-
RSC Advances Nov 2022Utilizing chemically synthesized an isotopically labeled internal standard, isodesmosine-C,N, an isotope-dilution LC-MS/MS method was established. Concentrations of...
Utilizing chemically synthesized an isotopically labeled internal standard, isodesmosine-C,N, an isotope-dilution LC-MS/MS method was established. Concentrations of desmosine and isodesmosine in plasma of acute cerebral stroke patients and healthy controls were determined. The concentration of desmosines was markedly higher in plasma from acute stroke patients compared with healthy controls. Desmosines are thus novel biomarkers for evaluating the extent of vascular injury after acute cerebral stroke.
PubMed: 36380946
DOI: 10.1039/d2ra06009d -
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 -
Chronic Obstructive Pulmonary Diseases... Jul 2022Prolonged past exposure to secondhand tobacco smoke (SHS) in never-smokers is associated with abnormal lung function and reduced diffusing capacity suggestive of an...
BACKGROUND
Prolonged past exposure to secondhand tobacco smoke (SHS) in never-smokers is associated with abnormal lung function and reduced diffusing capacity suggestive of an associated lung tissue injury and damage. The mechanisms by which past SHS exposure may contribute to lung tissue damage are unknown. Elastin is a major constituent of extracellular matrix in lung parenchyma.
OBJECTIVE
To determine whether past exposure to SHS is associated with ongoing lung tissue damage as indicated by elevated elastin degradation products that are linked to lung function.
METHODS
We measured the plasma levels of elastin degradation markers (EDM) from 193 never-smoking flight attendants with a history of remote SHS exposure in aircraft cabins and 103 nonsmoking flight attendants or sea-level control participants without such history of cabin SHS exposure and examined those levels versus their lung function with adjustment for covariates. The cabin SHS exposure was estimated based on airline employment history and years of the smoking ban enactment.
RESULTS
The median [interquartile range] plasma EDM level for all participants was 0.30 [0.24-0.36] ng/mL with a total range of 0.16-0.65 ng/mL. Plasma EDM levels were elevated in those with a history of exposure to cabin SHS compared to those not exposed (0.33±0.08 versus 0.26±0.06 ng/mL; age- and sex-adjusted <0.001). In those with a history of cabin SHS exposure, higher EDM levels were associated with a lower diffusing capacity (parameter estimate [PE] 95% [confidence interval(CI)]=4.2 [0.4-8.0] %predicted decrease per 0.1 ng/mL increase in EDM; =0.030). Furthermore, EDM levels were inversely associated with forced expiratory volume in 1 second (FEV), FEV to forced vital capacity (FVC) ratio , and forced expiratory flow rate between 25% and 75% ( FEF) (PE [95%CI]=5.8 [2.1-9.4], 4.0 [2.2-5.7], and 12.5 [5.8-19.2] %predicted decrease per 0.1 ng/mL increase in EDM, respectively; <0.001). Plasma EDM mediated a substantial fraction of the association of SHS with FEV, FVC, and FEF (<0.05).
CONCLUSIONS
Long after past exposure to SHS, there is ongoing elastin degradation beyond what is expected from the aging process, which likely contributes to lower lung function and a reduced pulmonary capillary bed as seen in chronic obstructive pulmonary disease (COPD).
PubMed: 35700534
DOI: 10.15326/jcopdf.2022.0289 -
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 -
Frontiers in Nutrition 2021Pathology during COVID-19 infection arises partly from an excessive inflammatory response with a key role for interleukin (IL)-6. Both vitamin D and K have been proposed...
BACKGROUND
Pathology during COVID-19 infection arises partly from an excessive inflammatory response with a key role for interleukin (IL)-6. Both vitamin D and K have been proposed as potential modulators of this process.
METHODS
We assessed vitamin D and K status by measuring circulating 25-hydroxyvitamin D (25(OH)D) and desphospho-uncarboxylated Matrix Gla-Protein (dp-ucMGP), respectively in 135 hospitalized COVID-19 patients in relation to inflammatory response, elastic fiber degradation and clinical outcomes.
RESULTS
Comparing good and poor disease outcomes of COVID-19 patients, vitamin 25(OH)D levels were not significantly different. IL-6 levels, however, were significantly higher in patients with poor outcome, compared to patients with good outcome (30.3 vs. 153.0 pg/mL; < 0.0001). Dp-ucMGP levels as biomarker of extrahepatic vitamin K status was associated with IL-6 levels (r = 0.35; < 0.0001). In contrast, 25(OH)D levels were only borderline statistically significant correlated with IL-6 (r = -0.14; <0.050). A significant association was also found between IL-6 and elastic fiber degradation. Contrary to vitamin K status, 25(OH)D did not correlate with elastic fiber degradation.
CONCLUSIONS
Dp-ucMGP associates with IL-6 as a central component of the destructive inflammatory processes in COVID-19. An intervention trial may provide insight whether vitamin K administration, either or not in combination with vitamin D, improves clinical outcome of COVID-19.
PubMed: 35111793
DOI: 10.3389/fnut.2021.761191 -
Frontiers in Cardiovascular Medicine 2021During arteriogenesis, outward remodeling of the arterial wall expands luminal diameter to produce increased conductance in developing collaterals. We have previously...
