Autophagy-mediated mucin degradation is necessary for resolution of mucous metaplasia

粘膜阻塞性气道疾病包括哮喘、慢性阻塞性肺病、囊性纤维化和非cf支气管扩张

Muco-obstructive airway diseases including asthma, COPD, cystic fibrosis, and non-CF bronchiectasis have diverse genetic and environmental origins, but have certain common features that includes pathologic epithelial changes referred to as mucous metaplasia. Airway secretory cells differentiate into mucous cells with a goblet cell morphology packed with mucin granules containing MUC5AC and, to lesser extent, MUC5B. These airway diseases are characterized by frequent exacerbations due to mucous hypersecretion and blockage of the airways that leads to loss of lung function, hospitalization, and risk of death. While many of the factors that cause mucous metaplasia have been identified, little is known about how it resolves. Autophagy is a key cellular protein recycling system that degrades proteins in response to nutrient deprivation, inflammation, and infection. We have spent the last several years studying the role of autophagy in airway disease using models with genetic deletions of a key autophagy regulatory genes. In this application, we propose a new paradigm in which mucin granule degradation contributes to resolution of mucous metaplasia through the action of autophagy. Three key findings in our preliminary data support this hypothesis: First, autophagy deficient mouse and cell culture models accumulate more cytoplasmic mucin granules during mucous metaplasia and particularly during resolution. Second, mucous metaplasia is associated with mTOR activation and increased epithelial metabolism which is then down-regulate during resolution. We propose that this shift in metabolism is the key trigger initiating mucin degradation during resolution. Third, mimicking this shift in metabolism with mTOR inhibitors leads to autophagy activation and mucin degradation in human airway epithelial secretory cells. To test our hypothesis that autophagy leads to degradation of mucin granules, we propose three research aims: First, we will determine how mTOR signaling contributes to metabolism change in the secretory cell and ultimately to autophagy-mediated mucin degradation. Second, we will characterize the importance of autolysosome-lysosome fusion during mucous metaplasia resolution by examinig vesicle trafficking, lysosome biogenesis, and lysosome proteolytic function. Third, we will explore mucin degradation as a therapeutic strategy in models of muco-obstructive airway diseases. These findings can provide the framework for a new therapeutic strategy to hasten the resolution of airway disease exacerbations.