Influence of highly effective modulator therapy on the sputum proteome in cystic fibrosis

Maher, Rosemary E ORCID: 0000-0002-2137-6619, Barry, Peter J, Emmott, Edward ORCID: 0000-0002-3239-8178, Jones, Andrew M, Lin, Lijing, McNamara, Paul S ORCID: 0000-0002-7055-6034, Smith, Jaclyn and Lord, Robert W (2024) Influence of highly effective modulator therapy on the sputum proteome in cystic fibrosis JOURNAL OF CYSTIC FIBROSIS, 23 (2). pp. 269-277. ISSN 1569-1993, 1873-5010

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Abstract

Background: 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. Methods: 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. Results: Post-ETI, mean FEV<inf>1</inf> % 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. Conclusions: 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
Uncontrolled Keywords:	Cystic fibrosis, Elexacaftor/tezacaftor/ivacaftor, Sputum proteomics, CFTR modulation
Divisions:	Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences Faculty of Health & Life Sciences > Tech, Infrastructure & Env Directorate
Depositing User:	Symplectic Admin
Date Deposited:	15 Mar 2024 11:07
Last Modified:	22 May 2026 22:48
DOI:	10.1016/j.jcf.2023.10.019
Open Access URL:	https://www.cysticfibrosisjournal.com/article/S156...
Related Websites:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3179427
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