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ERJ Open Research May 2023https://bit.ly/4015xZ9.
https://bit.ly/4015xZ9.
PubMed: 37377655
DOI: 10.1183/23120541.00078-2023 -
American Journal of Respiratory and... Aug 2019Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The... (Clinical Trial)
Clinical Trial
Augmentation therapy with intravenous AAT (alpha-1 antitrypsin) is the only specific therapy for individuals with pulmonary disease from AAT deficiency (AATD). The recommended standard dose (SD; 60 mg/kg/wk) elevates AAT trough serum levels to around 50% of normal; however, outside of slowing emphysema progression, its effects in other clinical outcomes have not been rigorously proven. To evaluate the biological effects of normalizing AAT trough levels with double-dose (DD) therapy (120 mg/kg/wk) in subjects with AATD already receiving SD therapy. Clinically stable subjects were evaluated after 4 weeks of SD therapy, followed by 4 weeks of DD therapy, and 4 weeks after return to SD therapy. At the end of each phase, BAL fluid (BALF) and plasma samples were obtained. DD therapy increased trough AAT levels to normal and, compared with SD therapy, reduced serine protease activity in BALF (elastase and cathepsin G), plasma elastase footprint (Aα-Val), and markers of elastin degradation (desmosine/isodesmosine) in BALF. DD therapy also further downregulated BALF ILs and cytokines including Jak-STAT (Janus kinases-signal transducer and activator of transcription proteins), TNFα (tumor necrosis factor-α), and T-cell receptor signaling pathways, cytokines involved in macrophage migration, eosinophil recruitment, humoral and adaptive immunity, neutrophil activation, and cachexia. On restarting SD after DD treatment, a possible carryover effect was seen for several biological markers. Subjects with AATD on SD augmentation therapy still exhibit inflammation, protease activity, and elastin degradation that can be further improved by normalizing AAT levels. Higher AAT dosing than currently recommended may lead to enhanced clinical benefits and should be explored further.Clinical trial registered with www.clinicaltrials.gov (NCT01669421).
Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Feasibility Studies; Female; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Trypsin Inhibitors; Young Adult; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency
PubMed: 30965011
DOI: 10.1164/rccm.201901-0010OC -
ERJ Open Research Apr 2019http://bit.ly/2VwZOcx.
http://bit.ly/2VwZOcx.
PubMed: 31218219
DOI: 10.1183/23120541.00250-2018 -
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 -
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 -
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 -
PloS One 2015The adaptor protein p66Shc regulates intracellular oxidant levels through the modulation of a forkhead-related transcription factor (FOXO3a). The genetic ablation of...
The adaptor protein p66Shc regulates intracellular oxidant levels through the modulation of a forkhead-related transcription factor (FOXO3a). The genetic ablation of p66Shc (p66Shc-/-) renders mice resistant to oxidative stress and p53-dependent apoptosis. We investigated whether p66Shc ablation in mice modifies lung cellular and molecular responses to cigarette smoke (CS) exposure. No differences between wild type (WT) and p66Shc-/- mice were observed in terms of inflammation and oxidant burden after acute CS exposure; however,p66Shc ablation modifies specific features of chronic inflammation induced by repeated exposure to CS. Unlike WT mice, p66Shc-/- mice did not develop emphysema, showing protection toward oxidative damage to DNA and apoptosis as revealed by a trivial 8-hydroxyguanosine staining and faint TUNEL and caspase-3 positivity on alveolar epithelial cells. Unexpectedly, CS exposure in p66Shc-/- mice resulted in respiratory bronchiolitis with fibrosis in surrounded alveoli. Respiratory bronchiolitis was characterized by peribronchiolar infiltrates of lymphocytes and histiocytes, accumulation of ageing pigmented macrophages within and around bronchioles, and peribronchiolar fibrosis. The blockage of apoptosis interferes with the macrophage "clearance" from alveolar spaces, favouring the accumulation of aging macrophages into alveoli and the progressive accumulation of iron pigment in long-lived senescent cells. The presence of areas of interstitial and alveolar fibrosis in peripheral parenchyma often accompanied the bronchiolar changes. Macrophages from smoking p66Shc-/- mice elaborate M2 cytokines (i.e., IL-4 and IL-13) and enzymes (i.e., chitinase and arginase I), which can promote TGF-beta expression, collagen deposition, and fibrosis in the surrounding areas. We demonstrate here that resistance to oxidative stress and p53-dependent apoptosis can modify tissue responses to CS caused by chronic inflammation without influencing early inflammatory response to CS exposure.
Topics: Animals; Apoptosis; Arginase; Bronchiolitis; Chitinases; Desmosine; Fibrosis; Hydroxyproline; Interleukin-13; Interleukin-4; Lung; Macrophages; Mice; Mice, Knockout; Oxidative Stress; Oxidoreductases; Pulmonary Emphysema; Shc Signaling Adaptor Proteins; Smoking; Src Homology 2 Domain-Containing, Transforming Protein 1; Transforming Growth Factor beta; Tumor Suppressor Protein p53
PubMed: 25790295
DOI: 10.1371/journal.pone.0119797 -
The European Respiratory Journal May 2016Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease...
Elastin degradation is a key feature of emphysema and may have a role in the pathogenesis of atherosclerosis associated with chronic obstructive pulmonary disease (COPD). Circulating desmosine is a specific biomarker of elastin degradation. We investigated the association between plasma desmosine (pDES) and emphysema severity/progression, coronary artery calcium score (CACS) and mortality.pDES was measured in 1177 COPD patients and 110 healthy control subjects from two independent cohorts. Emphysema was assessed on chest computed tomography scans. Aortic arterial stiffness was measured as the aortic-femoral pulse wave velocity.pDES was elevated in patients with cardiovascular disease (p<0.005) and correlated with age (rho=0.39, p<0.0005), CACS (rho=0.19, p<0.0005) modified Medical Research Council dyspnoea score (rho=0.15, p<0.0005), 6-min walking distance (rho=-0.17, p<0.0005) and body mass index, airflow obstruction, dyspnoea, exercise capacity index (rho=0.10, p<0.01), but not with emphysema, emphysema progression or forced expiratory volume in 1 s decline. pDES predicted all-cause mortality independently of several confounding factors (p<0.005). In an independent cohort of 186 patients with COPD and 110 control subjects, pDES levels were higher in COPD patients with cardiovascular disease and correlated with arterial stiffness (p<0.05).In COPD, excess elastin degradation relates to cardiovascular comorbidities, atherosclerosis, arterial stiffness, systemic inflammation and mortality, but not to emphysema or emphysema progression. pDES is a good biomarker of cardiovascular risk and mortality in COPD.
Topics: Adult; Aged; Biomarkers; Body Composition; Bronchodilator Agents; Calcinosis; Cardiovascular Diseases; Case-Control Studies; Coronary Vessels; Desmosine; Disease Progression; Elastin; Emphysema; Female; Forced Expiratory Volume; Humans; Inflammation; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pulse Wave Analysis; Respiratory Function Tests; Risk Factors; Smoking; Vascular Stiffness
PubMed: 27009168
DOI: 10.1183/13993003.01824-2015 -
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