cathepsin-g and Bronchitis

The discovery of the association of emphysema and homozygous alpha-1-proteinase inhibitor deficiency gave rise to the hypothesis that emphysema was caused by an imbalance between endogenous proteases and antiproteases. Experimental studies with enzymes have confirmed that emphysema is induced only by enzymes with elastolytic properties. The lesion produced is similar anatomically and physiologically to human emphysema. Genetic and nutritional models of emphysema that appear to be caused by elastic fiber degradation are also known. Alpha-1-protease inhibitor is normally present in the lung; alpha-2-macroglobulin which can loosely complex with elastases, may enter the injured lung and participate in its defense. Alpha-1-protease inhibitor may be inactivated by oxidants derived from cigarette smoke or endogenous phagocytes. The elastase/antielastase hypothesis of emphysema is also believed to be relevant in emphysema caused by cigarette smoking because cigarette smoke gives rise to increased numbers of neutrophils and macrophages in the lung thus increasing the elastase burden of the lung. The precise role of oxidation of alpha-1-protease inhibitor in-vivo by cigarette smoke is not yet clear. In-vitro and experimental data suggest that oxidants can also interfere with repair of lung matrix. A variety of injuries, including proteases, can give rise to secretory cell metaplasia in the central airways. Peripheral airways injury is produced by gases with oxidant properties such as ozone and NO2. The presence of a low molecular weight protease inhibitor in airway epithelial secretory cells when considered with enzyme-induced secretory cell metaplasia raises the possibility of a protease/antiprotease hypothesis of chronic bronchial injury. Although information on the pathogenesis of emphysema is still incomplete, efforts are being made to develop antiproteases which might be used in the prevention of emphysema and chronic bronchial injury.

Topics: alpha 1-Antitrypsin; Animals; Blood Proteins; Bronchitis; Cathepsin G; Cathepsins; Disease Models, Animal; Humans; Neutrophils; Pancreatic Elastase; Pulmonary Emphysema; Serine Endopeptidases

Topics: Animals; Binding, Competitive; Bronchi; Bronchitis; Cathepsin G; Cathepsins; Humans; Immune Sera; Lysosomes; Molecular Weight; Neutrophils; Pancreatic Elastase; Protease Inhibitors; Pulmonary Alveoli; Rabbits; Serine Endopeptidases

The cystic fibrosis airway is susceptible to Pseudomonas aeruginosa infection, which stimulates an intense inflammatory response leading to airway obstruction and bronchiectasis. Neutrophils migrate into the airway, and once there, release high concentrations of neutral serine proteases during phagocytosis and in death. In particular, neutrophil elastase is central to progression of bronchiectasis by interfering with bacterial clearance and directly perpetuating the inflammatory response in the airway. Using a murine model of endobronchial inflammation, we found that a different neutrophil-derived serine protease, cathepsin G, inhibited the host's ability to clear Pseudomonas from the lung, based on a 1-log reduction in bacteria recovered from cathepsin G-deficient mice. Higher antibody concentrations were found in respiratory epithelial lining fluid from mice lacking cathepsin G, but there was no difference in other opsonins, such as surfactant proteins A and D. Chemokine levels measured in the lung correlated with bacterial burden and not the animal's genotype, indicating that airway inflammation was not affected by the presence (or absence) of specific serine proteases. These findings suggest that cathepsin G interferes with airway defenses, showing that proteases other than neutrophil elastase have roles in the pathogenesis of suppurative airway diseases.

Topics: Animals; Bronchitis; Cathepsin G; Cathepsins; Cystic Fibrosis; Disease Models, Animal; Leukocyte Elastase; Lung; Mice; Mice, Knockout; Neutrophils; Pseudomonas aeruginosa; Serine Endopeptidases

In cystic fibrosis, colonization of the airways with Pseudomonas aeruginosa follows colonization with Staphylococcus aureus and is related to accelerated deterioration of pulmonary function. Because P. aeruginosa adheres better to cell surfaces devoid of fibronectin, we searched for fibronectin-cleaving activity in bronchial secretions and saliva from 24 patients with cystic fibrosis who were followed up for 4.5 y and from two control groups. Proteolytic activity against 125I-labeled fibronectin was continuously present in cystic fibrosis bronchial secretions; significantly higher fibronectin-cleaving activity was found in older vs. younger patients, in patients with advanced disease stages determined by a five-stage scoring system, and in those colonized with P. aeruginosa. The fibronectin-cleaving activity was due to neutrophil elastase and cathepsin G. Cystic fibrosis bronchial secretions had proteolytic activity against surface fibronectin of airway mucosal cells. Thus fibronectin-cleaving activity of bronchial secretions rather than of saliva may favor P. aeruginosa colonization of the upper respiratory tract in individuals with cystic fibrosis.

Topics: Adolescent; Adult; Bacterial Infections; Bronchi; Bronchitis; Cathepsin G; Cathepsins; Child; Child, Preschool; Cystic Fibrosis; Fibronectins; Humans; Infant; Pancreatic Elastase; Peptide Hydrolases; Saliva; Serine Endopeptidases; Sputum