-
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 -
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 -
The Spine Journal : Official Journal of... Mar 2021Pulmonary complications in patients age 75 years and older who undergo spinal fusion may have catastrophic consequences. The use of augmentation techniques with... (Clinical Trial)
Clinical Trial
BACKGROUND CONTEXT
Pulmonary complications in patients age 75 years and older who undergo spinal fusion may have catastrophic consequences. The use of augmentation techniques with polymethylmethacrylate (PMMA) have been associated with pulmonary damage. The use of fenestrated pedicle screws augmented with PMMA may increase the risk of lung injury in this population.
PURPOSE
To investigate whether the use of PMMA-augmented screws is correlated with increased lung injury in patients undergoing instrumented lumbar spinal fusion.
STUDY DESIGN
A nonrandomized, prospective, case-controlled clinical study was carried out.
PATIENT SAMPLE
We included 50 consecutive patients: 25 classifieds as patients who required PMMA-augmented screws in lumbar spinal fusion, and 25 classifieds as control participants because they underwent uncemented instrumented spinal fusion.
OUTCOME MEASURES
We compare the incidence of the event, lung damage, in both groups by measuring a series of parameters: arterial blood gas, transesophageal echocardiography, urinary desmosine, and chest radiograph. The epidemiological parameters analyzed were age, sex, body mass index, status as a smoker, and number of cement leaks.
METHODS
Changes in pulmonary damage markers were described in both groups of patients, comparing postsurgery values with baseline values. In control participants, each change was evaluated for the total number of patients. All changes are indicated in this report by mean differences for quantitative variables and by differing proportions for qualitative variables, with 95% confidence intervals provided for all values.
RESULTS
There was an increase in postinstrumentation PaO2 (arterial partial pressure of oxygen) in both groups, probably related to the use of mechanical ventilation and recruitment maneuvers. Even though the group that required augmentation had lower baseline levels, the difference between groups was not statistically significant. On transesophageal echocardiographs, we observed scattered small, snowflake-like emboli, and bright echo signals appeared in the right atrium during PMMA injection. Signal density was constant but gradually faded away when PMMA injection ended. No participants in the group without augmentation had radiological complications. Overall, desmosine levels increased in both groups, and the rise was similar in both. There was a slight average increase in urine desmosine levels after instrumentation and progressively continues to rise until 24 hours after instrumentation, with a subsequent decrease at 72 hours. Comparing the two groups, we found no statistically significant differences at any time.
CONCLUSIONS
We were not able to identify a significant difference in urine desmosine levels associated with the augmentation of with fenestrated pedicle screws with PMMA. Despite comparing patients age 75 years or older with a younger group, we found no clinical, analytical, or gasometric data indicating lung damage in patients who had augmentation.
Topics: Aged; Bone Cements; Humans; Lumbar Vertebrae; Lung Injury; Osteoporosis; Pedicle Screws; Polymethyl Methacrylate; Prospective Studies; Spinal Fusion
PubMed: 33259968
DOI: 10.1016/j.spinee.2020.11.006 -
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 -
Journal of Clinical Medicine Aug 2020Pseudoxanthoma elasticum (PXE) results in extensive fragmentation and calcification of elastin fibers in the peripheral arteries, which results in peripheral arterial...
Pseudoxanthoma elasticum (PXE) results in extensive fragmentation and calcification of elastin fibers in the peripheral arteries, which results in peripheral arterial disease (PAD). Current research focuses on the role of calcifications in the pathogenesis of PXE. Elastin degradation and calcification are shown to interact and may amplify each other. This study aims to compare plasma desmosines, a measure of elastin degradation, between PXE patients and controls and to investigate the association between desmosines and (1) arterial calcification, (2) PAD, and (3) PAD independent of arterial calcification in PXE. Plasma desmosines were quantified with liquid chromatography-tandem mass spectrometry in 93 PXE patients and 72 controls. In PXE patients, arterial calcification mass was quantified on CT scans. The ankle brachial index (ABI) after treadmill test was used to analyze PAD, defined as ABI < 0.9, and the Fontaine classification was used to distinguish symptomatic and asymptomatic PAD. Regression models were built to test the association between desmosines and arterial calcification and arterial functioning in PXE. PXE patients had higher desmosines than controls (350 (290-410) ng/L vs. 320 (280-360) ng/L, = 0.02). After adjustment for age, sex, body mass index, smoking, type 2 diabetes mellitus, and pulmonary abnormalities, desmosines were associated with worse ABI (β (95%CI): -68 (-132; -3) ng/L), more PAD (β (95%CI): 40 (7; 73) ng/L), and higher Fontaine classification (β (95%CI): 30 (6; 53) ng/L), but not with arterial calcification mass. Lower ABI was associated with higher desmosines, independent from arterial calcification mass (β (95%CI): -0.71(-1.39; -0.01)). Elastin degradation is accelerated in PXE patients compared to controls. The association between desmosines and ABI emphasizes the role of elastin degradation in PAD in PXE. Our results suggest that both elastin degradation and arterial calcification independently contribute to PAD in PXE.
PubMed: 32859086
DOI: 10.3390/jcm9092771 -
Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019.Clinical Infectious Diseases : An... Dec 2021Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2-infected patients. Vitamin K activates both hepatic coagulation...
BACKGROUND
Respiratory failure and thromboembolism are frequent in severe acute respiratory syndrome coronavirus 2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease.
METHODS
A total of 135 hospitalized COVID-19 patients were compared with 184 historic controls. Inactive vitamin K-dependent MGP (desphospho-uncarboxylated [dp-uc] MGP) and prothrombin (PIVKA-II) were measured inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed using computed tomography.
