Smoking cessation is the only treatment in patients with chronic obstructive pulmonary disease (COPD) effective in slowing down disease progression. Its effect on airway inflammation in COPD is unknown, although cross-sectional studies suggest ongoing inflammation in ex-smokers.In order to elucidate the effect of smoking cessation on airway inflammation, 28 smokers with COPD (mean age: 55 yrs; forced expiratory volume in one second: 71% predicted) and 25 asymptomatic smokers with normal lung function (aged 50 yrs) were included in a 1-yr smoking cessation programme. Effects of smoking cessation on airway inflammation were investigated in bronchial biopsies (baseline, 12 months) and sputum samples (baseline, 2, 6 and 12 months).In the 12 candidates with COPD who successfully ceased smoking, airway inflammation persisted in bronchial biopsies, while the number of sputum neutrophils, lymphocytes, interleukin (IL)-8 and eosinophilic-cationic-protein levels significantly increased at 12 months. In the 16 asymptomatic smokers who successfully quitted, inflammation significantly reduced (i.e. number of sputum macrophages, percentage of eosinophils and IL-8 levels) or did not change.The current authors suggest that the observed persistent airway inflammation in patients with chronic obstructive pulmonary disease is related to repair of tissue damage in the airways. It remains to be elucidated whether this reflects a beneficial or detrimental effect.

In order to determine the presence and distribution of Haemophilus influenzae in lung tissue sections, we obtained lung explants from 49 lung transplant recipients with cystic fibrosis (CF) (n = 16), chronic obstructive pulmonary disease (COPD) including emphysema (n = 16), bronchiectasis (n = 5), pulmonary hypertension (n = 9), Langerhans cell histiocytosis (n = 1), and idiopathic pulmonary fibrosis (n = 2). Analysis was done by selective culturing, immunoperoxidase (IP) staining, and by polymerase chain reaction (PCR). H. influenzae was cultured from specimens of the lung explants from one CF and one COPD patient. IP staining of tissue sections was positive in 24 patients (10 CF patients, eight COPD patients, two bronchiectasis patients, and four patients with noninfectious pulmonary diseases). IP-positive tissue sections were PCR-positive, and IP-negative sections were PCR-negative. H. influenzae was more frequently detected in tissue sections of lung explants from CF and COPD patients than from patients with bronchiectasis or noninfectious pulmonary diseases. H. influenzae was diffusely present in the epithelium, the submucosa of the bronchi, the bronchioles, the interstitium, and the alveolar epithelium. H. influenzae was localized extracellularly alone and in bacterial clusters, and was also associated with macrophages in CF patients. The results of this study demonstrate that H. influenzae is often present in the lungs of patients with end-stage pulmonary disease, especially CF and COPD patients. H. influenzae is diffusely present in the respiratory epithelium and subepithelial layers of the lungs of these patients.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease characterised by scarring of the lung that is believed to result from an atypical response to injury of the epithelium. The mechanisms by which this arises are poorly understood and it is likely that multiple pathways are involved. The strongest genetic association with IPF is a variant in the promoter of MUC5B where each copy of the risk allele confers a five-fold risk of disease. However, genome-wide association studies have reported additional signals of association implicating multiple pathways including host defence, telomere maintenance, signalling and cell-cell adhesion. Objectives:To improve our understanding of mechanisms that increase IPF susceptibility by identifying previously unreported genetic associations. Methods and measurements:We performed the largest genome-wide association study undertaken for IPF susceptibility with a discovery stage comprising up to 2,668 IPF cases and 8,591 controls with replication in an additional 1,467 IPF cases and 11,874 controls. Polygenic risk scores were used to assess the collective effect of variants not reported as associated with IPF. Main results:We identified and replicated three new genome-wide significant (P<5×10 −8 ) signals of association with IPF susceptibility (near KIF15, MAD1L1 and DEPTOR) and confirm associations at 11 previously reported loci. Polygenic risk score analyses showed that the combined effect of many thousands of as-yet unreported IPF risk variants contribute to IPF susceptibility. Conclusions:Novel association signals support the importance of mTOR signalling in lung fibrosis and suggest a possible role of mitotic spindle-assembly genes in IPF susceptibility.

Background: Chronic obstructive pulmonary disease (COPD) is associated with airway inflammation. Although smoking cessation improves symptoms and the decline in lung function in COPD, it is unknown whether bronchial inflammation in patients with established COPD varies with the duration of smoking cessation. Methods: 114 patients (99 men) with COPD of mean (SD) age 62 (8) years, a median (IQR) smoking history of 42 (31-55) pack years, no inhaled or oral corticosteroids, all current or ex-smokers (n = 42, quit .1 month, median cessation duration 3.5 years), post-bronchodilator FEV 1 63 (9)% predicted, and FEV 1 /IVC 48 (9)% were studied cross sectionally. The numbers of subepithelial T lymphocytes (CD3, CD4, CD8), neutrophils, macrophages, eosinophils, mast cells, and plasma cells were measured in bronchial biopsy specimens (median (IQR)/0.1 mm 2 ) using fully automated image analysis. Results: Ex-smokers with COPD had higher CD3+, CD4+, and plasma cell numbers than current smokers with COPD (149 (88-225) v 108 (61-164), p = 0.036; 58 (32-90) v 40 (25-66), p = 0.023; and 9.0 (5.5-20) v 7.5 (3.1-14), p = 0.044, respectively), but no difference in other inflammatory cells. Short term ex-smokers (,3.5 years) had higher CD4+ and CD8+ cell numbers than current smokers (p = 0.017, p = 0.023; respectively). Conversely, long term ex-smokers (quit >3.5 years) had lower CD8+ cell numbers than short term ex-smokers (p = 0.009), lower CD8/CD3 ratios than both current smokers and short-term ex-smokers (p = 0.012, p = 0.003; respectively), and higher plasma cell numbers than current smokers (p = 0.003). Conclusions: With longer duration of smoking cessation, CD8 cell numbers decrease and plasma cell numbers increase. This indicates that bronchial T lymphocyte and plasma cell counts, but not other inflammatory cells, are related to duration of smoking cessation in patients with COPD.