Chronic Obstructive Pulmonary Disease Emphysema Research Articles

Twenty-year survival following lung transplantation.

Lung transplantation median survival has seen improvements due to recognition of short-term survival factors but continues to trail behind other solid organs due to limited understanding of long-term survivorship. Given the creation of the United Network for Organ Sharing (UNOS) database in 1986, it was difficult to accrue data on long-term survivors until recently. This study characterizes factors impacting lung transplant survival beyond 20 years, conditional to 1-year survival. Lung transplant recipients listed in UNOS from 1987 to 2002 who survived to 1 post-transplant year were reviewed. Kaplan-Meier and adjusted Cox regression analyses were performed at 20 and 10 years to identify risk factors associated with long-term outcomes independent of their short-term effects. A total of 6,172 recipients were analyzed, including 472 (7.6%) recipients who lived 20+ years. Factors associated with increased likelihood of 20-year survival were female-to-female gender match, recipient age 25-44, waitlist time >1 year, human leukocyte antigen (HLA) mismatch level 3, and donor cause of death: head trauma. Factors associated with decreased 20-year survival included recipient age ≥55, chronic obstructive pulmonary disease/emphysema (COPD/E) diagnosis, donor smoking history >20 pack-years, unilateral transplant, blood groups O&AB, recipient glomerular filtration rate (GFR) <10 mL/min, and donor GFR 20-29 mL/min. This is the first study identifying factors associated with multiple-decade survival following lung transplant in the United States. Despite its challenges, long-term survival is possible and more likely in younger females in good waitlist condition without COPD/E who receive a bilateral allograft from a non-smoking, gender-matched donor of minimal HLA mismatch. Further analysis of the molecular and immunologic implications of these conditions are warranted.

Screening and identification of tissue-infiltrating immune cells and genes for patients with emphysema phenotype of COPD

ObjectiveTo study the tissue-infiltrating immune cells of the emphysema phenotype of chronic obstructive pulmonary disease (COPD) and find the molecular mechanism related to the development of emphysema to offer potential targets for more precise treatment of patients with COPD.MethodsCombined analyses of COPD emphysema phenotype lung tissue-related datasets, GSE47460 and GSE1122, were performed. CIBERSORT was used to assess the distribution of tissue-infiltrating immune cells. Weighted gene co-expression network analysis (WGCNA) was used to select immune key genes closely related to clinical features. Rt-qPCR experiments were used for the validation of key genes. Emphysema risk prediction models were constructed by logistic regression analysis and a nomogram was developed.ResultsIn this study, three immune cells significantly associated with clinical features of emphysema (FEV1 post-bronchodilator % predicted, GOLD Stage, and DLCO) were found. The proportion of neutrophils (p=0.025) infiltrating in the emphysema phenotype was significantly increased compared with the non-emphysema phenotype, while the proportions of M2 macrophages (p=0.004) and resting mast cells (p=0.01) were significantly decreased. Five immune-related differentially expressed genes (DEGs) were found. WGCNA and clinical lung tissue validation of patients with emphysema phenotype were performed to further screen immune-related genes closely related to clinical features. A key gene (SERPINA3) was selected and included in the emphysema risk prediction model. Compared with the traditional clinical prediction model (AUC=0.923), the combined prediction model, including SERPINA3 and resting mast cells (AUC=0.941), had better discrimination power and higher net benefit.ConclusionThis study comprehensively analyzed the tissue-infiltrating immune cells significantly associated with emphysema phenotype, including M2 macrophages, neutrophils, and resting mast cells, and identified SERPINA3 as a key immune-related gene.

Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.

SummaryBackgroundAlpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity.MethodsThe plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis.FindingsIn PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes.InterpretationUsing SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD.FundingThis work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

Phenotype of Chronic Obstructive Pulmonary Disease Based on Computed Tomography-Defined Underlying Pathology.