RESULTS
dp-ucMGP was elevated in COVID-19 patients compared with controls (P < .001), with even higher dp-ucMGP in patients with poor outcomes (P < .001). PIVKA-II was normal in 82.1% of patients. dp-ucMGP was correlated with desmosine (P < .001) and with coronary artery (P = .002) and thoracic aortic (P < .001) calcification scores.
CONCLUSIONS
dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome; hepatic procoagulant factor II remained unaffected. These data suggest pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively.
Topics: Biomarkers; COVID-19; Humans; Risk Factors; SARS-CoV-2; Vitamin K 1
PubMed: 32852539
DOI: 10.1093/cid/ciaa1258 -
American Journal of Respiratory Cell... Nov 2020The mechanisms responsible for the increased loss of pulmonary function following acute lung inflammation in chronic obstructive pulmonary disease remain poorly...
The mechanisms responsible for the increased loss of pulmonary function following acute lung inflammation in chronic obstructive pulmonary disease remain poorly understood. To investigate this process, our laboratory developed a hamster model that uses a single intratracheal instillation of LPS to superimpose an inflammatory response on lungs treated with intratracheal elastase 1 week earlier. Parameters measured at 2 days after LPS included total leukocyte content and percent neutrophils in BAL fluid (BALF), and BALF levels of both total and peptide-free elastin-specific crosslinks, desmosine and isodesmosine (DID). Airspace enlargement, measured by the mean linear intercept method, and relative interstitial elastic fiber surface area were determined at 1 week after LPS. Compared with animals only treated with elastase, those receiving elastase/LPS showed statistically significant increases in mean linear intercept (156.2 vs. 85.5 μm), BALF leukocytes (187 vs. 37.3 × 10 cells), neutrophils (39% vs. 3.4%), and free DID (182% vs. 97% of controls), which exceeded the sum of the individual effects of the two agents. Despite increased elastin breakdown, the elastase/LPS group had significantly greater elastic fiber surface area than controls (49% vs. 26%) owing to fragmentation and splaying of the fibers. Additional experiments showed that the combination of elastin peptides and LPS significantly enhanced their separate effects on BALF neutrophils and BALF DID and leukocyte chemotaxis . The results suggest that structural changes in elastic fibers have proinflammatory activity and may contribute to the decline in pulmonary function related to chronic obstructive pulmonary disease exacerbations.
Topics: Animals; Bronchoalveolar Lavage Fluid; Chemotaxis; Desmosine; Elastic Tissue; Elastin; Female; Inflammation; Isodesmosine; Leukocytes; Lipopolysaccharides; Lung; Male; Mesocricetus; Peptides
PubMed: 32790529
DOI: 10.1165/rcmb.2020-0064OC -
Andrology Nov 2020Males with short penises may suffer from sexual dysfunction and psychological problems. However, currently, managing short penis is a huge challenge.
BACKGROUND
Males with short penises may suffer from sexual dysfunction and psychological problems. However, currently, managing short penis is a huge challenge.
OBJECTIVES
To explore whether inhibition of lysyl oxidase (LOX) activity (anti-LOX) combined with a vacuum device could lengthen the penis of pubertal rat.
MATERIALS AND METHODS
Male rats of different ages were purchased, their exposed penile lengths and weights were measured, and protein expression and lysyl oxidase activity in the corpus cavernosum were analyzed. Fifteen-day-old rats were then purchased and divided into six groups: control, Anti-lysyl oxidase, -200 mm Hg (vacuum device under -200 mm Hg value), -200 mm Hg + Anti-lysyl oxidase, -300 mm Hg, and -300 mm Hg + Anti-lysyl oxidase groups. After the intervention duration of 7 weeks, rats' penile length was measured and erectile function was assessed. The corpus cavernosum was harvested for histopathology and molecular assessments.
RESULTS
Exposed penile length and weight significantly increased with age, especially between 4 and 8 weeks. Both the protein expression and lysyl oxidase activity in corpus cavernosum were the highest at 2 weeks; however, they quickly decreased with age and slowly declined after 8 weeks. Anti-lysyl oxidase significantly increased the penile length by 10.79% over controlled rats, -200 mm Hg + Anti-lysyl oxidase lengthened it by 14.05%, and -300 mm Hg + Anti-lysyl oxidase increased it by 19.84%. Anti-lysyl oxidase significantly reduced lysyl oxidase activity to decrease pyridinoline concentration; however, it did not change desmosine (P = .28), hydroxyproline (P = .14), and total elastin (P = .06) levels. Anti-lysyl oxidase with or without a vacuum device did not diminish erectile function or impair the normal microstructure of corpus cavernosum.
DISCUSSION AND CONCLUSION
The rats' penile growth peaks occurred between 4 and 8 weeks. Anti-lysyl oxidase with a vacuum device promoted penile lengthening by inhibiting pyridinoline production to induce tunica albuginea remodeling. The penile lengthening effect was more obvious in pubertal rats than the adult rats. None of the procedures decreased erectile function.
Topics: Animals; Arterial Pressure; Disease Models, Animal; Erectile Dysfunction; Male; Penile Erection; Penis; Protein-Lysine 6-Oxidase; Rats; Rats, Sprague-Dawley
PubMed: 32578359
DOI: 10.1111/andr.12845 -
American Journal of Respiratory and... Sep 2020
Topics: Aged; Biomarkers; Bronchiectasis; Cardiovascular Diseases; Cause of Death; Desmosine; Female; Humans; Male; Middle Aged
PubMed: 32402210
DOI: 10.1164/rccm.202002-0434LE -
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