Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

Abstract

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases.

COVID-19 and Liquid Homeostasis in the Lung—A Perspective through the Epithelial Sodium Channel (ENaC) Lens

“…This highlights the importance of CAP1 for ENaC regulation in the lung in situations associated with liquid accumulation in the alveolar region. This finding is in agreement with in vitro studies that found that proper ENaC function in the lung relies on the activity of multiple proteases and not just CAP1 [ 38 , 44 ]. Nevertheless, the understanding of how certain proteases regulate ENaC function in vivo remains mysterious, as indicated by the study of Donaldson and colleagues [ 41 ].…”

Reactive Oxygen Species and Antioxidative Defense in Chronic Obstructive Pulmonary Disease

“…Under the direction of these chemotactic mediators, neutrophils migrate into the respiratory tract and secrete serine proteases, including neutrophil elastase, cathepsin G, and proteinase-3, which damage tissues and stimulate mucus secretion from submucosal glands and goblet cells. Neutrophils also secrete matrix metalloproteinase (MMP)-8 and MMP-9, which contribute to alveolar destruction and development of emphysema [15,43,44].…”

The IRE1α–XBP1s Arm of the Unfolded Protein Response Activates N-Glycosylation to Remodel the Subepithelial Basement Membrane in Paramyxovirus Infection

“…Furthermore, KIRA8 strongly induced the secretion of serine protease inhibitors. Proteases and protease inhibitors in the normal lungs coordinate their functions in lung injury and repair [ 57 , 58 ]. Dysregulation of the proteases–antiproteases balance is crucial in the manifestation of different types of lung diseases, such as chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and acute respiratory distress syndrome, where a marked increase in protease activities was observed [ 59 , 60 , 61 , 62 , 63 ].…”