Autophagy Is Selectively Activated and Correlated with Airway Remodeling in Asthma

American Thoracic Society
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Conference Proceeding
American Journal of Respiratory and Critical Care Medicine, 2018, 197-A7267
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Rationale: Asthma affects more than 330 million people worldwide and poses a huge economic burden on the healthcare system. Current anti-asthma therapies provide symptomatic relief but fail to target airway remodeling which drives disease progression and loss of lung function with time. Macroautophagy (autophagy) is a fundamental process that occurs in all eukaryotic cells and can be referred to as the cell recycling mechanism. Emerging evidence suggest that autophagy is dysregulated in asthma and can modulate pro-fibrotic signaling in asthma. Autophagy modulation may be a novel effective therapy for unmanageable asthma. The aim of this study was to explore the role of autophagy in asthma by investigating the interrelationship between autophagy markers and features of airway remodeling in large airways obtained from asthmatics (n=6) and non-asthmatics (n=8). Methods: Selected asthmatic tissue with hallmark features of airway remodeling (correlates with severe disease) and non-asthmatics were immuno-stained for autophagy markers; Beclin1, ATG5, and p62. The percent area of positive staining was quantified in the epithelium and airway smooth muscle (ASM) using ImageJ software. Features of airway remodeling were also measured in the large airways of patients using H&E and Masson’s Trichrome staining. Results: Asthmatic airways in comparison with non-asthmatic airways displayed greater epithelium (p<0.01), and reticular basement membrane thickness (p<0.0001) with greater lamina propria depth (p<0.0001), and increased ASM bundles (p<0.005). Overall they displayed hallmark features of airway remodeling. In the ASM bundles, expression of ATG5 was significantly higher (p<0.05), while there was a trend for increased expression of Beclin-1 (p=0.08) and reduced expression of p62 (p=0.18) in asthmatics when compared with non-asthmatics. We found no difference in the expression profile of autophagy markers in the epithelium of asthmatics vs non-asthmatics. Interestingly, in asthmatic airways, Beclin-1 staining in the epithelial layer correlated with epithelium thickness (R2=-0.8228, p<0.05) while, Beclin-1 staining in the ASM bundles correlated with ASM thickness (R2=-0.7132, p<0.05). Similarly ATG5 (R2=-0.7814, p<0.05) and p62 (R2=0.7746, p<0.05) correlated with ASM mass in asthmatic airways. We found no correlation in the non-asthmatic airways. Furthermore asthmatic cilia showed marked Beclin-1 staining when compared to non-asthmatics suggesting potential role of ciliophagy in asthma. Conclusions: Our data demonstrates cell-context dependent, and selective activation of autophagy in asthma. Collectively, our study is the first to report that autophagy process correlates with key features of airway remodeling in asthma, and further understanding of this pathway may provide therapeutic targeting to ameliorate airway remodeling in asthma.
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