Inhibition der Mucindegradation als Ursache Für Mukusakkumulation im Verlauf einer pulmonalen COPD-Exazerbation

Chronic Obstructive Pulmonary Disease (COPD) is a lung disease with a high prevalence which is caused by an enhanced inflammatory response to chronic exposure to noxious particles or gases. The most important one among these noxious agents is cigarette smoke. The chronic inflammatory response leads to structural changes within the lung tissue causing persistent airflow limitation that is characteristic for COPD. The increased airflow resistance is not only caused by airway remodelling due to chronic inflammatory response but also by increased mucin synthesis und secretion leading to a narrowing of the airway radius. In this study, there were sputum samples taken from patients with an acute exacerbation of chronic obstructive pulmonary disease and 5-6 weeks after the exacerbation. Those samples were compared to a control group of samples from patients without a known lung disease. In all three groups the concentration of the main mucins in the sputum (MUC5AC and MUC5B) was measured by western blot. It was shown that the concentration of MUC5AC was higher in patients with COPD than in patients without a lung disease. Furthermore it could also be shown that this mucin was higher concentrated in sputum collected at the time of exacerbation than in samples of non-exacerbated COPD. For MUC5B a significant higher concentration could only be shown in exacerbated COPD compared to the control group. As a cause for this higher mucin concentration at the time of exacerbation there was found that in addition to the already known factors there is also a postsecretory influence on mucin concentration. Looking at the mucin degradation by incubating the sputum samples at body temperature, it was shown that the degradation process was significantly decreased in samples of exacerbated COPD than in those of non-exacerbated COPD. It was also found that in vitro it was possible to increase the degradation process by adding synthetic proteases like HNE or cathepsin G and to decrease the process by adding antiproteases. The reason for the differences in the degradation rate seems to be an imbalance in the protease/antiprotease network that leads to an increased effect of antiproteases during an acute exacerbation of COPD. One factor that could have influences on the balance of proteases and antiproteases in the airways is cigarette smoke. In this study, it was shown that cigarette smoke condensate (CSC) could decrease the activity of synthetic serin proteases measured by ELISA as well as it could decrease the mucin degradation in the sputum samples. In conclusion, the theory of a postsecretory modification of mucins that contributes to the mucus accumulation in the airways of COPD patients was supported by the described findings. Putting this theory into consideration, the use of mucolytic agents in the therapy of COPD should be reconsidered. Cigarette smoke, which is already known to have an increasing effect on mucin production and secretion, was now shown to have also negative effects on mucin degradation which supports the already well-established necessity of smoking cessation in the therapy of patients with COPD.