cBM-SMCs possess the ability to provide elastogenic impetus in a 3D collagenous AAA milieu which is otherwise not conducive to elastogenesis. Therefore our study strongly suggest the utility of cBM-SMCs as a potential cell source for cell therapy to augment elastic matrix neo-assembly and fiber formation and attenuate proteolysis in a collagenous milieu that is evocative of the de-elasticized aneurysmal wall. STATEMENT OF SIGNIFICANCE: Abdominal aortic aneurysm (AAA) or ballooning of the aorta is one of the leading causes of cardiovascular disease (CVD) related death caused by significantly increased proteolytic activity in the aortic wall. Reversing pathophysiology of this condition is challenging due to intrinsically poor regeneration of elastin by aortic smooth muscle cells. Current management of AAA is limited to passive monitoring of the disease until it becomes large enough to receive surgical intervention and no drug based therapy currently exists. Cell based therapy can be a potential alternative treatment in this scenario because it provides elastogenic impetus to the aneurysmal SMCs, compensates for the dead SMCs and serves as a robust source of elastin while being delivered with minimal invasiveness. Hence this work will have significant impact in the field of tissue engineering and regenerative medicine.
Topics: Animals; Cell Proliferation; Cell Survival; Collagen; Desmosine; Elasticity; Elastin; Extracellular Matrix; Fluorescence; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mesenchymal Stem Cells; Myocytes, Smooth Muscle; Proteolysis; Rats, Sprague-Dawley; Tissue Scaffolds
PubMed: 31982591
DOI: 10.1016/j.actbio.2020.01.030 -
Frontiers in Nutrition 2022[This corrects the article DOI: 10.3389/fnut.2021.761191.].
[This corrects the article DOI: 10.3389/fnut.2021.761191.].
PubMed: 35356738
DOI: 10.3389/fnut.2022.868324 -
Biomechanics and Modeling in... Feb 2020Deposition of elastin and collagen in the aorta correlates with increases in blood pressure and flow during development, suggesting that the aorta adjusts its mechanical...
Deposition of elastin and collagen in the aorta correlates with increases in blood pressure and flow during development, suggesting that the aorta adjusts its mechanical properties in response to hemodynamic stresses. Elastin knockout (Eln) mice have high blood pressure and pathological remodeling of the aorta and die soon after birth. We hypothesized that decreasing blood pressure in Eln mice during development may reduce hemodynamic stresses and alleviate pathological remodeling of the aorta. We treated Eln and Eln mice with the anti-hypertensive medication captopril throughout embryonic development and then evaluated left ventricular (LV) pressure and aortic remodeling at birth. We found that captopril treatment decreased Eln LV pressure to values near Eln mice and alleviated the wall thickening and changes in mechanical behavior observed in untreated Eln aorta. The changes in thickness and mechanical behavior in captopril-treated Eln aorta were not due to alterations in measured elastin or collagen amounts, but may have been caused by alterations in smooth muscle cell (SMC) properties. We used a constitutive model to understand how changes in stress contributions of each wall component could explain the observed changes in composite mechanical behavior. Our modeling results show that alterations in the collagen natural configuration and SMC properties in the absence of elastin may explain untreated Eln aortic behavior and that partial rescue of the SMC properties may account for captopril-treated Eln aortic behavior.
Topics: Animals; Animals, Newborn; Aorta; Biomechanical Phenomena; Blood Pressure; Captopril; Desmosine; Elastin; Extracellular Matrix Proteins; Gene Expression Regulation; Heart Rate; Heart Ventricles; Hydroxyproline; Mice, Knockout; Myocytes, Smooth Muscle; RNA, Messenger; Receptors, Angiotensin; Stress, Mechanical; Vascular Remodeling
PubMed: 31270728
DOI: 10.1007/s10237-019-01198-2 -
International Journal of Chronic... 2022Several mechanisms have been proposed to explain why chronic obstructive pulmonary disease (COPD) impairs the prognosis of coronary events. We aimed to explore COPD...