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease. Not all patients with COPD respond to available drugs. Identifying respondents to therapy is critical to delivering the most appropriate treatment and avoiding unnecessary medication. Recognition of individual patients’ dominant characteristics by phenotype is a useful tool to better understand their disease and tailor treatment accordingly. To look for a suitable phenotype, it is important to understand what makes COPD complex and heterogeneous. The pathology of COPD includes small airway disease and/or emphysema. Thus, COPD is not a single disease entity. In addition, there are two types (panlobular and centrilobular) of emphysema in COPD. The coexistence of different pathological subtypes could be the reason for the complexity and heterogeneity of COPD. Thus, it is necessary to look for the phenotype based on the difference in the underlying pathology. Review of the literature has shown that clinical manifestation and therapeutic response to pharmacological therapy are different depending on the presence of computed tomography–defined airway wall thickening in COPD patients. Defining the phenotype of COPD based on the underlying pathology is encouraging as most clinical manifestations can be distinguished by the presence of increased airway wall thickness. Pharmacological therapy has shown significant effect on COPD with airway wall thickening. However, it has limited use in COPD without an airway disease. The phenotype of COPD based on the underlying pathology can be a useful tool to better understand the disease and adjust treatment accordingly.

Early Diagnosis and Real-Time Monitoring of Regional Lung Function Changes to Prevent Chronic Obstructive Pulmonary Disease Progression to Severe Emphysema.

First- and second-hand exposure to smoke or air pollutants is the primary cause of chronic obstructive pulmonary disease (COPD) pathogenesis, where genetic and age-related factors predispose the subject to the initiation and progression of obstructive lung disease. Briefly, airway inflammation, specifically bronchitis, initiates the lung disease, leading to difficulty in breathing (dyspnea) and coughing as initial symptoms, followed by air trapping and inhibition of the flow of air into the lungs due to damage to the alveoli (emphysema). In addition, mucus obstruction and impaired lung clearance mechanisms lead to recurring acute exacerbations causing progressive decline in lung function, eventually requiring lung transplant and other lifesaving interventions to prevent mortality. It is noteworthy that COPD is much more common in the population than currently diagnosed, as only 16 million adult Americans were reported to be diagnosed with COPD as of 2018, although an additional 14 million American adults were estimated to be suffering from COPD but undiagnosed by the current standard of care (SOC) diagnostic, namely the spirometry-based pulmonary function test (PFT). Thus, the main issue driving the adverse disease outcome and significant mortality for COPD is lack of timely diagnosis in the early stages of the disease. The current treatment regime for COPD emphysema is most effective when implemented early, on COPD onset, where alleviating symptoms and exacerbations with timely intervention(s) can prevent steep lung function decline(s) and disease progression to severe emphysema. Therefore, the key to efficiently combatting COPD relies on early detection. Thus, it is important to detect early regional pulmonary function and structural changes to monitor modest disease progression for implementing timely interventions and effectively eliminating emphysema progression. Currently, COPD diagnosis involves using techniques such as COPD screening questionnaires, PFT, arterial blood gas analysis, and/or lung imaging, but these modalities are limited in their capability for early diagnosis and real-time disease monitoring of regional lung function changes. Hence, promising emerging techniques, such as X-ray phase contrast, photoacoustic tomography, ultrasound computed tomography, electrical impedance tomography, the forced oscillation technique, and the impulse oscillometry system powered by robust artificial intelligence and machine learning analysis capability are emerging as novel solutions for early detection and real time monitoring of COPD progression for timely intervention. We discuss here the scope, risks, and limitations of current SOC and emerging COPD diagnostics, with perspective on novel diagnostics providing real time regional lung function monitoring, and predicting exacerbation and/or disease onset for prognosis-based timely intervention(s) to limit COPD–emphysema progression.

Determinants of Pulmonary Emphysema Severity in Taiwanese Patients with Chronic Obstructive Pulmonary Disease: An Integrated Epigenomic and Air Pollutant Analysis.

