Clinical and inflammatory determinants of bronchial hyperresponsiveness in COPD

Abstract

Bronchial hyperresponsiveness (BHR) is regarded as a hallmark of asthma, yet it is also present in a considerable number of chronic obstructive pulmonary disease (COPD) patients. Epidemiological studies have shown that BHR provides complementary information to forced expiratory volume in 1 s (FEV1) for development and progression of COPD. We hypothesised that the severity of BHR and its longitudinal changes associate with both clinical and airway inflammation measures in COPD.Our hypothesis was tested in 114 COPD patients (median age 62.9 years, smoking exposure 45.9 pack-yrs) participating in the GLUCOLD (Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease) study, which previously showed an improvement in BHR with fluticasone and fluticasone/salmeterol. At baseline, and 6 and 30 months after treatment, we investigated lung function, including body plethysmography, provocative concentration of methacholine causing a 20% fall in FEV1, sputum induction, and bronchial biopsies.By performing both cross-sectional and longitudinal analyses, we show that BHR in COPD is predominantly associated with residual volume/total lung capacity (a measure of air trapping) and airway inflammation reflected by the number of neutrophils, macrophages and lymphocytes in sputum and bronchial biopsies.Our findings indicate that BHR is an independent trait in COPD and provides important information on phenotype heterogeneity and disease activity.

Asthma–COPD Overlap. Clinical Relevance of Genomic Signatures of Type 2 Inflammation in Chronic Obstructive Pulmonary Disease

“…We next studied the association of the endobronchial T2S metric with asthmarelated features and ICS therapy response in the GLUCOLD study (6).…”

“…Despite their broad antiinflammatory effects, ICS do not achieve marked long-term effects in the majority of patients with COPD (4). However, COPD is highly heterogeneous, and a subset may display asthma-like biology and a favorable ICS response (5)(6)(7)(8).…”

“…Although COPD is traditionally differentiated from asthma by poorly reversible airflow obstruction, a subset of patients with COPD displays bronchial hyperresponsiveness and at least partial reversibility of airflow obstruction with bronchodilators (6). Similarly, although inflammation in COPD is typically thought to be driven by T helper type 1 (Th1) immune responses (7), asthmaassociated inflammatory pathways (e.g., eosinophilia and Th2 inflammation) appear to underlie disease in some patients.…”

Treatment Responses of Procaterol and CD38 Inhibitors in an Ozone-Induced Airway Hyperresponsiveness Mice Model

“…26,27) In this study, compared with the Control group, the ozone-induced AHR mice model exhibited higher MDA levels in BALF, more leukocytes in BALF, pathological features of airway inflammation, and a significantly elevated RL ratio and reduced Cdyn ratio. MDA, as a by-product of lipid peroxidation, has been identified in the past as a marker of oxidative damage.…”

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease

“…In particular, very few COPD studies have assessed airway responsiveness, and, to our knowledge, there is no sufficiently sized COPD cohort available with airway responsiveness data to provide a reasonable replication cohort to confirm our results. The GLUCOLD study (39) enrolled patients with COPD and performed methacholine challenge testing on only 110 subjects, thereby limiting our ability to detect any statistically significant associations. We did not replicate our findings in asthma cohorts because the biologic mechanism and genetic determinants of airway responsiveness underlying asthma and COPD may be different, as is evidenced by a previous GWAS of airway responsiveness in asthma populations showing only nominal to no replication in the LHS COPD population and in a general population cohort (40).…”