Impact of Overexpression of Wild-Type Cftr and Elexacaftor-Texacaftor-Ivacaftor on Oxylipin Production by Cystic Fibrosis Bronchial Epithelial Cells

34 Pages Posted: 11 Apr 2024

See all articles by Dustin G. Brown

Dustin G. Brown

University of Colorado Anschutz Medical Campus

Jonathan Manke

University of Colorado Anschutz Medical Campus

Michael Armstrong

University of Colorado Anschutz Medical Campus

John O. Marentette

University of Colorado Anschutz Medical Campus

James R. Roede

University of Colorado Anschutz Medical Campus

Nichole Reisdorph

University of Colorado Anschutz Medical Campus

Vanessa V. Phelan

University of Colorado, Aurora - Department of Pharmaceutical Sciences

Abstract

Recently developed highly effective modulator therapy (HEMT) improves pulmonary health for people with CF (PwCF) by targeting the underlying biochemical dysfunction of mutant cystic fibrosis (CF) transmembrane conductance regulator (CFTR). However, its impact on dysregulated lipid metabolism remains under-investigated. In this study, targeted lipidomics revealed that overexpression of wild-type CFTR in the well-studied CFBE41o- CF bronchial epithelial cell line homozygous for the most common CFTR mutation, F508del, resulted in decreased production of prostaglandins and increased production of precursors of specialized pro-resolving mediators, including 14,15-epoxyeicosatrienoic acid (14(15)-EET). Conversely, treatment of CFBE41o- monolayers with the HEMT elexacaftor-tezacaftor-ivacaftor (ETI) increased levels of the prostaglandin E2 (PGE2). This disparity in cellular response by CFBE41o- cells to WT CFTR and ETI was due to differences in production of prostaglandin biosynthetic and regulatory proteins.

Note:
Funding declaration: This work was supported by NIH grant R35GM128690 and the ALSAM Foundation to V.V.P, NIH grant T32 ES029074 to D.G.B, NIH-NCRR grant 1S10OD010366-01A1 to N.R., and NIH grant R01ES027593 to J.R.R.

Conflict of Interests: None to disclose.

Keywords: cystic fibrosis, highly effective modulator therapy, oxylipins, inflammation, prostaglandins, elexacaftor-tezacaftor-ivacaftor

Suggested Citation

Brown, Dustin G. and Manke, Jonathan and Armstrong, Michael and Marentette, John O. and Roede, James R. and Reisdorph, Nichole and Phelan, Vanessa V., Impact of Overexpression of Wild-Type Cftr and Elexacaftor-Texacaftor-Ivacaftor on Oxylipin Production by Cystic Fibrosis Bronchial Epithelial Cells. Available at SSRN: https://ssrn.com/abstract=4785543 or http://dx.doi.org/10.2139/ssrn.4785543

Dustin G. Brown

University of Colorado Anschutz Medical Campus ( email )

CO
United States

Jonathan Manke

University of Colorado Anschutz Medical Campus ( email )

CO
United States

Michael Armstrong

University of Colorado Anschutz Medical Campus ( email )

CO
United States

John O. Marentette

University of Colorado Anschutz Medical Campus ( email )

CO
United States

James R. Roede

University of Colorado Anschutz Medical Campus ( email )

CO
United States

Nichole Reisdorph

University of Colorado Anschutz Medical Campus ( email )

CO
United States

Vanessa V. Phelan (Contact Author)

University of Colorado, Aurora - Department of Pharmaceutical Sciences ( email )

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