Background: Chronic obstructive pulmonary disease (COPD) continues to pose a therapeutic challenge. This may be connected with its nosological heterogeneity, broad symptomatology spectrum, varying disease course, and therapy response. The last three decades has been characterized by increased understanding of the pathobiology of COPD, with associated advances in diagnostic and therapeutic modalities; however, the identification of pathognomonic biomarkers that determine disease severity, affect disease course, predict clinical outcome, and inform therapeutic strategy remains a work in progress. Objectives: Hypothesizing that a multi-variable model rather than single variable model may be more pathognomonic of COPD emphysema (COPD-E), the present study explored for disease-associated determinants of disease severity, and treatment success in Taiwanese patients with COPD-E. Methods: The present single-center, prospective, non-randomized study enrolled 125 patients with COPD and 43 healthy subjects between March 2015 and February 2021. Adopting a multimodal approach, including bioinformatics-aided analyses and geospatial modeling, we performed an integrated analysis of selected epigenetic, clinicopathological, geospatial, and air pollutant variables, coupled with correlative analyses of time-phased changes in pulmonary function indices and COPD-E severity. Results: Our COPD cohort consisted of 10 non-, 57 current-, and 58 ex-smokers (median age = 69 ± 7.76 years). Based on the percentages of low attenuation area below − 950 Hounsfield units (%LAA-950insp), 36 had mild or no emphysema (%LAA-950insp < 6), 22 were moderate emphysema cases (6 ≤ %LAA-950insp < 14), and 9 presented with severe emphysema (%LAA-950insp ≥ 14). We found that BMI, lnc-IL7R, PM2.5, PM10, and SO2 were differentially associated with disease severity, and are highly-specific predictors of COPD progression. Per geospatial levels, areas with high BMI and lnc-IL7R but low PM2.5, PM10, and SO2 were associated with fewer and ameliorated COPD cases, while high PM2.5, PM10, and SO2 but low BMI and lnc-IL7R characterized places with more COPD cases and indicated exacerbation. The prediction pentad effectively differentiates patients with mild/no COPD from moderate/severe COPD cases, (mean AUC = 0.714) and exhibited very high stratification precision (mean AUC = 0.939). Conclusion: Combined BMI, lnc-IL7R, PM2.5, PM10, and SO2 levels are optimal classifiers for accurate patient stratification and management triage for COPD in Taiwan. Low BMI, and lnc-IL7R, with concomitant high PM2.5, PM10, and SO2 levels is pathognomonic of exacerbated/aggravated COPD in Taiwan.

Association Between Air Pollution and Lung Lobar Emphysema in COPD.

The development of emphysema has been linked to air pollution; however, the association of air pollution with the extent of lobar emphysema remains unclear. This study examined the association of particulate matter <2.5 μm in aerodynamic diameters (PM2.5) (≤2.5 μm), nitrogen dioxide (NO2), and ozone (O3) level of exposure with the presence of emphysema in 86 patients with chronic obstructive pulmonary disease (COPD). Exposure to the air pollution estimated using the land-use regression model was associated with lung function, BODE (a body mass index, degree of obstruction, dyspnea severity, and exercise capacity index) quartiles, and emphysema measured as low-attenuation areas on high-resolution CT (HR-CT) lung scans. Using paraseptal emphysema as the reference group, we observed that a 1 ppb increase in O3 was associated with a 1.798-fold increased crude odds ratio of panlobular emphysema (p < 0.05). We observed that PM2.5 was associated with BODE quartiles, modified Medical Research Council (mMRC) dyspnea score, and exercise capacity (all p < 0.05). We found that PM2.5, NO2, and O3 were associated with an increased degree of upper lobe emphysema and lower lobe emphysema (all p < 0.05). Furthermore, we observed that an increase in PM2.5, NO2, and O3 was associated with greater increases in upper lobe emphysema than in lower lobe emphysema. In conclusion, exposure to O3 can be associated with a higher risk of panlobular emphysema than paraseptal emphysema in patients with COPD. Emphysema severity in lung lobes, especially the upper lobes, may be linked to air pollution exposure in COPD.

Prediction of lung emphysema in COPD by spirometry and clinical symptoms: results from COSYCONET

