Clinical and Experimental Allergy, 2001, Volume 31, pages 193±205 REVIEW Markers of active airway inflammation and remodelling in chronic obstructive pulmonary disease S. R. RUTGERS * , W. TIMENS², H. F. KAUFFMAN³ and D. S. POSTMA * Departments of * Pulmonology, ²Pathology and ³Allergology, University Hospital Groningen, Groningen, The Netherlands Introduction Chronic obstructive pulmonary disease (COPD) is defined as a disorder characterized by reduced maximum expiratory flow and slow forced emptying of the lungs, features which do not change markedly over several months [1]. Most of the airflow limitation is slowly progressive and irreversible. COPD is a broad term and includes three clinical conditions: chronic bronchitis, small airways disease and emphysema. The airflow limitation is due to varying combinations of destruction and remodelling of the small airways and the lung parenchyma, which cause an increase in airway resistance mainly in the small airways [2]. Cigarette smoking has been shown to be the most important risk factor and accounts for 80±90% of the risk of developing COPD [3]. Airway hyperresponsive- ness, a 1 -antitrypsin deficiency and certain occupational exposures are other established risk factors for the development of COPD [4]. The mechanism via which the presence of these risk factors results in airflow limitation has been investigated intensively in the last decades, but has not been clarified yet. It is probable that the development of airflow limitation in COPD is mainly caused by inflammatory changes in the airways and lung parenchyma. The introduction of fiberoptic bronchoscopy in the early seventies opened the way to perform airway wall biopsies, thereby facilitating invasive research of the airways and providing tissue samples to study inflammation. It has demonstrated directly, combined with results of analysis of induced sputum, and indirectly via investigation of exhaled air and hyperrespon- siveness, the presence of airway inflammation. With regard to the development of airflow limitation, the emphasis until recently has been on tissue destruction caused by mediators of inflammatory cells. The parenchymal destruction as seen in emphysema was suggested to be caused by an inflam- matory process due to a protease-antiprotease-imbalance and oxidant-antioxidant-imbalance [5]. The basis for this theory of parenchymal destruction was the association of emphysema with congenital a 1 -antitrypsin deficiency and the occurrence of emphysema-like pathological changes in hamsters after intratracheal instillation of elastase. The protease-antiprotease-imbalance suggests that proteases with elastin degrading capacity are insufficiently inhibited by antiproteases and thereby induce emphysema. The oxidant- antioxidant-imbalance suggests that oxidants, which can injure lung tissue, interfere with repair of the extracellular matrix and inactivate antiproteases, are insufficiently inhibi- ted by antioxidants and thereby induce emphysema. The theory about oxidant-antioxidant-imbalance was excellently reviewed by Rahman and McNee recently [6]. However, as the activity of proteases and oxidants can be expected to be quite similar in all smokers, the protease-antiprotease- imbalance and the oxidant-antioxidant-imbalance theories do not explain why only 10±20% of all smokers develop emphysema. Moreover, these theories explain the paren- chymal destruction of emphysema but do not explain changes in the small airways. Therefore, the concept of airway remodelling caused by abnormal repair of the small airways and parenchyma has become more and more accepted [7]. Airway remodelling The concept of airway remodelling is that tissue destruction induces a repair process with proliferation and activation of resident airway cells, which produce proteins for the extracellular matrix (ECM), matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). In a part of the smoking population this remodelling process is insufficient, resulting in airflow limitation. This process is characterized by structural changes, which can be found in the large and small airways and in the parenchyma [8]. In the large airways, structural changes in COPD have been observed in mucous glands and epithelium. Mucous gland hypertrophy and goblet cell hyperplasia occur in chronic bronchitis and contribute to excess mucus production. Epithelial changes include atrophy, squamous metaplasia and loss of ciliated epithelial cells and decrease of cilia q 2001 Blackwell Science Ltd 193 Correspondence: Dr S. R. Rutgers, Department of Pulmonology, University Hospital Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.