Respiratory infections are associated with the majority of COPD exacerbations and their severity, especially those with viral/bacterial coinfection. Airway neutrophilia is related to exacerbation severity regardless of viral and/or bacterial infections. Eosinophilia is a good predictor of viral exacerbations.

There are increased numbers of activated T lymphocytes in the bronchial mucosa of stable chronic obstructive pulmonary disease (COPD) patients. T helper type 17 (Th17) cells release interleukin (IL)-17 as their effector cytokine under the control of IL-22 and IL-23. Furthermore, Th17 numbers are increased in some chronic inflammatory conditions. To investigate the expression of interleukin (IL)-17A, IL-17F, IL-21, IL-22 and IL-23 and of retinoic orphan receptor RORC2, a marker of Th17 cells, in bronchial biopsies from patients with stable COPD of different severity compared with age-matched control subjects. The expression of IL-17A, IL-17F, IL-21, IL-22, IL-23 and RORC2 was measured in the bronchial mucosa using immunohistochemistry and/or quantitative polymerase chain reaction. The number of IL-22(+) and IL-23(+) immunoreactive cells is increased in the bronchial epithelium of stable COPD compared with control groups. In addition, the number of IL-17A(+) and IL-22(+) immunoreactive cells is increased in the bronchial submucosa of stable COPD compared with control non-smokers. In all smokers, with and without disease, and in patients with COPD alone, the number of IL-22(+) cells correlated significantly with the number of both CD4(+) and CD8(+) cells in the bronchial mucosa. RORC2 mRNA expression in the bronchial mucosa was not significantly different between smokers with normal lung function and COPD. Further, we report that endothelial cells express high levels of IL-17A and IL-22. Increased expression of the Th17-related cytokines IL-17A, IL-22 and IL-23 in COPD patients may reflect their involvement, and that of specific IL-17-producing cells, in driving the chronic inflammation seen in COPD.

Scientific Knowledge on the Subject: Glucocorticoid unresponsiveness in severe asthma COPD may involve an oxidant mediated impairment of glucocorticoid receptor alpha (GRα) function through reduction of histone deacetylase activity and co-repressor expression.What This Study Adds to the Field: Histone deacetylase 2 activity is reduced in smoke exposed mice lungs correlating with reduced glucocorticoid function which is restored by PI3Kδ but not γ inhibition. GRα expression also is reduced in smoke exposed mouse and in COPD patient lungs. Abstract Rational:There is an increasing prevalence of reduced responsiveness to glucocorticoid therapy in severe asthma and chronic obstructive pulmonary disease, however the molecular mechanism of this remains unknown. Recent studies have shown that histone deacetylase activity, which is critical to glucocorticoid function, is altered by oxidant stress and may be involved in the development of glucocorticoid insensitivity.Objectives: To determine the role of phosphoinositol-3-kinase (PI3K) in the development of cigarette smoke induced glucocorticoid insensitivity. Methods:Wild type, PI3Kγ knock-out and PI3Kδ kinase dead knock-in transgenic mice were used in a model of cigarette smoke induced glucocorticoid insensitivity. Peripheral lung tissue was obtained 6 healthy non-smokers, 9 smokers with normal lung function and 8 patients with chronic obstructive pulmonary disease. Measurements and Main Results:Glucocorticoid receptor expression was significantly reduced in both the lungs of chronic obstructive pulmonary disease patients and in cigarette smoke-exposed mice. Furthermore, cigarette smoke exposure in mice increased tyrosine nitration of histone deacetylase 2 in the lung correlating with both reduced histone deacetylase 2 activity and reduced glucocorticoid function. Oxidative stress activated Akt and induced glucocorticoid insensitivity in vitro, which was restored by inhibition of PI3K. In vivo, histone deacetylase 2 activity and the anti-inflammatory effects of glucocorticoids were restored in PI3Kδ kinase dead knock-in but not PI3Kγ knock-out smoke exposed mice compared to wild types, correlating with reduced histone deacetylase 2 tyrosine nitration.Conclusion: Together these data shows that therapeutic inhibition of PI3Kδ may restore glucocorticoid function in oxidative stress induced glucocorticoid insensitivity. Abstract Word count: 247

The immunopathology of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune responses to the chronic inhalation of cigarette smoking. In the last quarter of the century, the analysis of specimens obtained from the lower airways of COPD patients compared with those from a control group of age-matched smokers with normal lung function has provided novel insights on the potential pathogenetic role of the different cells of the innate and acquired immune responses and their pro/anti-inflammatory mediators and intracellular signalling pathways, contributing to a better knowledge of the immunopathology of COPD both during its stable phase and during its exacerbations. This also has provided a scientific rationale for new drugs discovery and targeting to the lower airways. This review summarises and discusses the immunopathology of COPD patients, of different severity, compared with control smokers with normal lung function.

Inhaled corticosteroid-containing medications reduce the frequency of COPD exacerbations (mainly infectious in origin) while paradoxically increasing the risk of other respiratory infections The aim was to determine the effects of inhaled corticosteroids on airway microbial load in COPD patients and evaluate the influence of the underlying inflammatory profile on airway colonisation and microbiome.This is a proof-of-concept prospective, randomised, open-label, blinded endpoint study. Sixty patients with stable moderate COPD were randomised to receive one inhalation twice daily of either a combination of salmeterol 50 μg plus fluticasone propionate 500 μg or salmeterol 50 μg for 12 months. The primary outcome was the change of sputum bacterial loads over the course of treatment.Compared with salmeterol, 1-year treatment with salmeterol plus fluticasone was associated with a significant increase in sputum bacterial load (p=0.005), modification of sputum microbial composition and increased airway load of potentially pathogenic bacteria. The increased bacterial load was observed only in inhaled corticosteroid-treated patients with lower baseline sputum or blood eosinophil (≤2%) levels but not in patients with higher baseline eosinophils.Long-term inhaled corticosteroid treatment affects bacterial load in stable COPD. Lower eosinophil counts are associated with increased airway bacterial load.