BackgroundLung emphysema is an important phenotype of chronic obstructive pulmonary disease (COPD), and CT scanning is strongly recommended to establish the diagnosis. This study aimed to identify criteria by which physicians with limited technical resources can improve the diagnosis of emphysema.MethodsWe studied 436 COPD patients with prospective CT scans from the COSYCONET cohort. All items of the COPD Assessment Test (CAT) and the St George’s Respiratory Questionnaire (SGRQ), the modified Medical Research Council (mMRC) scale, as well as data from spirometry and CO diffusing capacity, were used to construct binary decision trees. The importance of parameters was checked by the Random Forest and AdaBoost machine learning algorithms.ResultsWhen relying on questionnaires only, items CAT 1 & 7 and SGRQ 8 & 12 sub-item 3 were most important for the emphysema- versus airway-dominated phenotype, and among the spirometric measures FEV1/FVC. The combination of CAT item 1 (≤ 2) with mMRC (> 1) and FEV1/FVC, could raise the odds for emphysema by factor 7.7. About 50% of patients showed combinations of values that did not markedly alter the likelihood for the phenotypes, and these could be easily identified in the trees. Inclusion of CO diffusing capacity revealed the transfer coefficient as dominant measure. The results of machine learning were consistent with those of the single trees.ConclusionsSelected items (cough, sleep, breathlessness, chest condition, slow walking) from comprehensive COPD questionnaires in combination with FEV1/FVC could raise or lower the likelihood for lung emphysema in patients with COPD. The simple, parsimonious approach proposed by us might help if diagnostic resources regarding respiratory diseases are limited.Trial registration ClinicalTrials.gov, Identifier: NCT01245933, registered 18 November 2010, https://clinicaltrials.gov/ct2/show/record/NCT01245933.

THE PECULIARITIES OF THE COMBINED COURSE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND CORONARY HEART DISEASE (LITERATURE REVIEW)

The aim – to analyze the literature data sources concerning the peculiarities of thecombined course of chronic obstructive pulmonary disease (COPD) and coronaryheart disease (CHD), taking into account the endothelial dysfunction of systemicinflammation and oxidative stress.Conclusions. The main mechanisms involved in the progression of the combinedcourse of chronic obstructive pulmonary disease and coronary heart disease are theendothelial dysfunction, the systemic inflammation and desynchronosis. The pleiotropiceffects and diverce molecular interactions of sirtuins have distinct physiological effects,such as preventing the development and progression of emphysema in COPD and avoiding the progression of myocardical hypertrophy and heart failure. The researchof intermolecular interactions with the help of Sirtuin is a promising area for findingnew effective diagnostic and prognostic criteria and therapeutic strategies for COPDand CVD.

PARC/CCL18 is Associated with Inflammation, Emphysema Severity and Application of Inhaled Corticosteroids in Hospitalized COPD Patients.

BackgroundPulmonary and activation-regulated chemokine (PARC) also named CC-chemokine ligand 18 (CCL18) is a lung-predominant inflammatory protein that is found in serum. The relationship of PARC/CCL18 with the chronic obstructive pulmonary disease (COPD) is not fully understood. The aim of the present study is to analyze the expression of PARC/CCL18 in COPD.MethodsNinety-eight hospitalized COPD patients and 60 healthy volunteers from January 2019 to December 2019 were recruited in this retrospective study. Gender, age, height, weight, disease duration, smoking status, blood cell classification and count, length of hospital stay (LOS), symptom score, including COPD Assessment Test (CAT) score, modified British Medical Research Council (mMRC) score, lung function and therapy were recorded and serum PARC/CCL18 was analyzed by ELISA. The correlation between symptom score, blood cell classification and count, CRP, lung function parameters and serum levels of PARC/CCL18 and ROC curves of PARC/CCL18 levels and inhaled corticosteroids (ICS) were accessed.ResultsIt was found that serum PARC/CCL18 level in hospitalized COPD population was significantly higher than that in healthy people (p=0.003). COPD patients with emphysema had significantly higher serum level of PARC/CCL18 than those without emphysema (p=0.049). Total lung capacity (TLC) and residual volume (RV)/TLC had positive correlation with serum level of PARC/CCL18 (p=0.001, 0.020, respectively). Furthermore, serum PARC/CCL18 level was predictive for the application ICS (p=0.003) and related to C-reactive protein (p <0.0001) in hospitalized COPD patients.ConclusionPARC/CCL18 is associated with the severity of inflammation and emphysema in COPD. Furthermore, PARC/CCL18 is a predictor of ICS application in the treatment of hospitalized COPD patients.

Circulating miR-1246 in the Progression of Chronic Obstructive Pulmonary Disease (COPD) in Patients from the BODE Cohort.

