Effect of hypoxia on Cystic Fibrosis Transmembrane conductance Regulator channel corrected by Elexacaftor/Tezacaftor/Ivacaftor
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Abstract
The accumulation of mucus resulting from the obstruction of bronchi of cystic fibrosis (CF) patients, induces a reduction of the oxygen (O2) pressure and produces a hypoxic environment for the epithelial cells of the lungs. Our study aims to better characterize the impact of hypoxia on CFTR function in the pathophysiological context of cystic fibrosis.
We used Human airway epithelial cells from two CF donors and human bronchial epithelial cell lines non-CF and CF, grown and expended in normoxia (21% O2) and then switched to hypoxia (1% O2) for 2 to 24 hours. Cells were treated by dimethyl sulfoxide or Elexacaftor/ Tezacaftor/Ivacaftor for 24 hours.
We show that the peak of Hypoxia Inducible Factor 1α is reached in a range of 4 to 6 hours post-hypoxia induction. We also demonstrate that the global amount of ETI corrected F508del-CFTR is significantly decreased after 24 hours of hypoxia. A decreased ETI corrected F508del-CFTR activity was recorded by both patch-clamp and Ussing chamber recordings.
Our results show that hypoxia, despite the effectiveness of Elexacaftor/ Tezacaftor/Ivacaftor correction, impacts the downstream effects of the F508del mutation, which suggests that oxygen availability in the lungs is a factor to take into account for the administration of Trikafta to patients.
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References
2. Rowe SM, Miller S, Sorscher EJ. Cystic Fibrosis. New England Journal of Medicine. 2005;352 (19):1992-2001. doi:10.1056/NEJMra043184
3. Welsh MJ, Smith AE. Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis. Cell. 1993;73(7):1251-1254. doi:10.1016/0092-8674(93)90353-r
4. Mirabile VS, Shebl E, Sankari A, Burns B. Respiratory Failure. In: StatPearls. StatPearls Publishing; 2023. Accessed November 8, 2023. http://www.ncbi.nlm.nih.gov/books/NBK526127/
5. Wang GL, Semenza GL. Purification and characterization of hypoxia-inducible factor 1. J Biol Chem. 1995;270(3):1230-1237. doi:10.1074/jbc.270.3.1230
6. Safran M, Kaelin WG. HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest. 2003;111(6):779-783. doi:10.1172/JCI200318181
7. Bartoszewski R, Matalon S, Collawn JF. Ion channels of the lung and their role in disease pathogenesis. Am J Physiol Lung Cell Mol Physiol. 2017;313(5):L859-L872. doi:10.1152/ajplung.00285.2017
8. Worlitzsch D, Tarran R, Ulrich M, et al. Effects of reduced mucus oxygen concentration in airway Pseudomonas infections of cystic fibrosis patients. J Clin Invest. 2002;109(3): 317-325. doi:10.1172/JCI13870
9. Boucher RC, Stutts MJ, Knowles MR, Cantley L, Gatzy JT. Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation. J Clin Invest. 1986;78(5):1245-1252. doi:10.1172/JCI112708
10. Mall M, Grubb BR, Harkema JR, O’Neal WK, Boucher RC. Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice. Nat Med. 2004;10(5): 487-493. doi:10.1038/nm1028
11. Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. New England Journal of Medicine. 2019;381(19): 1809-1819. doi:10.1056/NEJMoa1908639
12. Lopes-Pacheco M. CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine. Front Pharmacol. 2019;10:1662. doi:10.3389/fphar.2019.01662
13. Becq F, Mirval S, Carrez T, et al. The rescue of F508del-CFTR by elexacaftor/ tezacaftor/ivacaftor (Trikafta) in human airway epithelial cells is underestimated due to the presence of ivacaftor. Eur Respir J. 2022;59(2): 2100671. doi:10.1183/13993003.00671-2021
14. Rayner RE, Makena P, Prasad GL, Cormet- Boyaka E. Optimization of Normal Human Bronchial Epithelial (NHBE) Cell 3D Cultures for in vitro Lung Model Studies. Sci Rep. 2019;9(1):500. doi:10.1038/s41598-018-36735-z
15. Keating D, Marigowda G, Burr L, et al. VX-445–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. New England Journal of Medicine. 2018;379(17):1612-1620. doi:10.1056/NEJMoa1807120
16. Bartoszewski R, Moszyńska A, Serocki M, et al. Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia. FASEB j. 2019;33(7): 7929-7941. doi:10.1096/fj.201802650RR
17. Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, Semenza GL. Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. American Journal of Physiology-Lung Cellular and Molecular Physiology. 1998;275(4):L818-L826. doi:10.1152/ajplung.1998.275.4.L818
18. Legendre C, Mooij MJ, Adams C, O’Gara F. Impaired expression of hypoxia-inducible factor-1α in cystic fibrosis airway epithelial cells – A role for HIF-1 in the pathophysiology of CF? Journal of Cystic Fibrosis. 2011;10(4):286-290. doi:10.1016/j.jcf.2011.02.005
19. Zheng W, Kuhlicke J, Jäckel K, et al. Hypoxia inducible factor-1 (HIF-l)-mediated repression of cystic fibrosis transmembrane conductance regulator (CFTR) in the intestinal epithelium. The FASEB Journal. 2009;23(1):204-213. doi:10.1096/fj.08-110221
20. Guimbellot JS, Erickson SW, Mehta T, et al. Correlation of microRNA levels during hypoxia with predicted target mRNAs through genome-wide microarray analysis. BMC Med Genomics. 2009;2(1):15. doi:10.1186/1755-8794-2-15
21. Bartoszewska S, Kamysz W, Jakiela B, et al. miR-200b downregulates CFTR during hypoxia in human lung epithelial cells. Cell Mol Biol Lett. 2017;22:23. doi:10.1186/s11658-017-0054-0
22. Guimbellot JS, Fortenberry JA, Siegal GP, et al. Role of Oxygen Availability in CFTR Expression and Function. Am J Respir Cell Mol Biol. 2008;39(5):514-521. doi:10.1165/rcmb.2007-0452OC
23. Varga K, Goldstein RF, Jurkuvenaite A, et al. Enhanced cell-surface stability of rescued DeltaF508 cystic fibrosis transmembrane conductance regulator (CFTR) by pharmacological chaperones. Biochem J. 2008; 410(3):555-564. doi:10.1042/BJ20071420
24. Wong SL, Kardia E, Vijayan A, et al. Molecular and Functional Characteristics of Airway Epithelium under Chronic Hypoxia. Int J Mol Sci. 2023;24(7):6475. doi:10.3390/ijms24076475
25. Downes NL, Laham-Karam N, Kaikkonen MU, Ylä-Herttuala S. Differential but Complementary HIF1α and HIF2α Transcriptional Regulation. Mol Ther. 2018;26 (7):1735-1745. doi:10.1016/j.ymthe.2018.05.004
26. Jiang BH, Semenza GL, Bauer C, Marti HH. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol. 1996;271(4 Pt 1):C1172-1180. doi:10.1152/ajpcell.1996.271.4.C1172