Role of mitochondria in the development of airway remodeling in severe asthma

Subepithelial fibrosis is a characteristic feature of airway remodeling in asthma which correlates with disease severity. The accumulation of fibroblasts, their synthesis of extracellular matrix proteins and their innate resistance to apoptosis are characteristics of subepithelial fibrosis observed in severe asthma. Current asthma medications are ineffective in treating airway fibrosis necessitating a deeper understanding of the mechanism of fibrosis in asthma, particularly in the severe phenotype that represents a distinct phenotype with their mixed pattern of neutrophilic-eosinophilic inflammation and glucocorticoid insensitivity making them refractory to currently available therapies. Disrupted mitochondrial quality control mechanisms and mitochondrial dysfunction have been extensively studied in the pathogenesis of other chronic lung diseases, including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, but less explored in asthma and severe asthma per se.

In this study, we aimed to investigate mitochondrial health in bronchial fibroblasts isolated from airway biopsies of non-asthmatic and severe asthmatic subjects by examining their mitochondrial quality control machinery as a mechanism contributing to fibroblast persistence and thereby, fibrosis in severe asthma. We hypothesized that severe asthmatic fibroblasts exhibit mitochondrial damage resulting in their aberrant pro-fibrotic phenotype. Firstly, we provide evidence of increased activation of mitophagy and mitochondrial biogenesis in severe asthmatic fibroblasts as a result of significantly reduced mitochondrial membrane potential at baseline compared to non-asthmatic controls. Interestingly, these fibroblasts displayed neither an apoptotic nor senescent phenotype, but an adaptive survival mechanism triggered by increased AMPKα phosphorylation. 

Cytokines, such as IL-17A, TGF-β1 and IL-13 are enriched in severe asthmatic airways and are important regulators of airway remodeling in asthma. However, their regulation of mitochondrial function and pro-fibrotic phenotype in severe asthmatic fibroblasts is not well characterized. We hypothesized that these asthma-related cytokines impair mitochondrial function in severe asthmatic fibroblasts contributing to the development of fibrosis. To our knowledge, this is the first study to demonstrate that IL-17, TGF-β and IL-13 accelerated mitochondrial dysfunction in bronchial fibroblasts, but to a greater extent in severe asthmatic fibroblasts when compared to non-asthmatic controls. IL-17, in particular, intensified the mitochondrial dysfunction but impaired the mitochondrial quality control machinery in the non-asthmatic and severe asthmatic fibroblasts. Moreover, IL-17 augmented a pro-fibrotic and anti-apoptotic response in both group of fibroblasts. Inhibition of autophagy using bafilomycin-A1 appeared to reduce the need for mitophagy and restored the IL-17 mediated changes in these markers to their basal levels. Bafilomycin-A1 also reversed the IL-17 associated fibrotic response in these fibroblasts, suggesting a role for autophagy in the induction of fibrosis by IL-17 in bronchial fibroblasts. Our findings thus, suggest that IL-17 induced autophagy promotes mitochondrial dysfunction and fibrosis in bronchial fibroblasts from both non-asthmatic and severe asthmatic subjects.

Additionally, we also studied Bcl10-mediated NF-κB activation as a potential pathway regulating fibrotic signaling in severe asthmatic fibroblasts. This is the first report providing evidence of elevated protein expression of Bcl10 in the pathogenesis of severe asthma. Additionally, we also identified the participation of Bcl10-mediated NF-κB pathway in the LPS-induced activation of IL-8 in bronchial fibroblasts, where an exaggerated response was noted in severe asthmatic fibroblasts when compared to controls.