BackgroundCOPD is characterized by a persistent inflammatory response, especially against cigarette smoke. COPD patients may develop varying degrees of emphysematous destruction of the lungs. A pathophysiological role for miRNAs in COPD has been suggested in several studies. We examined changes in microRNAs expression profile during 10 years follow-up in relation to COPD progression.MethodsClinical and lung function parameters were registered from every subject included in the study. miRNAs expression was determined in 14 serum samples from 7 patients in two moments (4 smokers with COPD (BODE cohort) and 3 smokers without COPD) by next generation sequencing (NGS) at baseline and after 10 years follow-up. A validation study was performed by qPCR in 20 patients with COPD (13 emphysema-diagnosed by CTscan) and 10 smoker controls at baseline and after 10 years follow-up. hsa-miRNA-20a-5p and hsa-let-7d-5p were used as endogenous controls.ResultsA total of 198 miRNAs (≥10TPM) were identified by NGS. Between these, hsa-miR-1246 was found significantly downregulated in COPD patients after 10 years when compared to baseline (p<0.0001, FDR=0.05). Seventy-five percent of these patients had an emphysema diagnose. In the validation analysis, when analyzed longitudinally, hsa-miR-1246 was significantly downregulated in COPD patients with emphysema after 10 years (p= 0.019). However, no association was found between the expression of miR-1246 and any other lung function parameters (FEV1, PaO2, DLCO, IC/TLC) within the follow-up period. GO and KEGG enrichment analysis revealed miR-1246 to be associated with target genes in several pathways involved in COPD/emphysema development.ConclusionOur findings suggest that hsa-miR-1246 may act as a biomarker of emphysema in COPD. Functional analysis is guaranteed to elucidate its role in COPD.

Is serum iron responsive protein-2 level associated with pulmonary functions and frequent exacerbator phenotype in COPD?

Chronic Obstructive Pulmonary Disease (COPD) exacerbations contribute to the overall severity in individual patients because they are associated with airway inflammation, pulmonary function loss, decreased quality of life and increased mortality. Although, identifying frequent exacerbator patients is important due to severe outcomes associated with frequent exacerbator phenotype in COPD patients there is no single biomarker which can differentiate this phenotype. Iron responding protein-2 (IRP2) is the protein product of IREB2 gene, which is a COPD susceptibility gene that regulates cellular iron homeostasis and has a key role in hypoxic conditions. Previous research indicates that IREB2 expression in lung tissue is associated with spirometric measurements and emphysema in COPD. In this study, our aim was to investigate whether serum IRP2 levels were associated with frequent exacerbator phenotype, to evaluate whether IRP2 levels in serum are associated with pulmonary functions and selected systemic inflammation biomarkers. Designed as a single tertiary care center based, crosssectional study, included high risk (GOLD C, D) COPD patients who admitted to outpatient clinic consecutively between December 2015 and July 2016. The study included 80 COPD patients. Serum IRP2 levels were negatively correlated with FEV1 ml (r= -0.25, p= 0.02) and body weight (r= -0.35, p= 0.002) but not with markers of systemic inflammation. COPD patients with at least one exacerbation history in the last year tended to have higher IRP2 levels than patients without any exacerbation [12.3 (IQR 25-75: 10.4- 17.1) vs 10.5 (IQR 25-75: 8.8-18.5), p= 0.06]. Serum IRP2 level is significantly correlated with FEV1 mL but not with FEV1 % predicted and cannot be used to differentiate frequent exacer bator patients. Although IREB2 gene expressions in lung tissue and bronchoalveolar lavage results have significant associations with emphysema and FEV1/FVC, FEV1 %predicted in COPD patients, our results suggests serum IRP2 level is not as promising.

Dexamethasone and losartan combination treatment protected cigarette smoke-induced COPD in rats.

Chronic Obstructive Pulmonary Disease (COPD) is a dangerous prevalent smoking-related disease characterized by abnormal inflammation and oxidative stress and expected to be the third cause of death in the world next decade. Corticosteroids have low effects in decreasing numbers of inflammatory mediators specifically in long-term use. Our study designed to investigate the possible protective effects of combined dexamethasone (Dex) (2mg/kg) and losartan (Los) (30mg/kg angiotensin receptor blocker, it possesses antioxidant and anti-inflammatory properties in lung injury in mice) against cigarette -smoke (CS) induced COPD in rats compared with dexamethasone and losartan. Male Sprague Dawley rats (N = 40) divided into five groups (n = 8): control group, CS group, Dex group, Los group, and Dex +Los group. COPD induced in rats by CS exposure twice daily for 10 weeks. After the specified treatment period, bronchoalveolar lavage fluid (BALF) and lung tissue were collected for measurement of SOD, NO, MDA, ICAM-, MMP-9, CRP, NF-κB and histopathology scoring. Our results indicated that Los+Dex significantly prevent CS-induced COPD emphysema, congested alveoli, and elevation of lung injury parameters in BALF. They also showed a significant decrease in MDA, ICAM-1, MMP-9, CRP, and NF-κB and a significant increase in SOD and NO. In conclusion, adding Los to Dex potentiating their activity in inhibition the progression of COPD based on its activity on oxidative stress, inflammation, and NF-κB protein expression.

