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European Respiratory Review : An... Dec 2023Augmentation therapy with intravenous alpha-1 antitrypsin is the only specific treatment for alpha-1 antitrypsin deficiency (AATD)-associated emphysema. This treatment...
Augmentation therapy with intravenous alpha-1 antitrypsin is the only specific treatment for alpha-1 antitrypsin deficiency (AATD)-associated emphysema. This treatment has been available and remained basically unchanged for more than 35 years, but many questions persist regarding its indications, regimen of administration and efficacy. Because AATD is a rare disease, it has not been possible to conduct randomised, placebo-controlled trials that are adequately powered for the usual outcomes analysed in non-AATD-related COPD, such as lung function decline, exacerbations, symptoms or quality of life. New outcomes such as lung densitometry measured by computed tomography are more sensitive for identifying emphysema progression but are not widely accepted by regulatory agencies. In addition, clinical manifestations, severity and the natural history of lung disease associated with AATD are very heterogeneous, which means that individual prediction of prognosis is challenging. Therefore, the indication for augmentation is sometimes a dilemma between initiating treatment in individuals who may not develop significant lung disease or in whom disease will not progress and delaying it in patients who will otherwise rapidly and irreversibly progress.Other areas of debate are the possible indication for augmentation in patients with severe AATD and respiratory diseases other than emphysema, such as bronchiectasis or asthma, and the use of therapy after lung transplant in AATD patients. All these uncertainties imply that the indication for treatment must be personalised in expert reference centres after in-depth discussion of the pros and cons of augmentation with the patient.
Topics: Humans; Quality of Life; Treatment Outcome; alpha 1-Antitrypsin Deficiency; alpha 1-Antitrypsin; Pulmonary Emphysema; Lung; Pulmonary Disease, Chronic Obstructive
PubMed: 38056890
DOI: 10.1183/16000617.0170-2023 -
The Cochrane Database of Systematic... Oct 2016Lung volume reduction surgery (LVRS) performed to treat patients with severe diffuse emphysema was reintroduced in the nineties. Lung volume reduction surgery aims to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Lung volume reduction surgery (LVRS) performed to treat patients with severe diffuse emphysema was reintroduced in the nineties. Lung volume reduction surgery aims to resect damaged emphysematous lung tissue, thereby increasing elastic properties of the lung. This treatment is hypothesised to improve long-term daily functioning and quality of life, although it may be costly and may be associated with risks of morbidity and mortality. Ten years have passed since the last version of this review was prepared, prompting us to perform an update.
OBJECTIVES
The objective of this review was to gather all available evidence from randomised controlled trials comparing the effectiveness of lung volume reduction surgery (LVRS) versus non-surgical standard therapy in improving health outcomes for patients with severe diffuse emphysema. Secondary objectives included determining which subgroup of patients benefit from LVRS and for which patients LVRS is contraindicated, to establish the postoperative complications of LVRS and its morbidity and mortality, to determine which surgical approaches for LVRS are most effective and to calculate the cost-effectiveness of LVRS.
SEARCH METHODS
We identified RCTs by using the Cochrane Airways Group Chronic Obstructive Pulmonary Disease (COPD) register, in addition to the online clinical trials registers. Searches are current to April 2016.
SELECTION CRITERIA
We included RCTs that studied the safety and efficacy of LVRS in participants with diffuse emphysema. We excluded studies that investigated giant or bullous emphysema.
DATA COLLECTION AND ANALYSIS
Two independent review authors assessed trials for inclusion and extracted data. When possible, we combined data from more than one study in a meta-analysis using RevMan 5 software.
MAIN RESULTS
We identified two new studies (89 participants) in this updated review. A total of 11 studies (1760 participants) met the entry criteria of the review, one of which accounted for 68% of recruited participants. The quality of evidence ranged from low to moderate owing to an unclear risk of bias across many studies, lack of blinding and low participant numbers for some outcomes. Eight of the studies compared LVRS versus standard medical care, one compared two closure techniques (stapling vs laser ablation), one looked at the effect of buttressing the staple line on the effectiveness of LVRS and one compared traditional 'resectional' LVRS with a non-resectional surgical approach. Participants completed a mandatory course of pulmonary rehabilitation/physical training before the procedure commenced. Short-term mortality was higher for LVRS (odds ratio (OR) 6.16, 95% confidence interval (CI) 3.22 to 11.79; 1489 participants; five studies; moderate-quality evidence) than for control, but long-term mortality favoured LVRS (OR 0.76, 95% CI 0.61 to 0.95; 1280 participants; two studies; moderate-quality evidence). Participants identified post hoc as being at high risk of death from surgery were those with particularly impaired lung function, poor diffusing capacity and/or homogenous emphysema. Participants with upper lobe-predominant emphysema and low baseline exercise capacity showed the most favourable outcomes related to mortality, as investigators reported no significant differences in early mortality between participants treated with LVRS and those in the control group (OR 0.87, 95% CI 0.23 to 3.29; 290 participants; one study), as well as significantly lower mortality at the end of follow-up for LVRS compared with control (OR 0.45, 95% CI 0.26 to 0.78; 290 participants; one study). Trials in this review furthermore provided evidence of low to moderate quality showing that improvements in lung function parameters other than forced expiratory volume in one second (FEV), quality of life and exercise capacity were more likely with LVRS than with usual follow-up. Adverse events were more common with LVRS than with control, specifically the occurrence of (persistent) air leaks, pulmonary morbidity (e.g. pneumonia) and cardiovascular morbidity. Although LVRS leads to an increase in quality-adjusted life-years (QALYs), the procedure is relatively costly overall.
