Abstract
BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. In this study, we investigated if AE-COPD are associated with differential expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in bronchoalveolar lavage (BAL).MethodsCOPD patients undergoing diagnostic bronchoscopy, with either stable disease (n = 53) or AE-COPD (n = 44), matched for their demographics and lung function parameters were included in this study. Protein levels of MMP-2,–9,–12 and of TIMP-1 and -2 in BAL were measured by ELISA. Enzymatic activity of MMP-2 and -9 was assessed by gelatin zymography.ResultsWe observed that MMP-9, TIMP-1 and TIMP-2 were significantly increased in BAL during AE-COPD. Furthermore, there was a significant negative correlation of MMP-9, TIMP-1 and TIMP-2 with FEV1% predicted and a significant positive correlation of TIMP-1 and TIMP-2 with RV% predicted in AE-COPD. None of MMPs and TIMPs correlated with DLCO% predicted, indicating that they are associated with airway remodeling leading to obstruction rather than emphysema. In AE-COPD the gelatinolytic activity of MMP-2 was increased and furthermore, MMP-9 activation was significantly up-regulated irrespective of lung function, bacterial or viral infections and smoking.ConclusionsThe results of this study indicate that during AE-COPD increased expression of TIMP-1, TIMP-2, and MMP-9 and activation of MMP-9 may be persistent aggravating factors associated with airway remodeling and obstruction, suggesting a pathway connecting frequent exacerbations to lung function decline.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0240-4) contains supplementary material, which is available to authorized users.
Highlights
Acute exacerbations of chronic obstructive pulmonary disease (AE-Chronic obstructive pulmonary disease (COPD)) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function
Medication including short-acting β2-agonists alone or in combination with long-acting muscarinic antagonists (LAMA), long-acting β2-agonists alone or in combination with inhaled corticosteroids (ICS), ICS alone, oral corticosteroids and xanthines was similar between stable COPD and Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) patients
We showed that Tissue inhibitors of matrix metalloproteinases (TIMP)-1, as well as TIMP-2 levels were significantly increased in bronchoalveolar lavage (BAL) during AE-COPD and that the molar ratios of Matrix metalloproteinase (MMP)-9/TIMP-1 and MMP-2/TIMP
Summary
Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are associated with accelerated aggravation of clinical symptoms and deterioration of pulmonary function. The mechanisms by which exacerbations may contribute to airway remodeling and declined lung function are poorly understood. Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory condition, characterized by progressive airflow limitation that is not fully reversible. The associated episodes are called acute exacerbations of COPD (AE-COPD). Frequent AE-COPD hasten lung function decline affecting quality of life, exercise capacity and survival in patients with COPD [1]. Chronic inflammation in COPD and AE-COPD are associated with disturbances in the homeostasis of extracellular matrix (ECM) molecules, thereby contributing to airway remodeling, which is a hallmark of the disease [5, 6]. The ECM is subjected to a daily turnover of about 10 %, indicating that subtle changes in turnover rates accumulate to large changes in total ECM composition with time
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