Endothelium-related and neuro-mediated mechanisms of emphysema development in chronic obstructive pulmonary disease

Emphysema is one of the main manifestations of chronic obstructive pulmonary disease (COPD), and smoking is one of the most significant risk factors. The results of studies in humans and animals show the vascular endothelium initiates and modulates the main pathological processes in COPD and smoking is an important factor initiating, developing and persisting inflammation and remodeling of blood vessels and tissues, including the destruction of small respiratory tracts with the development of lung tissue destruction and emphysema. The latest studies describe mechanisms not just associated with the endothelium, but specific neuro-mediated mechanisms. There is reason to believe that neuro-mediated and neuro-similar mechanisms associated and not related to endothelial dysfunction may play the significant role in the pathogenesis of COPD and emphysema formation. Information about components and mechanisms of neurogenic inflammation in emphysema development is fragmentary and not systematized in the literature. It is described that long-term tobacco smoking can initiate processes not only of cells and tissues damage, but also become a trigger for excessive release of neurotransmitters, which entails whole cascades of adverse reactions that have an effect on emphysema formation. With prolonged and/or intensive stimulation of sensor fibers, excessive release of neuropeptides is accompanied by a number of plastic and destructive processes due to a cascade of pathological reactions of neurogenic inflammation, the main participants of which are classical neuropeptides and their receptors. The most important consequences can be the maintenance and stagnation of chronic inflammation, activation of the mechanisms of destruction and remodeling, inadequate repair processes in response to damage, resulting in irreversible loss of lung tissue. For future research, there is interest to evaluate the possibilities of therapeutic and prophylactic effects on neuro-mediated mechanisms of endothelial dysfunction and damage emphysema in COPD and smoking development.

Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice

Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool. Chronic obstructive pulmonary disease (COPD) displays hallmarks of senescence, including a diminished stem cell population. DNA damage from cigarette smoke (CS) induces senescence via the p16 pathway. This study evaluated the contribution of p16 to CS-associated lung pathologies. p16 expression was prominent in human COPD lungs compared with normal subjects. CS induces impaired pulmonary function, emphysema, and increased alveolar epithelial cell (AECII) senescence in wild-type mice, whereas CS-exposed p16−/− mice exhibit normal pulmonary function, reduced emphysema, diminished AECII senescence, and increased pro-growth IGF1 signaling, suggesting that improved lung function in p16−/− mice was due to increased alveolar progenitor cell proliferation. In conclusion, our study suggests that targeting senescence may facilitate alveolar regeneration in COPD emphysema by promoting IGF1 proliferative signaling.

Prediction of postoperative pulmonary complications in lung cancer surgery: Is proportion of emphysema important?

OBJECTIVE: Preoperative evaluation in thoracic surgery is highly important to determine surgical suitability, estimate postoperative pulmonary complications, and for patient follow-up. However, there is neither a definite explanation about the possible complications nor a gold standard method. MATERIALS AND METHODS: In this study, 297 patients undergoing anatomic lung resection for primary lung carcinoma were retrospectively evaluated. To form a homogeneous group, all factors that increase the rate of pulmonary complication were excluded except emphysema. Patients who did not meet these criteria were removed from the study. The study continued with 104 other patients. This patient subgroup was divided into groups according to Goddard Classification– Score (GdCS). The correlation between GdCS and other variables was statistically investigated. RESULTS: According to the GdCS of 104 patients, the patient distribution was as follows: 10 patients (9.6%) were G0, 28 patients (26.9%) were G1, 42 patients (40.4%) were G2, 22 patients (21.2%) were G3, and 2 patients (1.9%) were G4. Thirty-five (33.6%) of 104 patients had a pulmonary complication during the postoperative follow-up. The average drainage time was longer for higher GdCS scores, and the rate of exposition to a pulmonary complication was higher in the patients with increased GdCS. CONCLUSION: In view of these findings, Goddard's scoring for chronic obstructive pulmonary disease-emphysema patients was considered likely to be an indicative parameter in the preoperative evaluation and postoperative follow-up of thoracic surgery patients.

