Serum Derivatives of Reactive Oxygen Metabolites are Associated with Severity of Chronic Obstructive Pulmonary Disease and Affected by a p53 Gene Polymorphism.

Purpose: Oxidative stress is known to activate tumor suppressor p53, which inhibits cell cycle progression and induces apoptosis. Levels of p53 in lung tissues from patients with chronic obstructive pulmonary disease (COPD) are increased compared with levels in nonsmokers or smokers without emphysema. A polymorphism in p53 codon 72 (rs1042522) is associated with emphysematous changes in patients with COPD. However, whether oxidative stress in the serum is associated with the p53 polymorphism and disease severity in COPD patients is unclear. Patients and Methods: A total of 251 patients with a history of smoking more than 10 pack-years were enrolled in this study, and serum levels of derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), and d-ROMs/BAP ratio (oxidative stress index; OSI) were measured. The percent low-attenuation area (LAA%) and cross-sectional area of the erector spinae muscles (ESMCSA) at the Th12 level were calculated from chest high-resolution computed tomography images. p53 codon 72 C/G genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: In patients carrying the p53 GG genotype, LAA% was significantly higher than in those carrying the CC genotype. d-ROM levels and OSI were associated with COPD severity and correlated with airflow limitation and markers of muscle atrophy (ESMCSA and creatinine/cystatin C ratio). Associations between markers of oxidative stress and COPD severity were observed primarily in patients carrying the p53 codon 72 GG genotype. Conclusion: Susceptibility to pulmonary emphysema and responses to oxidative stress may be affected by the p53 gene polymorphism.

Association between plasma sRAGE and emphysema according to the genotypes of AGER gene.

BACKGROUND: Higher soluble receptor for advanced glycation end product (sRAGE) levels are considered to be associated with severe emphysema. However, the relationship remains uncertain when the advanced glycation end-product specific receptor (AGER) gene is involved. We aimed to analyse the association between sRAGE levels and emphysema according to the genotypes of rs2070600 in the AGER gene. METHODS: We genotyped rs2070600 and measured the plasma concentration of sRAGE in each participant. Emphysema was quantified based on the chest computed tomography findings. We compared sRAGE levels based on the presence or absence and severity of emphysema in each genotype. Multiple logistic and linear regression models were used for the analyses. RESULTS: A total of 436 participants were included in the study. Among them, 64.2% had chronic obstructive pulmonary disease and 34.2% had emphysema. Among the CC-genotyped participants, the sRAGE level was significantly higher in participants without emphysema than in those with emphysema (P < 0.001). In addition, sRAGE levels were negatively correlated with emphysema severity in CC-genotyped patients (r = - 0.268 P < 0.001). Multiple regression analysis revealed that sRAGE was an independent protective factor for the presence of emphysema (adjusted odds ratio, 0.24; 95% confidence interval (CI) 0.11-0.51) and severity of emphysema (ß = - 3.28, 95% CI - 4.86 to - 1.70) in CC-genotyped participants. CONCLUSION: Plasma sRAGE might be a biomarker with a protective effect on emphysema among CC-genotyped patients of rs2070600 on the AGER gene. This is important in determining the target group for the future prediction and treatment of emphysema.

Plasma sRAGE levels strongly associate with centrilobular emphysema assessed by HRCT scans.