During arteriogenesis, outward remodeling of the arterial wall expands luminal diameter to produce increased conductance in developing collaterals. We have previously shown that diameter expansion without loss of internal elastic lamina (IEL) integrity requires both degradation of elastic fibers and LOX-mediated repair. The aim of this study was to investigate the expression of genes involved in remodeling of the extracellular matrix (ECM) using a model of arteriogenesis. Sprague-Dawley rats underwent femoral artery ligation with distal arteriovenous fistula (FAL + AVF) placement. Profunda femoral arteries (PFA) were harvested for analysis at various time points. Serum desmosine, an amino acid found exclusively in elastin, was evaluated with enzyme-linked immunosorbent assay (ELISA) as a marker of tissue elastolysis. Tissue mRNA isolated from FAL + AVF exposed PFAs was compared to the contralateral sham-operated using qPCR. HCAECs were cultured under low shear stress (8 · ) for 24 h and then exposed to high shear stress (40 · ) for 2-6 h. Primers used included FBN-1, FBN-2, Timp-2, LOX-1, Trop-E, Cath-K, Cath-S, MMP-2, MMP-9, FBLN-4, and FBLN-5 and were normalized to GAPDH. mRNA fold changes were quantified using the 2-ΔΔCq method. Comparisons between time points were made with non-parametric ANOVA analysis with Bonferroni adjustment. PFAs showed IEL reorganization during arteriogenesis. Serum desmosine levels are significantly elevated at 2 days and one week, with a return to baseline thereafter ( < 0.01). Expression of ECM structural proteins (FBN-1, FBN-2, FBLN-4, FBLN-5, Tropoelastin, TIMP-2, LOX-1) and elastolytic proteins (MMP-2, MMP-9, Cathepsin S, Cathepsin K) exhibited an early peak ( < 0.05) relative to sham PFAs. After two weeks, expression returned to baseline. HCAECs demonstrated upregulation of FBN-2, FBLN-5, LOX-1 and Trop-E at 4 h of high shear stress, as well as elastolytic protein MMP-2. Elastin degradation begins early in arteriogenesis and is mediated by local upregulation of elastolytic genes. Elastolysis appears to be simultaneously balanced by production of elastic fiber components which may facilitate stabilization of the IEL. Endothelial cells are central to initiation of arteriogenesis and begin ECM remodeling in response to altered shear stress.
PubMed: 35096993
DOI: 10.3389/fcvm.2021.762094 -
International Journal of Molecular... Dec 2021Perlecan (HSPG2), a basement membrane-type heparan sulfate proteoglycan, has been implicated in the development of aortic tissue. However, its role in the development...
Perlecan (HSPG2), a basement membrane-type heparan sulfate proteoglycan, has been implicated in the development of aortic tissue. However, its role in the development and maintenance of the aortic wall remains unknown. Perlecan-deficient mice (-Tg: Perl KO) have been found to show a high frequency (15-35%) of aortic dissection (AD). Herein, an analysis of the aortic wall of Perl KO mice revealed that perlecan deficiency caused thinner and partially torn elastic lamina. Compared to the control aortic tissue, perlecan-deficient aortic tissue showed a significant decrease in desmosine content and an increase in soluble tropoelastin levels, implying the presence of immature elastic fibers in Perl KO mice. Furthermore, the reduced expression of the smooth muscle cell contractile proteins actin and myosin in perlecan-deficient aortic tissue may explain the risk of AD. This study showed that a deficiency in perlecan, which is localized along the elastic lamina and at the interface between elastin and fibrillin-1, increased the risk of AD, largely due to the immaturity of extracellular matrix in the aortic tissue. Overall, we proposed a new model of AD that considers the deficiency of extracellular molecule perlecan as a risk factor.
Topics: Aortic Dissection; Animals; Aorta; Biomarkers; Elasticity; Elastin; Extracellular Matrix Proteins; Fibrillin-1; Heparan Sulfate Proteoglycans; Matrix Metalloproteinases; Mice, Transgenic; Myocardial Contraction; Myocytes, Smooth Muscle; Protein Biosynthesis; RNA, Messenger; Risk Factors
PubMed: 35008739
DOI: 10.3390/ijms23010315 -
Bioorganic & Medicinal Chemistry Dec 2021Desmosine and isodesmosine are crosslinking amino acids of elastin, which is an essential component of the dermal extracellular matrix protein. Quantitative analysis of...
Desmosine and isodesmosine are crosslinking amino acids of elastin, which is an essential component of the dermal extracellular matrix protein. Quantitative analysis of crosslinker desmosines in human skin dermis has not been fully achieved due to the insoluble nature of elastin protein. In the present study, chemical synthesis of isotopically labeled desmosine, desmosine-C,N, was carried out via isoChichibabin pyridinium synthesis starting from corresponding isotopically labeled amino acids. Isotope-dilution LC-MS/MS analysis of desmosine and isodesmosine utilizing synthetic desmosine-C,N enabled the quantitative analysis of desmosines in human skin for the first time. Thus, ca. 1.43 μg of desmosines was detected from analysis of 1 mg of dry human skin.
Topics: Carbon Isotopes; Chromatography, Liquid; Desmosine; Humans; Isodesmosine; Molecular Structure; Nitrogen Isotopes; Skin; Tandem Mass Spectrometry
PubMed: 34839160
DOI: 10.1016/j.bmc.2021.116519 -
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 -
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