Rationale: Severe exacerbations of chronic obstructive pulmonary disease (COPD) are major causes of health care costs mostly related to hospitalization. The role of infections in COPD exacerbations is controversial. Objectives: We investigated whether COPD exacerbations requiring hospitalization are associated with viral and/or bacterial infection and evaluated relationships among infection, exacerbation severity, assessed by reduction of FEV₁, and specific patterns of airway inflammation. Methods: We examined 64 patients with COPD when hospitalized for exacerbations, and when in stable convalescence. We measured lung function, blood gases, and exhaled nitric oxide, and examined sputum for inflammation and for viral and bacterial infection. Results: Exacerbations were associated with impaired lung function (p < 0.01) and increased sputum neutrophilia (p < 0.001). Viral and/or bacterial infection was detected in 78% of exacerbations: viruses in 48.4% (6.2% when stable, p < 0.001) and bacteria in 54.7% (37.5% when stable, p = 0.08). Patients with infectious exacerbations (29.7% bacterial, 23.4% viral, 25% viral/bacterial coinfection) had longer hospitalizations (p < 0.02) and greater impairment of several measures of lung function (all p < 0.05) than those with noninfectious exacerbations. Patients with exacerbations with coinfection had more marked lung function impairment (p < 0.02) and longer hospitalizations (p = 0.001). Sputum neutrophils were increased in all exacerbations (p < 0.001) and were related to their severity (p < 0.001), independently of the association with viral or bacterial infections; sputum eosinophils were increased during (p < 0.001) virus-associated exacerbations. Conclusions: 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.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation that is greater in patients with advanced disease. We asked whether there is a link between the severity of disease and the reduction in histone deacetylase (HDAC) activity in the peripheral lung tissue of patients with COPD of varying severity. HDAC is a key molecule in the repression of production of proinflammatory cytokines in alveolar macrophages. HDAC activity and histone acetyltransferase (HAT) activity were determined in nuclear extracts of specimens of surgically resected lung tissue from nonsmokers without COPD, patients with COPD of varying severity, and patients with pneumonia or cystic fibrosis. Alveolar macrophages from nonsmokers, smokers, and patients with COPD and bronchial-biopsy specimens from nonsmokers, healthy smokers, patients with COPD, and those with mild asthma were also examined. Total RNA extracted from lung tissue and macrophages was used for quantitative reverse-transcriptase–polymerase-chain-reaction assay of HDAC1 through HDAC8 and interleukin-8. Expression of HDAC2 protein was quantified with the use of Western blotting. Histone-4 acetylation at the interleukin-8 promoter was evaluated with the use of a chromatin immunoprecipitation assay. Specimens of lung tissue obtained from patients with increasing clinical stages of COPD had graded reductions in HDAC activity and increases in interleukin-8 messenger RNA (mRNA) and histone-4 acetylation at the interleukin-8 promoter. The mRNA expression of HDAC2, HDAC5, and HDAC8 and expression of the HDAC2 protein were also lower in patients with increasing severity of disease. HDAC activity was decreased in patients with COPD, as compared with normal subjects, in both the macrophages and biopsy specimens, with no changes in HAT activity, whereas HAT activity was increased in biopsy specimens obtained from patients with asthma. Neither HAT activity nor HDAC activity was changed in lung tissue from patients with cystic fibrosis or pneumonia. Patients with COPD have a progressive reduction in total HDAC activity that reflects the severity of the disease.

The molecular mechanism for the anti-inflammatory action of theophylline is currently unknown, but low-dose theophylline is an effective add-on therapy to corticosteroids in controlling asthma. Corticosteroids act, at least in part, by recruitment of histone deacetylases (HDACs) to the site of active inflammatory gene transcription. They thereby inhibit the acetylation of core histones that is necessary for inflammatory gene transcription. We show bothin vitroandin vivothat low-dose theophylline enhances HDAC activity in epithelial cells and macrophages. This increased HDAC activity is then available for corticosteroid recruitment and predicts a cooperative interaction between corticosteroids and theophylline. This mechanism occurs at therapeutic concentrations of theophylline and is dissociated from phosphodiesterase inhibition (the mechanism of bronchodilation) or the blockade of adenosine receptors, which are partially responsible for its side effects. Thus we have shown that low-dose theophylline exerts an anti-asthma effect through increasing activation of HDAC which is subsequently recruited by corticosteroids to suppress inflammatory genes.

The expression of nuclear factor (NF)-κB is an indicator of cellular activation and of inflammatory mediator production. The aim of the present study was to characterise the expression and localisation of p65, the major subunit of NF-κB, in the bronchial mucosa of patients with chronic obstructive pulmonary disease (COPD), and to examine the relationship between p65 expression and disease status.Bronchial biopsies were obtained from 14 smokers with COPD, 17 smokers with normal lung function and 12 nonsmokers with normal lung function. The number of p65 positive (+) cells was quantified by immunohistochemistry and the expression of p65 in bronchial biopsies from the three groups was examined by Western blotting (WB).Smokers with normal lung function and patients with COPD had increased numbers of p65+ cells in the epithelium and increased p65 nuclear expression. In COPD patients the number of epithelial p65+ cells correlated with the degree of airflow limitation. WB analysis showed an increase in p65 in smokers with normal lung function and COPD patients (p<0.05).Bronchial biopsies in smokers with normal lung function and chronic obstructive pulmonary disease patients show increased expression of p65 protein, predominantly in the bronchial epithelium. Disease severity is associated with an increased epithelial expression of nuclear factor-κB.

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.