BACKGROUND: There is a strong need for biomarkers to better characterize individuals with COPD and to take into account the heterogeneity of COPD. The blood protein sRAGE has been put forward as promising biomarker for COPD in general and emphysema in particular. Here, we measured plasma sRAGE levels using quantitative LC-MS and assessed whether the plasma sRAGE levels associate with (changes in) lung function, radiological emphysema parameters, and radiological subtypes of emphysema. METHODS: Three hundred and twenty-four COPD patients (mean FEV1: 63%predicted) and 185 healthy controls from the COPDGene study were selected. Plasma sRAGE was measured by immunoprecipitation in 96-well plate methodology to enrich sRAGE, followed by targeted quantitative liquid chromatography-mass spectrometry. Spirometry and HRCT scans (inspiration and expiration) with a 5-year follow-up were used; both subjected to high quality control standards. RESULTS: Lower sRAGE values significantly associated with the presence of COPD, the severity of airflow obstruction, the severity of emphysema on HRCT, the heterogeneous distribution of emphysema, centrilobular emphysema, and 5-year progression of emphysema. However, sRAGE values did not associate with airway wall thickness or paraseptal emphysema. CONCLUSIONS: Rather than being a general COPD biomarker, sRAGE is especially a promising biomarker for centrilobular emphysema. Follow-up studies should elucidate whether sRAGE can be used as a biomarker for other COPD phenotypes as well.

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD.

BACKGROUND: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes. METHODS: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV1) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity). RESULTS: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV1 (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log10-transformed sRAGE was associated with 105 ± 22 mL lower FEV1 and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV1 decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar. CONCLUSIONS: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.

Prognostic Significance of Red Cell Distribution Width in Idiopathic Pulmonary Fibrosis and Combined Pulmonary Fibrosis Emphysema.

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.

[Screening for alpha1-antitrypsin deficiency using dried blood spot: Assessment of the first 20 months]. / Dépistage du déficit en alpha1-antitrypsine sur sang capillaire recueilli sur papier-filtre : bilan des 20 premiers mois.

INTRODUCTION: Alpha1-antitrypsin deficiency is a predisposing factor for pulmonary disease and under-diagnosis is a significant problem. The results of a targeted screening in patients with respiratory symptoms possibly indicative of severe deficiency are reported here. METHODS: Data were collected from March 2016 to October 2017 on patients who had a capillary blood sample collected during a consultation with a pulmonologist and sent to the laboratory for processing to determine alpha1-antitrypsin concentration, phenotype and possibly genotype. RESULTS: In 20 months, 3728 test kits were requested by 566 pulmonologists and 718 (19 %) specimens sent: among these, 708 were analyzable and 613 were accompanied by clinical information. Of the 708 samples, 70 % had no phenotype associated with quantitative alpha1- antitrypsin deficiency, 7 % had a phenotype associated with a severe deficiency and 23 % had a phenotype associated with an intermediate deficiency. One hundred and eight patients carried at least one PI*Z allele which is considered to be a risk factor for liver disease. CONCLUSIONS: The results of this targeted screening program for alpha1- antitrypsin deficiency using a dried capillary blood sample reflect improvement in early diagnosis of this deficiency in lung disease with good adherence of the pulmonologists to this awareness campaign.

Serum vitamin D is associated with improved lung function markers but not with prevalence of asthma, emphysema, and chronic bronchitis.

Hypovitaminosis D has been linked to several non-bone diseases. Relation between 25-hydroxyvitamin D [25(OH)D] and lung function and lung diseases has received little attention at the global level. Cross-sectional data from three National Health and Nutrition Examination Surveys, 2007-2008, 2009-2010, and 2011-2012 were used to investigate the relationship between serum 25(OH)D concentrations and lung function makers [forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)] and lung diseases (asthma, emphysema, and chronic bronchitis) with multivariate regression models (n = 11,983; men, 6,010; women, 5,973). Serum 25(OH)D concentrations were directly associated with FVC and FEV1 (P for trend < 0.01). Individuals in the 4th quartile serum 25(OH)D had significantly higher FVC and FEV1 compared to those in the 1st quartile (P < 0.01). When data were stratified based on gender and smoking status, we found similar associations between serum 25(OH)D concentrations and lung function markers. There was no relation between serum 25(OH)D and prevalence of asthma, chronic bronchitis, and emphysema in US adults. Serum 25(OH)D concentration is associated with improved lung function markers but not with the prevalence of asthma, emphysema, and chronic bronchitis. Controlled studies are needed to determine if the vitamin D supplementation improves lung function in adults and in smokers.

