Maher, Rosemary E ORCID: 0000-0002-2137-6619, Barry, Peter J ORCID: 0000-0001-6326-4431, Emmott, Edward, Jones, Andrew M, Lin, Lijing, McNamara, Paul S ORCID: 0000-0002-7055-6034, Smith, Jaclyn A ORCID: 0000-0001-8837-4928 and Lord, Robert W ORCID: 0000-0001-9008-2502
(2023)
Influence of highly effective modulator therapy on the sputum proteome in cystic fibrosis.
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society.
S1569-1993(23)01669-7-.
Abstract
<h4>Background</h4>There have been dramatic clinical improvements in people with cystic fibrosis (PwCF) commenced on the cystic fibrosis conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (ETI). Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms. Using this technique, we evaluated how ETI changes the sputum proteome in PwCF.<h4>Methods</h4>Sputum samples from 21 CF subjects pre- and post- ETI, 6 CF controls ineligible for ETI, and 15 healthy controls were analysed by liquid chromatography mass spectrometry.<h4>Results</h4>Post-ETI, mean FEV<sub>1</sub> % increased by 13.7 % (SD 7.9). Principal component and hierarchical clustering analysis revealed that the post-ETI proteome shifted to an intermediate state that was distinct from pre-ETI and healthy controls, even for those achieving normal lung function. Functional analysis showed incomplete resolution of neutrophilic inflammation. The CF control sputum proteome did not alter. At the protein-level many more proteins increased in abundance than decreased following ETI therapy (80 vs 30; adjusted p value <0.05), including many that have anti-inflammatory properties. Of those proteins that reduced in abundance many were pro-inflammatory neutrophil-derived proteins. Several important respiratory proteases were unchanged.<h4>Conclusions</h4>Sputum proteomics can provide insights into CF lung disease mechanisms and how they are modified by therapeutic intervention, in this case ETI. This study identifies imbalances in pro- and anti- inflammatory proteins in sputum that partially resolve with ETI even in those achieving normal spirometry values. This post-ETI intermediate state could contribute to ongoing airway damage and therefore its relevance to clinical outcomes needs to be established.
Item Type: | Article |
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Uncontrolled Keywords: | CFTR modulation, Cystic fibrosis, Elexacaftor/tezacaftor/ivacaftor, Sputum proteomics |
Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences Faculty of Health and Life Sciences > Tech, Infrastructure and Environmental Directorate |
Depositing User: | Symplectic Admin |
Date Deposited: | 15 Mar 2024 11:07 |
Last Modified: | 15 Mar 2024 14:57 |
DOI: | 10.1016/j.jcf.2023.10.019 |
Open Access URL: | https://www.cysticfibrosisjournal.com/article/S156... |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3179427 |