AUTHORS' CONCLUSIONS
Lung volume reduction surgery, an effective treatment for selected patients with severe emphysema, may lead to better health status and lung function outcomes, specifically for patients who have upper lobe-predominant emphysema with low exercise capacity, but the procedure is associated with risks of early mortality and adverse events.
Topics: Adult; Humans; Laser Therapy; Lung; Pneumonectomy; Pulmonary Emphysema; Randomized Controlled Trials as Topic; Surgical Stapling; Sutures
PubMed: 27739074
DOI: 10.1002/14651858.CD001001.pub3 -
International Journal of Chronic... 2020Evidence suggests that chronic obstructive pulmonary disease (COPD) symptoms and progression may differ between men and women. However, limited information is currently... (Review)
Review
PURPOSE
Evidence suggests that chronic obstructive pulmonary disease (COPD) symptoms and progression may differ between men and women. However, limited information is currently available on the pathophysiological and biological factors that may underlie these sex-related differences. The objective of this review is to systematically evaluate reports of potential sex-related differences, including genetic, pathophysiological, structural, and other biological factors, that may influence COPD development, manifestation, and progression in women.
PATIENTS AND METHODS
A PubMed literature search was conducted from inception until January 2020. Original reports of genetic, hormonal, and physiological differences, and biological influences that could contribute to COPD development, manifestation, and progression in women were included.
RESULTS
Overall, 491 articles were screened; 29 articles met the inclusion criteria. Results from this analysis demonstrated between-sex differences in inflammatory, immune, genetic, structural, and physiological factors in patients with COPD.
CONCLUSION
Various biological differences are observed between men and women with COPD including differences in inflammatory and metabolic pathways related to obesity and fat distribution, immune cell function and autophagy, extent and distribution of emphysema and airway wall remodeling. An enhanced understanding of these differences has the potential to broaden our understanding of how COPD develops and progresses, thereby providing an opportunity to ultimately improve diagnosis, treatment, and monitoring of COPD in both men and women.
Topics: Airway Remodeling; Emphysema; Female; Humans; Male; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema
PubMed: 32280209
DOI: 10.2147/COPD.S237228 -
American Journal of Respiratory Cell... Sep 2021Patients with pulmonary emphysema often develop locomotor muscle dysfunction, which is independently associated with disability and higher mortality in that population....
Patients with pulmonary emphysema often develop locomotor muscle dysfunction, which is independently associated with disability and higher mortality in that population. Muscle dysfunction entails reduced force generation capacity, which partially depends on fibers' oxidative potential, yet very little mechanistic research has focused on muscle respiration in pulmonary emphysema. Using a recently established animal model of pulmonary emphysema-driven skeletal muscle dysfunction, we found downregulation of SDHC (succinate dehydrogenase subunit C) in association with lower oxygen consumption and fatigue tolerance in locomotor muscles. Reduced SDH activity has been previously observed in muscles from patients with pulmonary emphysema, and we found that SDHC is required to support respiration in cultured muscle cells. Moreover, gain of SDH function in emphysema animals' muscles resulted in better oxygen consumption rate and fatigue tolerance. These changes correlated with a larger number of relatively more oxidative type 2-A and 2X fibers and a reduced amount of 2B fibers. Our data suggest that SDHC is a key regulator of respiration and fatigability in pulmonary emphysema-driven skeletal muscles, which could be impactful in developing strategies aimed at attenuating this comorbidity.