Risk factors associated with the detection of pulmonary emphysema in older asymptomatic respiratory subjects.

BACKGROUND: Several lung structural and functional abnormalities may occur associated with aging, including emphysema. In this study, we evaluated the frequency and risk factors associated with emphysema in respiratory asymptomatic individuals enrolled in our Lung Aging Program. From a cohort of 687 subjects, we found by high-resolution computed tomography (HRCT) 29 individuals (4%) with emphysematous changes that were compared with 87 controls (3:1) randomly selected from the same cohort. METHODS: This was a transversal, observational, case-control study where we examined demographics and functional characteristics, as well as telomere length and serum Klotho concentration, two conditions that have been associated with aging and some aging-associated diseases including emphysema. RESULTS: Individuals with subclinical pulmonary emphysema were older (72 ± 9 versus 67 ± 6 years), and primarily smoker males with low body mass index. Despite that they were asymptomatic, two of them exhibited a decrease of forced expiratory volume in 1 s (FEV1), with a lower FEV1/FVC suggesting airway obstruction. Cigarette smoking (OR = 5.43, CI95% 1.8-16.7), family history of lung disease (OR = 4.32, CI95% 1.0-19.0) and lower body mass index (OR 7.22, CI95% 1.2-3.5) were risk factors for the development of lung emphysematous changes. No association was found with telomere length and Klotho serum concentration. CONCLUSION: Our findings reveal that a small but important percentage of older people without respiratory symptoms, present pulmonary emphysema and indicate that smoking exposure and genetic background may contribute to etiological factors.

Increased von Willebrand Factor Processing in COPD, Reflecting Lung Epithelium Damage, Is Associated with Emphysema, Exacerbations and Elevated Mortality Risk.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and lung tissue deterioration. Given the high vascularity of the lung, von Willebrand factor (VWF), a central component of wound healing initiation, has previously been assessed in COPD. VWF processing, which is crucial for regulating the primary response of wound healing, has not been assessed directly. Therefore, this study aimed to characterize wound healing initiation in COPD using dynamic VWF-processing biomarkers and to evaluate how these relate to disease severity and mortality. Methods: A cross-sectional analysis of plasma samples from the ECLIPSE study collected at year 1 from moderate to very severe COPD subjects (GOLD 2-4, n=984) was performed. We applied competitive neo-epitope ELISAs specifically targeting the formation of and ADAMTS13-processed form of VWF, VWF-N and VWF-A, respectively. Results: VWF-A and VWF-N were significantly increased (VWF-N, p=0.01; VWF-A, p=0.0001) in plasma of symptomatic (mMRC score ≥2) compared to asymptomatic/mild symptomatic COPD subjects. Increased VWF-N and VWF-A levels were specifically associated with emphysema (VWF-N, p<0.0001) or prior exacerbations (VWF-A, p=0.01). When dichotomized, high levels of both biomarkers were associated with increased risk of all-cause mortality (VWF-N, HR 3.5; VWF-A, HR 2.64). Conclusion: We demonstrate that changes in VWF processing were related to different pathophysiological aspects of COPD. VWF-N relates to the chronic condition of emphysema, while VWF-A was associated with the more acute events of exacerbations. This study indicates that VWF-A and VWF-N may be relevant markers for characterization of disease phenotype and are associated with mortality in COPD. Study Identifier: NCT00292552; GSK study code SCO104960.

The Efficacy of Lung Volume Reduction Coil Treatment in Patients with Severe Chronic Obstructive Pulmonary Disease (COPD) Type II Respiratory Failure.

