Mast Cell-Mediated Orchestration of Airway Epithelial Responses in Chronic Respiratory Diseases

Abstract: Chronic respiratory diseases, such as asthma, are an increasing health issue worldwide and cause about 3.9 million deaths annually. Despite this, little is know about the molecular mechanisms underpinning disease pathogenesis. Bronchial and alveolar remodeling and impaired epithelial function are typical characteristics of chronic respiratory diseases. In these patients, an increased number of mast cells, positive for the serine proteases; tryptase and chymase, infiltrate the epithelium and the alveolarparenchyma. While it is likely that the epithelial cells are exposed to various amounts of released tryptase and chymase, the interaction between mast cells and epithelial cells remains unknown. This thesis aimed to investigate the impact of mast cell proteases on bronchial and alveolar remodelling. Human bronchial and alveolar epithelial cells were treated with tryptase and chymase. Holographic live cell imaging, fluorescent microscopy, and gene and protein assays were used to analyze various parameters such as proliferation patterns, protein expressions and distributions. The results showed that both tryptase and chymase promoted epithelial remodelling in several ways. Tryptase induced cell growth, cell survival, and wound healing, whereas chymase reduced cell growth, altered cell morphology and impaired epithelial barrier properties. In conclusion, our results suggest that intraepithelial and alveolar mast cell release of proteases plays a crucial role in epithelial homeostasis, and that an imbalance of the protease release may be involved in respiratory disease progression and in disruption of critical epithelial functions.