Impact of Spirometrically Confirmed Chronic Obstructive Pulmonary Disease on Arterial Stiffness and Surfactant Protein D After Percutaneous Coronary Intervention. The CATEPOC Study.
BACKGROUND
Several mechanisms have been proposed to explain why chronic obstructive pulmonary disease (COPD) impairs the prognosis of coronary events. We aimed to explore COPD variables related to a worse prognosis in patients undergoing percutaneous coronary intervention (PCI).
METHODS
Patients with an acute coronary event treated by PCI were prospectively included. One month after discharge, clinical characteristics, comorbidities measured with the Charlson index, and prognostic coronary scales (logistic EuroSCORE; GRACE 2.0) were collected. Post-bronchodilator spirometry, arterial stiffness, and serum inflammatory and myocardial biomarkers were measured. Lung plasmatic biomarkers (Surfactant protein D, desmosine, and Clara cell secretory protein-16) were determined with ELISA. COPD was defined by the fixed ratio (FEV1/FVC <70%). Spirometric values were also analyzed as continuous variables using adjusted and non-adjusted ANCOVA analysis. Finally, we evaluated the presence of a respiratory pattern defined by non-stratified spirometric values and pulmonary biomarkers.
RESULTS
A total of 164 patients with a mean age of 65 (±10) years (79% males) were included. COPD was diagnosed in 56 (34%) patients (68% previously undiagnosed). COPD patients had a longer smoking history, higher scores on the EuroSCORE (p < 0.0001) and GRACE 2.0 (p < 0.001) scales, and more comorbidities (p = 0.006). Arterial stiffness determined by pulse wave velocity was increased in COPD patients (7.35 m/s vs 6.60 m/s; p = 0.006). Serum values of high sensitive T troponin (p = 0.007) and surfactant protein D (p = 0.003) were also higher in COPD patients. FEV1% remained significantly associated with arterial stiffness and surfactant protein D in the adjusted ANCOVA analysis. In the cluster exploration, 53% of the patients had a respiratory pattern.
CONCLUSION
COPD affects one-third of patients with an acute coronary event and frequently remains undiagnosed. Several mechanisms, including arterial stiffness and SPD, were increased in COPD patients. Their relationship with the prognosis should be confirmed with longitudinal follow-up of the cohort.
Topics: Aged; Female; Humans; Male; Biomarkers; Bronchodilator Agents; Desmosine; Percutaneous Coronary Intervention; Pulmonary Disease, Chronic Obstructive; Pulmonary Surfactant-Associated Protein D; Pulse Wave Analysis; Troponin; Uteroglobin; Vascular Stiffness; Middle Aged
PubMed: 36267326
DOI: 10.2147/COPD.S373853 -
Respiratory Research Mar 2021Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and abnormal inflammatory response in the lungs, mainly caused by cigarette smoking.... (Comparative Study)
Comparative Study
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and abnormal inflammatory response in the lungs, mainly caused by cigarette smoking. Animal models exposed to cigarette smoke (CS) are used to mimic human COPD but the use of different CS protocols makes it difficult to compare the immunological and structural consequences of using a nose-only or whole-body CS exposure system. We hypothesized that when using a standardized CS exposure protocol based on particle density and CO (carbon monoxide) levels, the whole-body CS exposure system would generate a more severe inflammatory response than the nose-only system, due to possible sensitization by uptake of CS-components through the skin or via grooming.
METHODS
In this study focusing on early COPD, mice were exposed twice daily 5 days a week to CS either with a nose-only or whole-body exposure system for 14 weeks to assess lung function, remodeling and inflammation.
RESULTS
At sacrifice, serum cotinine levels were significantly higher in the whole-body (5.3 (2.3-6.9) ng/ml) compared to the nose-only ((2.0 (1.8-2.5) ng/ml) exposure system and controls (1.0 (0.9-1.0) ng/ml). Both CS exposure systems induced a similar degree of lung function impairment, while inflammation was more severe in whole body exposure system. Slightly more bronchial epithelial damage, mucus and airspace enlargement were observed with the nose-only exposure system. More lymphocytes were present in the bronchoalveolar lavage (BAL) and lymph nodes of the whole-body exposure system while enhanced IgA and IgG production was found in BAL and to a lesser extent in serum with the nose-only exposure system.