Purpose: Emphysema is a progressive and irreversible disease, proceeding with the decrease in elastic recoil which is connected to tissue damage caused by chronic inflammation. Lung volume reduction coil (LVRC) method in patients with an advanced level of emphysema and irresponsive to medical treatment is shown to provide increase in lung volumes and exercise capacity, decrease in dyspnea, and increase in quality of life. The purpose of this study is to reveal that LVRC treatment is also efficient in severe COPD patients with hypercapnic respiratory failure. Patients and Methods: Eleven cases with severe COPD and emphysema were included in the study. LVRC treatment method was applied in upper lobes of both lungs in patients with severe COPD (FEV1 < %45) and Type-2 respiratory insufficiency (PCO2 55-80 mmHg) who were having medical treatment and CPAP treatment. The patients were followed up for a period of twelve months using arterial blood gas analysis. Results: Beginning with the first month of the LVRC treatment, PCO2 levels were found to be significantly decreased in all patients using arterial blood gas analysis. Conclusion: LVRC method can provide physiological and functional recovery and progress in quality of life in severe COPD cases. It is demonstrated that LVRC treatment caused significant decreases in carbon dioxide levels as well as causing improvement in life quality and respiratory function tests in the patients with hypercapnic respiratory failure.

Activation of complement component 3 is associated with airways disease and pulmonary emphysema in alpha-1 antitrypsin deficiency.

INTRODUCTION: Alpha-1 antitrypsin (AAT) deficiency (AATD) is associated with early onset emphysema. The aim of this study was to investigate whether AAT binding to plasma constituents could regulate their activation, and in AATD, exploit this binding event to better understand the condition and uncover novel biomarkers of therapeutic efficacy. METHODS: To isolate AAT linker proteins, plasma samples were separated by size exclusion chromatography, followed by co-immunoprecipitation. AAT binding proteins were identified by mass spectrometry. Complement turnover and activation was determined by ELISA measurement of C3, C3a and C3d levels in plasma of healthy controls (n=15), AATD (n=51), non-AATD patients with obstructive airway disease (n=10) and AATD patients post AAT augmentation therapy (n=5). RESULTS: Direct binding of complement C3 to AAT was identified in vivo and in vitro. Compared with healthy controls, a breakdown product of C3, C3d, was increased in AATD (0.04 µg/mL vs 1.96 µg/mL, p=0.0002), with a significant correlation between radiographic pulmonary emphysema and plasma levels of C3d (R2=0.37, p=0.001). In vivo, AAT augmentation therapy significantly reduced plasma levels of C3d in comparison to patients not receiving AAT therapy (0.15 µg/mL vs 2.18 µg/mL, respectively, p=0.001). DISCUSSION: Results highlight the immune-modulatory impact of AAT on the complement system, involving an important potential role for complement activation in disease pathogenesis in AATD. The association between plasma C3d levels and pulmonary disease severity, that decrease in response to AAT augmentation therapy, supports the exploration of C3d as a candidate biomarker of therapeutic efficacy in AATD.

Severity of chronic obstructive pulmonary disease with 'exacerbator with emphysema phenotype' is associated with potential biomarkers.

OBJECTIVE: The present study was designed to investigate the biomarkers levels of fractalkine (FKN), neutrophil elastase (NE) and matrix metalloproteinase-12 (MMP-12) in chronic obstructive pulmonary disease (COPD) with 'exacerbator with emphysema phenotype' and to evaluate the associations between the biomarkers levels and the severity of disease by spirometric measurements. METHODS: A total of 84 COPD patients and 49 healthy controls were enrolled in our study. ELISA were utilised to detect the FKN, MMP-12 and NE in serum from all subjects. RESULTS: FKN (p<0.001), NE (p=0.039) and MMP-12 (p<0.001) in serum of COPD patients showed higher levels than that of healthy control subjects. Serum FKN (p<0.001), MMP-12 (p<0.001) and NE (p=0.043) levels were significantly higher in severe and very severe COPD patients than that in mild and moderate COPD patients. Circulating FKN, MMP-12 and NE expression levels were significantly elevated (p<0.001) in COPD smokers compared with COPD non-smokers. The smoke pack years were negatively correlated with FEV1%pred (r=-0.5036), FEV1/FVC ratio (r=-0.2847) (FEV, forced expiratory volume; FVC, forced vital capacity). Similarly, we observed a strong positive correlation between the smoke pack years and serum levels of FKN (r=0.4971), MMP-12 (r=0.4315) and NE (r=0.2754). FEV1%pred was strongly negatively correlated with cytokine levels of FKN (r=-0.4367), MMP-12 (r=-0.3295) and NE (r=-0.2684). Likewise, FEV1/FVC ratio was negatively correlated with mediators of inflammation levels of FKN (r=-0.3867), MMP-12 (r=-0.2941) and NE (r=-0.2153). CONCLUSION: Serum FKN, MMP-12 and NE concentrations in COPD patients are directly associated with the severity of COPD with 'exacerbator with emphysema phenotype'. This finding suggests that FKN, MMP-12 and NE might play an important role in the pathophysiology of COPD.