Topics: Animals; Disease Models, Animal; Fatigue; Membrane Proteins; Mice; Mice, Transgenic; Muscle, Skeletal; Oxygen Consumption; Pulmonary Emphysema
PubMed: 33909984
DOI: 10.1165/rcmb.2020-0551OC -
BMC Pulmonary Medicine Apr 2021Establishment of a mouse model is important for investigating the mechanism of chronic obstructive pulmonary disease (COPD). In this study, we observed and compared the... (Comparative Study)
Comparative Study
BACKGROUND
Establishment of a mouse model is important for investigating the mechanism of chronic obstructive pulmonary disease (COPD). In this study, we observed and compared the evolution of the pathology in two mouse models of COPD induced by cigarette smoke (CS) exposure alone or in combination with lipopolysaccharide (LPS).
METHODS
One hundred eight wild-type C57BL/6 mice were equally divided into three groups: the (1) control group, (2) CS-exposed group (CS group), and (3) CS + LPS-exposed group (CS + LPS group). The body weight of the mice was recorded, and noninvasive lung function tests were performed monthly. Inflammation was evaluated by counting the number of inflammatory cells in bronchoalveolar lavage fluid and measuring the expression of the IL-6 mRNA in mouse lung tissue. Changes in pathology were assessed by performing hematoxylin and eosin and Masson staining of lung tissue sections.
RESULTS
The two treatments induced emphysema and airway remodeling and decreased lung function. Emphysema was induced after 1 month of exposure to CS or CS + LPS, while airway remodeling was induced after 2 months of exposure to CS + LPS and 3 months of exposure to CS. Moreover, the mice in the CS + LPS group exhibited more severe inflammation and airway remodeling than the mice in the CS group, but the two treatments induced similar levels of emphysema.
CONCLUSION
Compared with the single CS exposure method, the CS + LPS exposure method is a more suitable model of COPD in airway remodeling research. Conversely, the CS exposure method is a more suitable model of COPD for emphysema research due to its simple operation.
Topics: Airway Remodeling; Animals; Cigarette Smoking; Disease Models, Animal; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema
PubMed: 33902528
DOI: 10.1186/s12890-021-01456-z -
Biomedicine & Pharmacotherapy =... Feb 2023Chronic obstructive pulmonary disease (COPD) has high morbidity and mortality, with no effective treatment at present. Emphysema, a major component of COPD, is a leading...
INTRODUCTION
Chronic obstructive pulmonary disease (COPD) has high morbidity and mortality, with no effective treatment at present. Emphysema, a major component of COPD, is a leading cause of human death worldwide. Fibroblast growth factor 2 (FGF2) is implicated in the pathogenesis of pulmonary emphysema and may play an important role in the lung repair process after injury, but concerns remain with respect to its effectiveness.
OBJECTIVE
In the present work, we sought to determine how the timing (early and late intervention) of sustained-release FGF2 system administration impacted its effectiveness on a porcine pancreatic elastase (PPE)-induced lung injury mouse model.
METHODS
To examine the early intervention efficiency of collagen-binding FGF2 (CBD-FGF2), mice received intratracheally nebulized CBD-FGF2 with concurrent intratracheal injection of PPE. To explore the late intervention effect, CBD-FGF2 was intratracheally aerosolized after PPE administration, and lungs were collected after CBD-FGF2 treatment for subsequent analysis.
RESULT
In response to PPE, mice had significantly increased alveolar diameter, collagen deposition and expression of inflammatory factors and decreased lung function indices and expression of alveolar epithelium markers. Our results indicate that CBD-FGF2 administration was able to prevent and repair elastase-induced lung injury partly through the suppression of the inflammatory response and recovery of the alveolar epithelium. The early use of CBD-FGF2 for the prevention of PPE-induced emphysema showed better results than late therapeutic administration against established emphysema.
CONCLUSION
These data provide insight regarding the prospective role of a drug-based option (CBD-FGF2) for preventing and curing emphysema.
Topics: Humans; Mice; Swine; Animals; Pancreatic Elastase; Fibroblast Growth Factor 2; Lung Injury; Lung; Pulmonary Emphysema; Pulmonary Disease, Chronic Obstructive; Emphysema; Collagen; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36584430
DOI: 10.1016/j.biopha.2022.114147 -
Journal of Applied Physiology... Jan 2020Patients with chronic obstructive pulmonary disease (COPD) usually develop skeletal muscle dysfunction, which represents a major comorbidity in these patients and is...
