Increased Autophagy-Related 5 Gene Expression Is Associated with Collagen Expression in the Airways of Refractory Asthmatics

Abstract

BackgroundFibrosis, particularly excessive collagen deposition, presents a challenge for treating asthmatic individuals. At present, no drugs can remove or reduce excessive collagen in asthmatic airways. Hence, the identification of pathways involved in collagen deposition would help to generate therapeutic targets to interfere with the airway remodeling process. Autophagy, a cellular degradation process, has been shown to be dysregulated in various fibrotic diseases, and genetic association studies in independent human populations have identified autophagy-related 5 (ATG5) to be associated with asthma pathogenesis. Hence, the dysregulation of autophagy may contribute to fibrosis in asthmatic airways.ObjectiveThis study aimed to determine if (1) collagen deposition in asthmatic airways is associated with ATG5 expression and (2) ATG5 protein expression is associated with asthma per se and severity.MethodsGene expression of transforming growth factor beta 1, various asthma-related collagen types [collagen, type I, alpha 1; collagen, type II, alpha 1; collagen, type III, alpha 1; collagen, type V, alpha 1 (COL5A1) and collagen, type V, alpha 2], and ATG5 were measured using mRNA isolated from bronchial biopsies of refractory asthmatic subjects and assessed for pairwise associations. Protein expression of ATG5 in the airways was measured and associations were assessed for asthma per se, severity, and lung function.Main resultsIn refractory asthmatic individuals, gene expression of ATG5 was positively associated with COL5A1 in the airways. No association was detected between ATG5 protein expression and asthma per se, severity, and lung function.Conclusion and clinical relevancePositive correlation between the gene expression patterns of ATG5 and COL5A1 suggests that dysregulated autophagy may contribute to subepithelial fibrosis in the airways of refractory asthmatic individuals. This finding highlights the therapeutic potential of ATG5 in ameliorating airway remodeling in the difficult-to-treat refractory asthmatic individuals.

IL-17 Induced Autophagy Regulates Mitochondrial Dysfunction and Fibrosis in Severe Asthmatic Bronchial Fibroblasts

“…Moreover, inhibiting autophagy using chloroquine was found to attenuate airway inflammation, airway hyperresponsiveness and airway remodeling, including a reduction in α-SMA immunoreactivity in the airways, in allergic asthmatic mice. We have also previously reported that dysregulation of autophagy is associated with subepithelial fibrosis in the airways of refractory asthmatics (19). In this study, ATG5 gene expression positively correlated with COL5A1 expression in bronchial biopsies from refractory asthmatics.…”

“…Paraffin slides of bronchial biopsy tissues obtained by fiberoptic bronchoscopy from non-asthmatic control subjects archived at the Biobank of the Quebec Respiratory Health Research Network Canada with MUHC REB number BMB-02-039-t (19), were obtained. Severe asthmatic subjects, who fulfilled the American Thoracic Society (ATS) criteria and were taking treatments based on the Global Initiative for Asthma (GINA), were recruited by the treating physician and nurse who obtained written informed consent, from the Severe Asthma Clinic in the Pulmonary Medicine department at Rashid Hospital, Dubai, UAE.…”

Autophagy Activation in Asthma Airways Remodeling

“…However, there has been limited histopathological evidence to show similar trends in the lungs of patients with asthma. Although there are early reports on increased gene expression of ATG5 with additional measurement of ATG5 protein expression in the airways of patients with refractory asthma (16,19), our study provides a comprehensive analysis of multiple autophagy markers and their association with airway remodeling in asthma. More importantly, our data on Beclin-1 expression in both large and small airways and in the ciliated cells provide novel insight into how the autophagy pathway may regulate and control airway remodeling in asthma.…”

“…Autophagy is involved in the pathogenesis of various diseases, and links between autophagy and asthma are emerging (16)(17)(18). A positive correlation of ATG5 and collagen alpha-1 (V) gene expression in the airways of patients with refractory asthma supports this link between dysregulated autophagy and fibrosis in the airways (19). ECM-regulated autophagy is proposed to maintain tissue homeostasis, and thus dysfunctional autophagy in the presence of increased TGF-b may propel the progression of airway remodeling (20).…”

Role of Autophagy in Lung Inflammation

“…Dysfunctional autophagy pathways also lead to metabolic remodeling that leads to airway inflammation (28,30). Epithelial cells are also involved in exacerbating pulmonary inflammation and are available therapeutic targets (48,49). Autophagy plays a key role in the regulation of cytokine signaling in a variety of cell types, likely leading to the pathogenesis of pulmonary diseases.…”