Loss of skin elasticity is associated with pulmonary emphysema, biomarkers of inflammation, and matrix metalloproteinase activity in smokers.

BACKGROUND: Elastin breakdown and the resultant loss of lung elastic recoil is a hallmark of pulmonary emphysema in susceptible individuals as a consequence of tobacco smoke exposure. Systemic alterations to the synthesis and degradation of elastin may be important to our understanding of disease phenotypes in chronic obstructive pulmonary disease. We investigated the association of skin elasticity with pulmonary emphysema, obstructive lung disease, and blood biomarkers of inflammation and tissue protease activity in tobacco-exposed individuals. METHODS: Two hundred and thirty-six Caucasian individuals were recruited into a sub-study of the University of Pittsburgh Specialized Center for Clinically Orientated Research in chronic obstructive pulmonary disease, a prospective cohort study of current and former smokers. The skin viscoelastic modulus (VE), a determinant of skin elasticity, was recorded from the volar forearm and facial wrinkling severity was determined using the Daniell scoring system. RESULTS: In a multiple regression analysis, reduced VE was significantly associated with cross-sectional measurement of airflow obstruction (FEV1/FVC) and emphysema quantified from computed tomography (CT) images, ß = 0.26, p = 0.001 and ß = 0.24, p = 0.001 respectively. In emphysema-susceptible individuals, elasticity-determined skin age was increased (median 4.6 years) compared to the chronological age of subjects without emphysema. Plasma biomarkers of inflammation (TNFR1, TNFR2, CRP, PTX3, and SAA) and matrix metalloproteinase activity (MMP1, TIMP1, TIMP2, and TIMP4) were inversely associated with skin elasticity. CONCLUSIONS: We report that an objective non-invasive determinant of skin elasticity is independently associated with measures of lung function, pulmonary emphysema, and biomarkers of inflammation and tissue proteolysis in tobacco-exposed individuals. Loss of skin elasticity is a novel observation that may link the common pathological processes that drive tissue elastolysis in the extracellular matrix of the skin and lung in emphysema-susceptible individuals.

Effects of Bronchoscopic Lung Volume Reduction Coil Treatment on Arterial Blood Gases.

BACKGROUND: Bronchoscopic lung volume reduction (BLVR) coil treatment is an increasingly used treatment modality for selected severe emphysema patients in recent years. Emphysema causes dynamic hyperinflation, loss of elastic recoil, air trapping, and decreased exercise capacity in advanced stages. This process progresses over time, leading to hypoxic and hypercapnic respiratory failure. The goal of this study is to elucidate the effects of BLVR coil treatment on arterial blood gas parameters in severe emphysema patients with respiratory failure. METHODS: This is a retrospective study performed at a single pneumology center in Turkey. In total, this study included 39 patients diagnosed with severe emphysema who underwent bilateral BLVR coil treatment according to the general inclusion and exclusion criteria in the literature. The patients baseline and 12-month data were collected from medical records. RESULTS: Twelve months after BLVR coil treatment, significant improvements were observed in patients' pulmonary function tests, an increase in partial pressure of oxygen in arterial blood (PaO2) from 58.05±9.36 to 73.82±13.3 (P<0.000) and decrease in partial pressure of carbon dioxide in arterial blood (PaCO2) of hypercapnic patients (from 51.60±4.1 to 46.55±6.6 mm Hg; P=0.001). CONCLUSION: BLVR coil treatment is reliable and effective in emphysema patients who have hypoxic or mild hypercapnic respiratory failure. Besides improving lung function, BLVR coil treatment can significantly increase PaO2 and decrease PaCO2 in the medium term.

