Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes.

Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term "response to bacterium" was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term "response to stress" was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.

Emphysema- and airway-dominant COPD phenotypes defined by standardised quantitative computed tomography.

EvA (Emphysema versus Airway disease) is a multicentre project to study mechanisms and identify biomarkers of emphysema and airway disease in chronic obstructive pulmonary disease (COPD). The objective of this study was to delineate objectively imaging-based emphysema-dominant and airway disease-dominant phenotypes using quantitative computed tomography (QCT) indices, standardised with a novel phantom-based approach.441 subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 1-3) were assessed in terms of clinical and physiological measurements, laboratory testing and standardised QCT indices of emphysema and airway wall geometry.QCT indices were influenced by scanner non-conformity, but standardisation significantly reduced variability (p<0.001) and led to more robust phenotypes. Four imaging-derived phenotypes were identified, reflecting "emphysema-dominant", "airway disease-dominant", "mixed" disease and "mild" disease. The emphysema-dominant group had significantly higher lung volumes, lower gas transfer coefficient, lower oxygen (PO2 ) and carbon dioxide (PCO2 ) tensions, higher haemoglobin and higher blood leukocyte numbers than the airway disease-dominant group.The utility of QCT for phenotyping in the setting of an international multicentre study is improved by standardisation. QCT indices of emphysema and airway disease can delineate within a population of patients with COPD, phenotypic groups that have typical clinical features known to be associated with emphysema-dominant and airway-dominant disease.

Prevalence and radiological outcomes of lung nodules in alpha 1-antitrypsin deficiency.

Pulmonary nodules are a frequent incidental finding on computed tomography (CT) imaging. This study sought to investigate the prevalence and radiological outcomes of lung nodules in patients with alpha 1-antitrypsin deficiency (AATD), and determine any association with systemic inflammation and disease progression. A retrospective study was conducted using thoracic CT imaging from 494 patients on the AATD U.K. registry. Patients were categorised according to radiological and clinical outcome, and comparisons made with respect to baseline demographics, lung function and high-sensitivity CRP (hs-CRP). Sixty-four patients (13%) had a nodule present on baseline imaging, and in total 132 patients (27%) had a nodule on at least one scan, of which 2 were malignant. The presence of a lung nodule was associated with significantly lower baseline percent predicted forced expiratory volume in 1 s (FEV1 % predicted) (p = 0.037) and percent predicted transfer coefficient of the lung for carbon monoxide (Kco % predicted, p = 0.001). Patients with self-resolving nodules had higher baseline hs-CRP concentrations (p < 0.01) and more rapid decline in Kco (p = 0.03) compared to patients in whom no nodules were observed. The prevalence of 'incidental' pulmonary nodules on CT imaging in patients with AATD was 13%. Self-resolving pulmonary nodules were associated with increased systemic inflammation and progression of emphysema and may therefore reflect an important component of emphysema pathogenesis or a marker of emphysema.

Assessment of pulmonary neutrophilic inflammation in emphysema by quantitative positron emission tomography.

RATIONALE: Neutrophilic inflammation is understood to be of pathogenetic importance in chronic obstructive pulmonary disease (COPD) and may be quantified using 18-fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET-CT) as a noninvasive, spatially informative biomarker. OBJECTIVES: To assess the potential usefulness of (18)FDG PET-CT as a surrogate measure of pulmonary neutrophilic inflammation in patients with usual COPD and α(1)-antitrypsin deficiency (AATD). METHODS: (18)FDG PET-CT imaging was performed in 10 patients with usual COPD, 10 patients with AATD, and 10 healthy control subjects. Pulmonary (18)FDG uptake was estimated by three-dimensional Patlak graphical analysis as an indicator of pulmonary neutrophilic glycolytic activity. Patients with AATD were treated with 12 weekly intravenous infusions of AAT augmentation therapy before repeat imaging. (18)FDG uptake, lung physiology, lung density, and systemic markers of inflammation were compared for all groups at baseline and, in patients with AATD, at baseline and on treatment. MEASUREMENTS AND MAIN RESULTS: (18)FDG uptake in the upper lung of patients with usual COPD was greater compared with the healthy control group (P = 0.009) and correlated with measures of disease severity (FEV(1)% predicted, r = -0.848, P = 0.001; FEV(1)/FVC, r = -0.918, P < 0.001; Kco% predicted, r = -0.624, P = 0.027; 15th percentile point, r = -0.709, P = 0.011). No significant difference was observed between measurements at baseline and on treatment in patients with AATD. CONCLUSIONS: Quantitative (18)FDG PET-CT has a potential role as an imaging biomarker in mechanistic and interventional studies in patients with usual COPD. The data support previous evidence of distinct functional characteristics of neutrophils in COPD. Clinical trial registered with https://eudract.ema.europa.eu/index.html (EudraCT 2007-004869-18).