Augmentation of S-Nitrosoglutathione Controls Cigarette Smoke-Induced Inflammatory-Oxidative Stress and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis by Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function.

Cigarette smoke (CS)-mediated acquired cystic fibrosis transmembrane conductance regulator (CFTR)-dysfunction, autophagy-impairment, and resulting inflammatory-oxidative/nitrosative stress leads to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Moreover, nitric oxide (NO) signaling regulates lung function decline, and low serum NO levels that correlates with COPD severity. Hence, we aim to evaluate here the effects and mechanism(s) of S-nitrosoglutathione (GSNO) augmentation in regulating inflammatory-oxidative stress and COPD-emphysema pathogenesis. Our data shows that cystic fibrosis transmembrane conductance regulator (CFTR) colocalizes with aggresome bodies in the lungs of COPD subjects with increasing emphysema severity (Global Initiative for Chronic Obstructive Lung Disease [GOLD] I - IV) compared to nonemphysema controls (GOLD 0). We further demonstrate that treatment with GSNO or S-nitrosoglutathione reductase (GSNOR)-inhibitor (N6022) significantly inhibits cigarette smoke extract (CSE; 5%)-induced decrease in membrane CFTR expression by rescuing it from ubiquitin (Ub)-positive aggresome bodies (p < 0.05). Moreover, GSNO restoration significantly (p < 0.05) decreases CSE-induced reactive oxygen species (ROS) activation and autophagy impairment (decreased accumulation of ubiquitinated proteins in the insoluble protein fractions and restoration of autophagy flux). In addition, GSNO augmentation inhibits protein misfolding as CSE-induced colocalization of ubiquitinated proteins and LC3B (in autophagy bodies) is significantly reduced by GSNO/N6022 treatment. We verified using the preclinical COPD-emphysema murine model that chronic CS (Ch-CS)-induced inflammation (interleukin [IL]-6/IL-1β levels), aggresome formation (perinuclear coexpression/colocalization of ubiquitinated proteins [Ub] and p62 [impaired autophagy marker], and CFTR), oxidative/nitrosative stress (p-Nrf2, inducible nitric oxide synthase [iNOS], and 3-nitrotyrosine expression), apoptosis (caspase-3/7 activity), and alveolar airspace enlargement (Lm) are significantly (p < 0.05) alleviated by augmenting airway GSNO levels. As a proof of concept, we demonstrate that GSNO augmentation suppresses Ch-CS-induced perinuclear CFTR protein accumulation (p < 0.05), which restores both acquired CFTR dysfunction and autophagy impairment, seen in COPD-emphysema subjects. GSNO augmentation alleviates CS-induced acquired CFTR dysfunction and resulting autophagy impairment. Overall, we found that augmenting GSNO levels controls COPD-emphysema pathogenesis by reducing CS-induced acquired CFTR dysfunction and resulting autophagy impairment and chronic inflammatory-oxidative stress. Antioxid. Redox Signal. 27, 433-451.

Master Autophagy Regulator Transcription Factor EB Regulates Cigarette Smoke-Induced Autophagy Impairment and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis.

