SPLUNC1 degradation by the cystic fibrosis mucosal environment drives airway surface liquid dehydration. Issue 4 (4th October 2018)

• Record Type: Journal Article
• Authors: Webster, Megan J.; Reidel, Boris; Tan, Chong D.; Ghosh, Arunava; Alexis, Neil E.; Donaldson, Scott H.; Kesimer, Mehmet; Ribeiro, Carla M.P.; Tarran, Robert
• Is Part Of: European respiratory journal. Volume 52:Issue 4(2018)
• Publication Date: 2018-10-04
• Subjects: Respiratory organs -- Diseases -- Periodicals; Respiration -- Periodicals; 616.2
• DOI: 10.1183/13993003.00668-2018
• Languages: English
• ISSNs: 0903-1936

Abstract

The multi-organ disease cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator gene ( CFTR ) that lead to diminished transepithelial anion transport. CF lungs are characterised by airway surface liquid (ASL) dehydration, chronic infection/inflammation and neutrophilia. Dysfunctional CFTR may upregulate the epithelial Na + channel (ENaC), further exacerbating dehydration. We previously demonstrated that short palate lung and nasal epithelial clone 1 (SPLUNC1) negatively regulates ENaC in normal airway epithelia. Here, we used pulmonary tissue samples, sputum and human bronchial epithelial cells (HBECs) to determine whether SPLUNC1 could regulate ENaC in a CF-like environment. We found reduced endogenous SPLUNC1 in CF secretions, and rapid degradation of recombinant SPLUNC1 (rSPLUNC1) by CF secretions. Normal sputum, containing SPLUNC1 and SPLUNC1-derived peptides, inhibited ENaC in both normal and CF HBECs. Conversely, CF sputum activated ENaC, and rSPLUNC1 could not reverse this phenomenon. Additionally, we observed upregulation of ENaC protein levels in human CF bronchi. Unlike SPLUNC1, the novel SPLUNC1-derived peptide SPX-101 resisted protease degradation, bound apically to HBECs, inhibited ENaC and prevented ASL dehydration following extended pre-incubation with CF sputum. Our data indicate that CF mucosal secretions drive ASL hyperabsorption and that protease-resistant peptides, e.g. SPX-101, can reverse this effect to rehydrate CF ASL. The extracellular cystic fibrosis (CF) environment plays a key role in regulating transepithelial ion transport. CF secretions degrade SPLUNC1 and activate ENaC, causing airway dehydration. http://ow.ly/6WJA30lnDyC