High Serum Fractalkine/CX3CL1 in Patients with Chronic Obstructive Pulmonary Disease: Relationship with Emphysema Severity and Frequent Exacerbation.

OBJECTIVE: The purpose of this study was to investigate the relationship between serum fractalkine (CX3CL1/FKN) level and the multi-slice spiral computed tomography (MSCT) emphysema index in Chinese patients with chronic obstructive pulmonary disease (COPD). METHODS: We detected chemokine CX3CL1 in serum from 95 Chinese patients with COPD by using an enzyme-linked immunosorbent assay. According to the MSCT emphysema index, the selected cases were divided into an emphysema-dominant group (n = 25) and a non-emphysema-dominant group (n = 70). RESULTS: There were significant differences in body mass index and lung function between the two groups. The serum level of CX3CL1 in the emphysema-dominant group was significantly higher than that in the non-emphysema-dominant group. Through multivariate logistic regression analysis, it was found that high serum CX3CL1 levels were independently associated with emphysema, with a relative risk of 2.617 (95% CI 1.018-6.121; P = 0.029). The percentage of frequent acute exacerbations during the first year of follow-up was significantly higher in the high-level serum CX3CL1 group (P = 0.039). After 3 years of follow-up, there was no significant difference in the CT emphysema index between the high and low serum CX3CL1 groups (P = 0.503). CONCLUSION: Our results suggest that the serum level of CX3CL1 is related to the MSCT emphysema index. Chemokine CX3CL1 might be a useful predictor for identifying frequent exacerbation and emphysema severity in patients with COPD.

Emphysema-associated Autoreactive Antibodies Exacerbate Post-Lung Transplant Ischemia-Reperfusion Injury.

Chronic obstructive pulmonary disease-associated chronic inflammation has been shown to lead to an autoimmune phenotype characterized in part by the presence of lung autoreactive antibodies. We hypothesized that ischemia-reperfusion injury (IRI) liberates epitopes that would facilitate preexisting autoantibody binding, thereby exacerbating lung injury after transplant. We induced emphysema in C57BL/6 mice through 6 months of cigarette smoke (CS) exposure. Mice with CS exposure had significantly elevated serum autoantibodies compared with non-smoke-exposed age-matched (NS) mice. To determine the impact of a full preexisting autoantibody repertoire on IRI, we transplanted BALB/c donor lungs into NS or CS recipients and analyzed grafts 48 hours after transplant. CS recipients had significantly increased lung injury and immune cell infiltration after transplant. Immunofluorescence staining revealed increased IgM, IgG, and C3d deposition in CS recipients. To exclude confounding alloreactivity and confirm the role of preexisting autoantibodies in IRI, syngeneic Rag1-/- (recombination-activating protein 1-knockout) transplants were performed in which recipients were reconstituted with pooled serum from CS or NS mice. Serum from CS-exposed mice significantly increased IRI compared with control mice, with trends in antibody and C3d deposition similar to those seen in allografts. These data demonstrate that pretransplant CS exposure is associated with increased IgM/IgG autoantibodies, which, upon transplant, bind to the donor lung, activate complement, and exacerbate post-transplant IRI.

Centrilobular emphysema and coronary artery calcification: mediation analysis in the SPIROMICS cohort.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized to be mediated by systemic inflammation but this link has not been established. METHODS: We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC. RESULTS: FEV1/FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p = 0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p = 0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV1/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC. CONCLUSIONS: The association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier: NCT01969344 .