Recent studies have shown that cigarette smoke (CS)-induced oxidative stress impairs autophagy, resulting in aggresome-formation that correlates with severity of chronic obstructive pulmonary disease (COPD)-emphysema, although the specific step in autophagy pathway that is impaired is unknown. Hence, in this study, we aimed to evaluate the role of master autophagy transcription factor EB (TFEB) in CS-induced COPD-emphysema pathogenesis. We first observed that TFEB accumulates in perinuclear spaces as aggresome-bodies in COPD lung tissues of tobacco smokers and severe emphysema subjects, compared with non-emphysema or nonsmoker controls. Next, Beas2b cells and C57BL/6 mice were exposed to either cigarette smoke extract (CSE) or subchronic-CS (sc-CS), followed by treatment with potent TFEB-inducing drug, gemfibrozil (GEM, or fisetin as an alternate), to experimentally verify the role of TFEB in COPD. Our in vitro results indicate that GEM/fisetin-mediated TFEB induction significantly (p < 0.05) decreases CSE-induced autophagy-impairment (Ub/LC3B reporter and autophagy flux assay) and resulting aggresome-formation (Ub/p62 coexpression/accumulation; immunoblotting and staining) by controlling reactive oxygen species (ROS) activity. Intriguingly, we observed that CS induces TFEB accumulation in the insoluble protein fractions of Beas2b cells, which shows a partial rescue with GEM treatment. Moreover, TFEB knockdown induces oxidative stress, autophagy-impairment, and senescence, which can all be mitigated by GEM-mediated TFEB induction. Finally, in vivo studies were used to verify that CS-induced autophagy-impairment (increased Ub, p62, and valosin-containing protein in the insoluble protein fractions of lung/cell lysates), inflammation (interleukin-6 [IL-6] levels in bronchoalveolar lavage fluid and iNOS expression in lung sections), apoptosis (caspase-3/7), and resulting emphysema (hematoxylin and eosin [H&E]) can be controlled by GEM-mediated TFEB induction (p < 0.05). CS exposure impairs autophagy in COPD-emphysema by inducing perinuclear localization of master autophagy regulator, TFEB, to aggresome-bodies. TFEB-inducing drug(s) can control CS-induced TFEB/autophagy-impairment and COPD-emphysema pathogenesis. Antioxid. Redox Signal. 27, 150-167.

Body height as risk factor for emphysema in COPD.

Pulmonary emphysema is a phenotypic component of chronic obstructive pulmonary disease (COPD) which carries substantial morbidity and mortality. We explored the association between emphysema and body height in 726 patients with COPD using computed tomography as the reference diagnostic standard for emphysema. We applied univariate analysis to look for differences between patients with emphysema and those without, and multivariate logistic regression to identify significant predictors of the risk of emphysema. As covariates we included age, sex, body height, body mass index, pack-years of smoking, and forced expiratory volume in one second (FEV1) as percent predicted. The overall prevalence of emphysema was 52%. Emphysemic patients were significantly taller and thinner than non-emphysemic ones, and featured significantly higher pack-years of smoking and lower FEV1 (P < 0.001). The prevalence of emphysema rose linearly by 10-cm increase in body height (r2 = 0.96). In multivariate analysis, the odds of emphysema increased by 5% (95% confidence interval, 3 to 7%) along with one-centimeter increase in body height, and remained unchanged after adjusting for all the potential confounders considered (P < 0.001). The odds of emphysema were not statistically different between males and females. In conclusion, body height is a strong, independent risk factor for emphysema in COPD.

Determinants of exercise-induced oxygen desaturation including pulmonary emphysema in COPD: Results from the ECLIPSE study

Exercise-induced oxygen desaturation (EID) is related to mortality in patients with chronic obstructive pulmonary disease (COPD). We investigated: (1) the prevalence of EID; (2) the relative-weight of several physiological determinants of EID including pulmonary emphysema, and (3) the relationship of EID with certain patients' clinical characteristics.Data from 2050 COPD patients (age: 63.3 ± 7.1years; FEV1: 48.7 ± 15.7%pred.) were analyzed. The occurrence of EID (SpO2post ≤88%) at the six-minute walking test (6MWT) was investigated in association with emphysema quantified by computed-tomography (QCT), and several clinical characteristics.435 patients (21%) exhibited EID. Subjects with EID had more QCT-emphysema, lower exercise capacity and worse health-status (BODE, ADO indexes) compared to non-EID. Determinant of EID were obesity (BMI≥30 kg/m2), impaired FEV1 (≤44%pred.), moderate or worse emphysema, and low SpO2 at rest (≤93%). Linear regression indicated that each 1-point increase on the ADO-score independently elevates odds ratio (≤1.5fold) for EID.About one in five COPD patients in the ECLIPSE cohort present EID. Advanced emphysema is associated with EID. In addition, obesity, severe airflow limitation, and low resting oxygen saturation increase the risk for EID. Patients with EID in GOLD stage II have higher odds to have moderate or worse emphysema compared those with EID in GOLD stage III-IV. Emphysematous patients with high ADO-score should be monitored for EID.