Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta

Liessi, Nara; Pesce, Emanuela; Braccia, Clarissa; Bertozzi, Sine Mandrup; Giraudo, Alessandro; Bandiera, Tiziano; Pedemonte, Nicoletta; Armirotti, Andrea

doi:10.1172/jci.insight.138722

Cited by 22 publications

(19 citation statements)

References 64 publications

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“…This is consistent with the involvement of CFTR function in regulating oxidative stress and lipid metabolism, considering the significant effect of these compounds on F508del CFTR cAMP-induced chloride transport function in Ussing chamber experiments within 24 h. Using a different approach in submerged immortalized epithelial cells overexpressing F508del CFTR (CFBE). Liessi et al (2020) showed recently that CFTR targeted therapeutics, including an elexacaftor/tezacaftor/ivacaftor, changes ceramide and lysolipid pools.…”

Section: Discussionmentioning

confidence: 99%

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

et al. 2021

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A deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) function in CF leads to chronic lung disease. CF is associated with abnormalities in fatty acids, ceramides, and cholesterol, their relationship with CF lung pathology is not completely understood. Therefore, we examined the impact of CFTR deficiency on lipid metabolism and pro-inflammatory signaling in airway epithelium using mass spectrometric, protein array. We observed a striking imbalance in fatty acid and ceramide metabolism, associated with chronic oxidative stress under basal conditions in CF mouse lung and well-differentiated bronchial epithelial cell cultures of CFTR knock out pig and CF patients. Cell-autonomous features of all three CF models included high ratios of ω-6- to ω-3-polyunsaturated fatty acids and of long- to very long-chain ceramide species (LCC/VLCC), reduced levels of total ceramides and ceramide precursors. In addition to the retinoic acid analog fenretinide, the anti-oxidants glutathione (GSH) and deferoxamine partially corrected the lipid profile indicating that oxidative stress may promote the lipid abnormalities. CFTR-targeted modulators reduced the lipid imbalance and oxidative stress, confirming the CFTR dependence of lipid ratios. However, despite functional correction of CF cells up to 60% of non-CF in Ussing chamber experiments, a 72-h triple compound treatment (elexacaftor/tezacaftor/ivacaftor surrogate) did not completely normalize lipid imbalance or oxidative stress.Protein array analysis revealed differential expression and shedding of cytokines and growth factors from CF epithelial cells compared to non-CF cells, consistent with sterile inflammation and tissue remodeling under basal conditions, including enhanced secretion of the neutrophil activator CXCL5, and the T-cell activator CCL17. However, treatment with antioxidants or CFTR modulators that mimic the approved combination therapies, ivacaftor/lumacaftor and ivacaftor/tezacaftor/elexacaftor, did not effectively suppress the inflammatory phenotype.We propose that CFTR deficiency causes oxidative stress in CF airway epithelium, affecting multiple bioactive lipid metabolic pathways, which likely play a role in CF lung disease progression. A combination of anti-oxidant, anti-inflammatory and CFTR targeted therapeutics may be required for full correction of the CF phenotype.

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Section: Discussionmentioning

confidence: 99%

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

et al. 2021

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“…Ivacaftor (VX-770), and lumacaftor/ivacaftor (VX-809/VX-770), and the triple combination (VX-661/VX-445/VX-770) have all been shown to influence lipid signatures in blood or bronchial epithelial cells, respectively [ 31 , 54 , 55 ]. All tested combinations of modulators in immortalized bronchial cells markedly influenced lipids by both up- and downregulations.…”

Section: Enac In Cfmentioning

confidence: 99%

“…CFTR has its function in lipid structures, and lipid abnormalities have been associated with the disease for more than 50 years [ 23 ], but the interest to find treatment modalities in this field has not been encouraged. However, in recent years an increasing interest has focused on the bidirectional relation between proteins and lipids [ 24 , 25 , 26 ], also in relation to CFTR [ 27 , 28 , 29 , 30 ], and lately, the interaction between the modern CFTR modulators and membrane lipids have been shown [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Is the ENaC Dysregulation in CF an Effect of Protein-Lipid Interaction in the Membranes?

Strandvik

2021

IJMS

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While approximately 2000 mutations have been discovered in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), only a small amount (about 10%) is associated with clinical cystic fibrosis (CF) disease. The discovery of the association between CFTR and the hyperactive epithelial sodium channel (ENaC) has raised the question of the influence of ENaC on the clinical CF phenotype. ENaC disturbance contributes to the pathological secretion, and overexpression of one ENaC subunit, the β-unit, can give a CF-like phenotype in mice with normal acting CFTR. The development of ENaC channel modulators is now in progress. Both CFTR and ENaC are located in the cell membrane and are influenced by its lipid configuration. Recent studies have emphasized the importance of the interaction of lipids and these proteins in the membranes. Linoleic acid deficiency is the most prevailing lipid abnormality in CF, and linoleic acid is an important constituent of membranes. The influence on sodium excretion by linoleic acid supplementation indicates that lipid-protein interaction is of importance for the clinical pathophysiology in CF. Further studies of this association can imply a simple clinical adjuvant in CF therapy.

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“…Importantly, the addition of the next-generation corrector elexacaftor lowered the annual rate of pulmonary exacerbations by 63% in comparison to F508del homozygotes receiving Symdeko ® , which showed a reduction of 35% versus placebo [ 122 ]. Notably, an in vitro study by Liessi and collaborators [ 123 ] highlighted that the triple combination is the only treatment able to concomitantly and significantly lower the levels of 6 different ceramides in CFBE41o- cells, which are known to trigger inflammation and death by accumulating in CF epithelial cells [ 124 ]. Moreover, since these sphingolipids can act as second messengers in the stimulation of apoptosis [ 125 , 126 ], Trikafta ® may decrease the susceptibility of epithelial cells to death in response to severe proapoptotic stimuli, such as in vitro application of etoposide.…”

Section: Anti-inflammatory Effects Of Cftr Modulatorsmentioning

confidence: 99%

Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches

Ghigo

Prono

Riccardi

et al. 2021

IJMS

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Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.

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Distinctive lipid signatures of bronchial epithelial cells associated with cystic fibrosis drugs, including Trikafta

Cited by 22 publications

References 64 publications

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

CFTR Correctors and Antioxidants Partially Normalize Lipid Imbalance but not Abnormal Basal Inflammatory Cytokine Profile in CF Bronchial Epithelial Cells

Is the ENaC Dysregulation in CF an Effect of Protein-Lipid Interaction in the Membranes?

Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches

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