Roles of Mast Cell Proteases in Airways: Cleavage of Epithelial Glycocalyx

10 Nov

Roles of Mast Cell Proteases in Airways: Cleavage of Epithelial GlycocalyxCleavage of Epithelial Glycocalyx
Dog tracheal epithelial cells in culture synthesize sulfated macromolecular glycoconjugates and release them from the cell surface upon exposure to extracellular proteinases. In these studies, chymase potently released these glycoconjugates from the epithelial cell glycocalyx. The release of glycoconjugates by chymase provides a mechanism by which mast cell degranulation may affect such processes as bacterial adhesion, the viscoelastic properties of airway secretions, and perhaps the responsiveness of airway epithelial cells to mediators or drugs. read more

Airway Submucosal Gland Secretion
Abnormalities in secretion are hallmarks of various chronic diseases of airways, including cystic fibrosis, chronic bronchitis, and asthma. Study of gland secretion in whole tissues is confounded by potential contamination by cell-surface macromolecules from epithelial cells and by secretions from goblet cells. To study uncontaminated gland cell secretions, we were fortunate to have access to a pure cell line of bovine tracheal gland serous cells developed by our colleagues. These cells maintain characteristics of differentiated serous cells, including the presence of secretory granules and the ability to secrete macromolecules in response to various agonists. Mast cell supernatant stimulated the release of radiolabeled macromolecules, and this secretagogue effect was prevented by an inhibitor of chymase (soybean trypsin inhibitor) but was unaltered by an inhibitor of tryptase (aprotinin). These results were confirmed by studies of purified enzymes: chymase markedly stimulated secretion (threshold, 10“M), whereas tryptase had no effect. The effect was nontoxic and was prevented by chymase inhibitors.

Chymase is the most potent secretagogue yet described for these serous cells. These results suggest a possible role for chymase-containing mast cells in hypersecretory states. It is interesting that chymase-containing mast cells are rare in peripheral airways, but their numbers are substantially increased in bronchi where the submucosal glands are located. It is intriguing that in cystic fibrosis, a disease characterized by hypersecretion, the numbers of tryptase-containing mast cells are reported to be increased. These results raise interesting questions: Does the milieu in locations inhabited by submucosal glands modify the phenotype of mast cells to increase expression of chymase? How do various diseases modify the characteristics of local mast cells? Can hypersecretory effects in diseases be modified by treatment with chymase inhibitors? These studies indicate that the mast cell proteases tryptase and chymase have potent effects on multiple cells in airways, and they suggest new approaches to the treatment of diseases such as asthma.