Putting the CAP on ENaC: The role of serine proteases in the regulation of airways hydration and mucociliary clearance in chronic airways diseases.

Lorraine Martin*

*Corresponding author for this work

Research output: Contribution to conferencePaperpeer-review

Abstract

Chronic airways diseases. such as cystic fibrosis (CF), are associated with significant airways dehydration that contributes to mucus obstruction and impaired mucociliary clearance (MCC). In normal airways an optimal volume of airways surface liquid (ASL) is regulated by the cystic fibrosis transmembrane conductance regulator (CFTR) working in concert with the epithelial sodium channel (ENaC), to balance Cl- secretion with Na+ absorption. In CF, mutations in CFTR, coupled with a dysregulation of ENaC, thickens airways secretions leading to devastating cycles of infection and inflammation and irreversible tissue injury. A major development in recent years has been the approval of CFTR modulator therapies which have been found to help stall the progressive decline in lung function characteristic of this disease. Other therapeutic strategies are however, urgently required for those who have no access to these drugs and for the 10% of people with CF worldwide who have nonsense mutations and thus, are non-responsive to CFTR modulation. Inhibition of ENaC offers an attractive, mutation-agnostic approach to treatment that would be suitable for all people with CF, as well as those suffering from other chronic airways diseases such as chronic obstructive pulmonary disease (COPD). ENaC is activated by the proteolytic cleavage of its subunits (alpha, beta and gamma), each of which include two membrane-spanning domains connected by a large extracellular loop. The channel activating proteases (CAPs) predominantly belong to the trypsin-like family of serine proteases, although neutrophil elastase can induce activation of ENaC subsequent to pre-processing by the proprotein convertase, furin. The presentation will include a discussion of both the broad-spectrum inhibition of putative CAPs, to include human airways trypsin-like protease (HAT), prostasin and matriptase and the selective inhibition of furin, which result in diminished ENaC-mediated Na+ absorption in CF primary human airway epithelial cells grown at air liquid interface, an increase in ASL height and restoration of MCC. In particular, selective furin inhibition has the potential to be used as a treatment for all people with CF, independent of CFTR mutation, and in combination with CFTR modulators.
Original languageEnglish
Publication statusPublished - 02 Nov 2023
EventASBMB Serine proteases in pericellular proteolysis and signaling - Virtual
Duration: 02 Nov 202303 Nov 2023
https://www.asbmb.org/meetings-events/serine-proteases-2023

Conference

ConferenceASBMB Serine proteases in pericellular proteolysis and signaling
Period02/11/202303/11/2023
Internet address

Keywords

  • ENaC
  • serine proteases
  • cystic fibrosis
  • airways hydration
  • mucociliary clearance

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