CONCLUSION
The current standardized CS-exposure protocol resulted in a higher internal load of serum cotinine in the whole-body exposure system, which was associated with more inflammation. However, both exposure systems resulted in a similar lung function impairment. Data also highlighted differences between the two models in terms of lung inflammation and remodelling, and potential sensitization to CS. Researchers should be aware of these differences when designing their future studies for an early intervention in COPD.
Topics: Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Cotinine; Cytokines; Disease Models, Animal; Immunity, Humoral; Immunoglobulin A; Immunoglobulin G; Inflammation Mediators; Inhalation Exposure; Lung; Lymphoid Tissue; Male; Mice, Inbred C57BL; Nose; Pneumonia; Pulmonary Disease, Chronic Obstructive; Smoke; Time Factors; Tobacco Products; Mice
PubMed: 33731130
DOI: 10.1186/s12931-021-01680-5 -
Journal of Clinical Medicine Jul 2019Elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD) and is partially regulated by Matrix Gla Protein (MGP), via a vitamin K-dependent...
Elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD) and is partially regulated by Matrix Gla Protein (MGP), via a vitamin K-dependent pathway. The aim was to assess vitamin K status in COPD as well as associations between vitamin K status, elastin degradation, lung function parameters and mortality. A total of 192 COPD patients and 186 age-matched controls were included. In addition to this, 290 COPD patients from a second independent longitudinal cohort were also included. Vitamin K status was assessed by measuring plasma inactive MGP levels and rates of elastin degradation by measuring plasma desmosine levels. Reduced vitamin K status was found in COPD patients compared to smoking controls ( < 0.0005) and controls who had never smoked ( = 0.001). Vitamin K status was inversely associated with desmosine (cohort 1: = 0.001; cohort 2: = 0.004). Only few significant associations between vitamin K status and lung function parameters were found. Mortality was higher in COPD patients within the quartile with the lowest vitamin K status compared to those within the other quartiles (hazard ratio 1.85, 95% confidence interval (CI), 1.21-2.83, = 0.005). In conclusion, we demonstrated reduced vitamin K status in COPD and an inverse association between vitamin K status and elastin degradation rate. Our results therefore suggest a potential role of vitamin K in COPD pathogenesis.
PubMed: 31357639
DOI: 10.3390/jcm8081116 -
Bioorganic & Medicinal Chemistry Feb 2024Moyamoya disease (MMD) is a cerebrovascular disease which is characterized by the chronic progression of steno-occlusive changes at the terminal portion of internal...
Moyamoya disease (MMD) is a cerebrovascular disease which is characterized by the chronic progression of steno-occlusive changes at the terminal portion of internal carotid arteries and the development of "moyamoya vessels." Dysregulation of the extracellular matrix is regarded as a key pathophysiology underlying unique vascular remodeling. Here, we measured the concentration of elastin crosslinkers desmosine and isodesmosine in the plasma of MMD patients. We aimed to reveal its diagnostic values of desmosines in the progression of steno-occlusive lesions. The concentrations of plasma desmosines were determined by liquid chromatography-tandem mass spectrometry. The temporal profiles of steno-occlusive lesions on magnetic resonance angiography were retrospectively evaluated, and the correlation between the progression of steno-occlusive changes in intracranial arteries and plasma desmosines concentrations was further analyzed. Plasma desmosines were significantly higher in MMD patients with disease progression compared to MMD patients without disease progression. Also, the incidence of disease progression was higher in MMD patients with plasma desmosines levels over limit of quantitation (LOQ) than those with plasma desmosines levels below LOQ. In conclusion, plasma desmosines could be potential biomarkers to predict the progression of steno-occlusive changes in MMD patients.
Topics: Humans; Prognosis; Moyamoya Disease; Desmosine; Retrospective Studies; Elastic Tissue; Disease Progression
PubMed: 38324946
DOI: 10.1016/j.bmc.2024.117602