Patients with chronic obstructive pulmonary disease (COPD) usually develop skeletal muscle dysfunction, which represents a major comorbidity in these patients and is strongly associated with mortality and other poor outcomes. Although clinical data indicates that accelerated protein degradation and metabolic disruption are common associations of muscle dysfunction in COPD, there is very limited data on the mechanisms regulating the process, in part, due to the lack of research performed on a validated animal model of pulmonary emphysema. This model deficiency complicates the translational value of data generated with highly reductionist settings. Here, we use an established transgenic animal model of COPD based on inducible IL-13-driven pulmonary emphysema (IL-13) to interrogate the mechanisms of skeletal muscle dysfunction. Skeletal muscles from these emphysematous mice develop most features present in COPD patients, including atrophy, decreased oxygen consumption, and reduced force-generation capacity. Analysis of muscle proteome indicates downregulation of succinate dehydrogenase C (SDH-C), which correlates with reduced enzymatic activity, also consistent with previous clinical observations. Ontology terms identified with human data, such as ATP binding/bioenergetics are also downregulated in this animal's skeletal muscles. Moreover, chronic exercise can partially restore muscle mass, metabolic and force-generation capacity, and SDH activity in COPD mice. We conclude that this animal model of COPD/emphysema is an adequate platform to further investigate mechanisms of muscle dysfunction in this setting and demonstrates multiple approaches that can be used to address specific mechanisms regulating this process. Skeletal muscle dysfunction is a relevant comorbidity in patients with chronic obstructive pulmonary disease (COPD). Mechanistic research in the area has so far been accomplished with models based on specific exposures to otherwise healthy animals, and no investigation using an established and validated animal model of COPD has been accomplished. We present an animal model of COPD that was previously shown to recapitulate pulmonary functional and histologic features present in patients with COPD, and demonstrates most of the features present in patients with pulmonary emphysema-associated muscle dysfunction, which we proposed as an adequate tool to develop mechanistic research in the area.
Topics: Animals; Female; Interleukin-13; Male; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Atrophy; Physical Conditioning, Animal; Pulmonary Emphysema; Respiratory Function Tests
PubMed: 31774358
DOI: 10.1152/japplphysiol.00627.2019 -
Medical Principles and Practice :... 2021The red cell distribution width (RDW) is an inexpensive, readily available prognostic indicator of several diseases. RDW has been assessed as a prognostic biomarker in...
OBJECTIVE
The red cell distribution width (RDW) is an inexpensive, readily available prognostic indicator of several diseases. RDW has been assessed as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) in only one study; furthermore, the relationship between the RDW and combined pulmonary fibrosis emphysema (CPFE) has yet to be reported.
SUBJECTS AND METHODS
This single-center study was conducted between January 2015 and December 2018 in the Atatürk Chest Diseases and Chest Surgery Education and Research Hospital. Baseline characteristics, laboratory results, and survival status of patients were recorded.
RESULTS
The RDW value was significantly higher in the CPFE group than in the IPF group (median [IQR 25-75]; 16.8 [15.5-19] vs. 15.3 [13.7-16.8], p = 0.028). High RDW values were correlated with carbon monoxide diffusion capacity (DLCO) (r: -0.653 p = 0.001), 6-minute walking test (6MWT) distance (r: -0.361 p = 0.017), arterial partial oxygen pressure (PaO2) (r: -0.692 p < 0.001), and systolic pulmonary arterial pressure (SPAP) (r: 0.349 p = 0.022) in patients with fibrotic lung disease. The RDW value was significantly higher in the exitus group than in the survivors (median [IQR 25-75]; 18.4 [15.4-19] vs. 15.2 [13.5-17.2], p = 0.016). A univariate Cox regression analysis identified DLCO, SPAP, PaO2, and RDW as potential covariates of mortality. In a multivariate analysis, the DLCO (HR 1.21, 95% CI 1.11-1.47, p = 0.012) and RDW level (HR 1.65, 95% CI 1.09-2.47, p = 0.023) remained independent predictors of mortality.
CONCLUSION
High RDW values appear to be a simple prognostic factor in patients with IPF or CPFE.
Topics: Age Factors; Aged; Body Mass Index; Diagnosis, Differential; Erythrocyte Indices; Hematologic Tests; Humans; Idiopathic Pulmonary Fibrosis; Middle Aged; Prognosis; Pulmonary Emphysema; Respiratory Function Tests; Sex Factors
PubMed: 32841950
DOI: 10.1159/000511106 -
Cells Dec 2022Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at...
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet.
AIM
we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice.
METHODS
four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery.
RESULTS
iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus.
CONCLUSION
taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard.
Topics: Mice; Swine; Animals; Pancreatic Elastase; Nitric Oxide Synthase Type II; Pulmonary Emphysema; Emphysema; Epithelium
PubMed: 36611917
DOI: 10.3390/cells12010125 -
Jornal Brasileiro de Pneumologia :... 2017
Topics: Animals; Disease Models, Animal; Humans; Leukocyte Elastase; Pulmonary Emphysema; Reproducibility of Results; Tobacco Smoke Pollution; Tomography, X-Ray Computed
PubMed: 28538771
DOI: 10.1590/S1806-37562017000200002