BACKGROUND Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with accelerated loss of lung function and death. Identification of patients at risk for these events, particularly those requiring hospitalization, is of major importance. Severe pulmonary hypertension is an important complication of advanced COPD and predicts acute exacerbations, though pulmonary vascular abnormalities also occur early in the course of the disease. We hypothesized that a computed tomographic (CT) metric of pulmonary vascular disease (pulmonary artery enlargement, as determined by a ratio of the diameter of the pulmonary artery to the diameter of the aorta [PA:A ratio] of >1) would be associated with severe COPD exacerbations. METHODS We conducted a multicenter, observational trial that enrolled current and former smokers with COPD. We determined the association between a PA:A ratio of more than 1 and a history at enrollment of severe exacerbations requiring hospitalization and then examined the usefulness of the ratio as a predictor of these events in a longitudinal follow-up of this cohort, as well as in an external validation cohort. We used logistic-regression and zero-inflated negative binomial regression analyses and adjusted for known risk factors for exacerbation. RESULTS Multivariate logistic-regression analysis showed a significant association between a PA:A ratio of more than 1 and a history of severe exacerbations at the time of enrollment in the trial (odds ratio, 4.78; 95% confidence interval [CI], 3.43 to 6.65; P<0.001). A PA:A ratio of more than 1 was also independently associated with an increased risk of future severe exacerbations in both the trial cohort (odds ratio, 3.44; 95% CI, 2.78 to 4.25; P<0.001) and the external validation cohort (odds ratio, 2.80; 95% CI, 2.11 to 3.71; P<0.001). In both cohorts, among all the variables analyzed, a PA:A ratio of more than 1 had the strongest association with severe exacerbations. CONCLUSIONS Pulmonary artery enlargement (a PA:A ratio of >1), as detected by CT, was associated with severe exacerbations of COPD. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT00608764 and NCT00292552.)

An NADPH-oxidase complex containing at least two protein components (gp91-phox and p22-phox) and a unique low redox potential (-245 mV) cytochrome b-245 is the source of superoxide generated for bacterial killing in neutrophils and has been suggested as the oxygen sensor in the carotid body. In pure cultures of smooth muscle cells from calf small pulmonary arteries (300 microns diameter) the presence of the 91 kD protein specific to this cytochrome was demonstrated by Western blot analysis with monoclonal antibody 48. Low-temperature-difference spectrophotometry of homogenates of these cells demonstrated the characteristic cytochrome b-245 spectrum when titrated between redox potentials of -152 and -345 mV, consistent with the low redox potential form. When these same cells were exposed to hypoxia (approximately 40 mmHg), superoxide production increased significantly from 1.4 +/- 0.2 to 73 +/- 12 nmoles.min-1 mg-1 protein. Hypoxic generation of superoxide was inhibited by the NADPH-oxidase inhibitor diphenyleneiodonium (DPI: 10 microM) but not by the mitochondrial inhibitor myxathiazole (10 microM). The hypoxic superoxide increase was significantly greater than that observed from smooth muscle cells from large pulmonary arteries or from large or small systemic arteries. Fluorescence immunocytochemistry revealed the presence of the NADPH-oxidase protein in the walls of pulmonary arteries in rat lung slices, and confocal microscopy showed the complex to be widely distributed in the vicinity of the arterial smooth muscle walls. In hypoxia or norepinephrine (NP)-induced vasoconstriction of pulmonary artery rings from cats, the sensitivity to inhibition by DPI was observed to be significantly greater for hypoxia (ED50 = 0.8 microM) than for NP-induced (ED50 = 13.4 microM) constriction. Together these observations demonstrate that the unique cytochrome b-245 containing NADPH-oxidase is present in pulmonary artery smooth muscle and that an NADPH-oxidase or NADH-oxidoreductase complex is activated to release superoxide by hypoxic conditions. It is concluded that a trans-membrane NADPH-oxidase is the most likely and that activation of this system may be involved in the initiation of hypoxic pulmonary vasoconstriction.

Background Cigarette smoking is a major risk factor for COPD and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a Dopamine Beta-Hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in COPD subjects. Methods GWAS were conducted in 4 independent cohorts encompassing 3,441 ever-smoking COPD subjects (GOLD stage II or higher). Untyped SNPs were imputed using HapMap (phase II) panel. Results from all cohorts were meta-analyzed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10−7. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10−6. Nominally significant associations with candidate SNPs within alpha-nicotinic acetylcholine receptors 3/5 (CHRNA3/CHRNA5; e.g. p=0.00011 for SNP rs1051730) and Cytochrome P450 2A6 (CYP2A6; e.g. p=2.78×10−5 for a nonsynonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in the DBH was significantly (p=0.015) associated with smoking cessation. Conclusion We identified two candidate regions associated with age at smoking initiation in COPD subjects. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviors of COPD patients.

Scientific Knowledge on the Subject: COPD progresses over decades so little is known about longitudinal changes in individual patients, and whether there are different patterns of disease progression in different patient subgroups.What this Study Adds to the Field: Computational modelling of CT biomarkers suggests there are two patterns of disease progression in COPD. These disease progression patterns or 'subtypes' can be used to stratify individuals into two groups with distinct clinical characteristics, and to stage individuals along their disease time-course. Early stages of both subtypes are identifiable in a proportion of 'healthy smokers' providing a biomarker of early COPD.

The COPD Genetic Epidemiology (COPDGene®) study provides a rich cross-sectional dataset of patients with substantial tobacco smoke exposure, varied by race, gender, chronic obstructive pulmonary disease (COPD) diagnosis, and disease. We aimed to determine the influence of race, gender and Global initiative for chronic Obstructive Lung Disease (GOLD) stage on prevalence of prior COPD diagnosis at COPDGene® enrollment. Data from the complete phase 1 cohort of 10,192 participants were analyzed. Participants were non-Hispanic white and African-American, ≥45 years of age with a minimum of 10 pack years of cigarette smoking. Characterization upon enrollment included spirometry, demographics and history of COPD diagnosis determined by questionnaire. We evaluated the effects of race and gender on the likelihood of prior diagnosis of COPD and the interaction of race and GOLD stage, and gender and GOLD stage, as determined at study enrollment, on likelihood of prior diagnosis of COPD. We evaluated the 3-way interaction of race, gender and GOLD stage on prior diagnosis. African-Americans had higher odds of not having a prior COPD diagnosis at all GOLD stages of airflow obstruction versus non-Hispanic whites (p<0.0001). Women had higher odds of having a prior COPD diagnosis at all GOLD stages versus men (p<0.0001). Three-way interaction of race, gender and GOLD stage was not significant. African-Americans were less likely to have prior COPD regardless of the severity of airflow obstruction determined at study enrollment. Women were more likely to have a prior COPD diagnosis regardless of the severity of measured airflow obstruction. Race and gender are associated with significant disparities in COPD diagnosis. AbstractAbbreviations: COPD Genetic Epidemiology, COPDGene; chronic obstructive pulmonary disease, COPD; Global initiative for chronic Obstructive Lung Disease, GOLD; African American, AA; non-Hispanic white, NHW; American Thoracic Society, ATS; forced expiratory volume in 1 second, FEV 1 ; forced vital capacity, FVC; odds ratio, OR; analysis of variance, ANOVA; Preserved Ratio Impaired Spirometry, PRISm; body mass index, BMI; European Respiratory Society, ERS