Abstract
In the past decade, an emerging process named "autophagy" has generated intense interest in many chronic lung diseases. Tissue remodeling and fibrosis is a common feature of many airway diseases, and current therapies do not prevent or reverse these structural changes. Autophagy has evolved as a conserved process for bulk degradation and recycling of cytoplasmic components to maintain basal cellular homeostasis and healthy organelle populations in the cell. Furthermore, autophagy serves as a cell survival mechanism and can also be induced by chemical and physical stress to the cell. Accumulating evidence demonstrates that autophagy plays an essential role in vital cellular processes, including tissue remodeling. This review will discuss some of the recent advancements made in understanding the role of this fundamental process in airway fibrosis with emphasis on airway remodeling, and how autophagy can be exploited as a target for airway remodeling in asthma and chronic obstructive pulmonary disease.
Highlights
Autophagy is an evolutionarily conserved pathway for the turnover of organelles and proteins by lysosomal-dependent processing[1]
Autophagy-mediated TGFβ1-induced fibrosis plays a key role in the pathogenesis of heart and kidney diseases[42,43], and recent studies in human airway smooth muscle cells have demonstrated that TGFβ1 induced autophagy is required for collagen and fibronectin production, while silencing of key autophagy-inducing proteins Atg[5] and Atg[7] leads to reduction in pro-fibrotic signaling and extracellular matrix (ECM) protein release[44,45]
We propose that blockade of autophagy in the lungs can lead to reduction in airway fibrosis, as seen in airway remodeling in asthma and chronic obstructive pulmonary disease (COPD)
Summary
Autophagy is an evolutionarily conserved pathway for the turnover of organelles and proteins by lysosomal-dependent processing[1]. Autophagy-mediated TGFβ1-induced fibrosis plays a key role in the pathogenesis of heart and kidney diseases[42,43], and recent studies in human airway smooth muscle cells have demonstrated that TGFβ1 induced autophagy is required for collagen and fibronectin production, while silencing of key autophagy-inducing proteins Atg[5] and Atg[7] leads to reduction in pro-fibrotic signaling and ECM protein release[44,45]. There is a need for more research in exploring the role of various PI3K inhibitors in the context of autophagy dependent-airway remodeling, using the most suitable models of asthma and COPD, as modulation of autophagy by the PI3K pathway can be an attractive target for both severe asthma and COPD47–50 Kinases, such as adenosine monophosphate activated protein kinase (AMPK) and ULK1 (mammalian orthologue of yeast protein kinase Atg1) are required for autophagy. There is a need to identify the right autophagy mechanism in the progression and development of airway remodeling in asthma and COPD, which can become a realistic drug target to prevent structural changes in the lung
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