Autophagy Activation in Asthma Airways Remodeling.

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Journal Article
Am J Respir Cell Mol Biol, 2018
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01 Nov 2018_Autophagy Activation in Asthma Airways Remodeling.2018-0169oc.pdfPublished Version11.45 MB
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Current asthma therapies fail to target airway remodeling which correlates with asthma severity driving disease progression that ultimately leads to loss of lung function. Macroautophagy (here after autophagy) is a fundamental cell recycling mechanism in all eukaryotic cells; emerging evidence suggests that it is dysregulated in asthma. We investigated the interrelationship between autophagy and airway remodeling and assessed preclinical efficacy of a known autophagy inhibitor in murine models of asthma. Human asthmatic and non-asthmatic lung tissues were histologically evaluated and were immuno-stained for key autophagy markers. The percent area of positive staining was quantified in the epithelium and airway smooth muscle (ASM) bundles using ImageJ software. Furthermore, autophagy inhibitor chloroquine (CQ) was tested (i.n.) in prophylactic (3-week) and treatment (5-week) models of allergic asthma in mice. Human asthmatic tissues showed greater tissue inflammation and demonstrated hallmark features of airway remodeling displaying thickened epithelium (p<0.001) and reticular basement membrane (p<0.0001), greater lamina propria depth (p<0.005), and increase in ASM bundles (p<0.001) with higher expression of Beclin1 (p<0.01) and ATG5 (p<0.05) along with reduced p62 (p<0.05) compared to non-asthmatic controls. Beclin1 expression was significantly higher in asthmatic epithelium and ciliated cells (p<0.05) suggesting potential role of ciliophagy in asthma. Murine asthma models demonstrated effective preclinical efficacy (reduced key features of allergic asthma: airway inflammation, AHR and airway remodeling) of autophagy inhibitor CQ. Our data demonstrates cell-context dependent, and selective activation of autophagy in structural cells in asthma. Further, this pathway can be effectively targeted to ameliorate airway remodeling in asthma.
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