Pulmonary surfactant dysfunction in pediatric cystic fibrosis: Mechanisms and reversal with a lipid-sequestering drug

Gunasekara, Lasantha; Al-Saiedy, Mustafa; Green, Francis; Pratt, Ryan; Bjornson, Candice; Yang, Ailian; Schoel, W. Michael; Mitchell, Ian; Brindle, Mary; Montgomery, Mark; Keys, Elizabeth; Dennis, John; Shrestha, Grishma; Amrein, Matthias

doi:10.1016/j.jcf.2017.04.015

Cited by 26 publications

(31 citation statements)

References 29 publications

(53 reference statements)

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“…Cholesterol is one of the main lipid and structural component of the cell membranes and is involved in maintaining airway function. For example, airway surfactant dysfunction in cystic fibrosis was suggested to involve excess cholesterol and its interaction with oxidized lipids (22). Treatment with M␤CD was suggested to improve airway surfactant function in cystic fibrosis patients (22).…”

Section: Discussionmentioning

confidence: 99%

“…For example, airway surfactant dysfunction in cystic fibrosis was suggested to involve excess cholesterol and its interaction with oxidized lipids (22). Treatment with M␤CD was suggested to improve airway surfactant function in cystic fibrosis patients (22). The present work is aimed at understanding the role of membrane cholesterol in T2R14 signaling, and the underlying mechanism governing the T2R14-cholesterol interaction.…”

Section: Discussionmentioning

confidence: 99%

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Cholesterol modulates the signaling of chemosensory bitter taste receptor T2R14 in human airway cells

Shaik

Medapati

Chelikani

2019

American Journal of Physiology-Lung Cellular and Molecular Phys

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Bitter taste receptors (T2Rs) are a group of 25 chemosensory receptors expressed at significant levels in the human airways. In human airways, bitter taste receptor 14 (T2R14)-mediated physiological response in ameliorating obstructive airway disorders is an active area of investigation. Therefore, understanding various factors regulating the structure and function of T2R14 will be beneficial. We hypothesize that membrane lipids like cholesterol play a regulatory role in T2R14 signaling in airway cells. We confirmed the expression and signaling of T2R14 in primary human airway smooth muscle (HASM) cells and the human airway epithelial cell line (NuLi-1) using immunoblot analysis and intracellular calcium concentration mobilization experiments, respectively. Next, T2R14 signaling was examined in membrane cholesterol-altered environments by methyl-β-cyclodextrin or cholesterol oxidase treatments. In the cells analyzed, cholesterol depletion affected the agonist-induced T2R14 signaling, and cholesterol replenishment rescued its efficacy. An alternative approach for cholesterol depletion (with cholesterol oxidase pretreatment) also negatively affected the agonist potency at T2R14 in HASM cells. To understand the molecular mechanism of interaction between cholesterol and T2R14, we used site-directed mutagenesis coupled with functional assays and examined the role of putative cholesterol-binding motifs (CRAC and CARC) in T2R14. Functional characterization of wild-type and mutant T2R14 receptors suggests that amino acid residues K110, F236, and L239 are crucial in T2R14-cholesterol functional interaction. In conclusion, our results show that cholesterol influences the T2R14 signaling efficacy by forming direct interactions with the receptor and consequently plays a regulatory role in T2R14-mediated signaling in human airway cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cholesterol modulates the signaling of chemosensory bitter taste receptor T2R14 in human airway cells

Shaik

Medapati

Chelikani

2019

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Therefore, alterations to membrane lipids can have an important influence on several diseases. For example, cystic fibrosis causes lipid imbalances that affect surfactant function, producing a negative effect on breathing [102,103]. In mouse models of cystic fibrosis, a similar lipid imbalance was found in affected organs, although administration of docosahexaenoic acid (DHA) normalized both these lipid changes and the animal's health status [104].…”

Section: Altered Membrane Lipid and Amphitropic Protein Interactions mentioning

confidence: 99%

The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

Torres

Rosselló

Fernández‐García

et al. 2020

IJMS

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The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist–receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation. These proteins localize to the plasma membrane or internal compartments; however, they are only activated by ligand-receptor complexes when both come into physical contact in membranes. These interactions enable signal propagation. Thus, signals may not propagate into the cell if peripheral proteins do not co-localize with receptors even in the presence of messengers. As the translocation of an amphitropic protein greatly depends on the membrane’s lipid composition, regulation of the lipid bilayer emerges as a novel therapeutic strategy. Some of the signals controlled by proteins non-permanently bound to membranes produce dramatic changes in the cell’s physiology. Indeed, changes in membrane lipids induce translocation of dozens of peripheral signaling proteins from or to the plasma membrane, which controls how cells behave. We called these changes “lipid switches”, as they alter the cell’s status (e.g., proliferation, differentiation, death, etc.) in response to the modulation of membrane lipids. Indeed, this discovery enables therapeutic interventions that modify the bilayer’s lipids, an approach known as membrane-lipid therapy (MLT) or melitherapy.

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“…Cellular accumulation of cholesterol in CF causes defects in intracellular protein trafficking, increases inflammation, and reduces airway surfactant surface tension that may lead to alveolar collapse (9). In addition, cholesterol levels are elevated in CF bronchoalveolar fluid (BALF), which reduces surfactant surface tension and film stability (17). A reduction in BALF cholesterol with M␤CD restores surface tension (17).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, cholesterol levels are elevated in CF bronchoalveolar fluid (BALF), which reduces surfactant surface tension and film stability (17). A reduction in BALF cholesterol with M␤CD restores surface tension (17). Taken together, these observations suggest that a reduction in cholesterol in BALF and airway epithelial cells may have numerous beneficial effects.…”

Section: Introductionmentioning

confidence: 99%

Cyclodextrins reduce the ability of Pseudomonas aeruginosa outer-membrane vesicles to reduce CFTR Cl⁻ secretion

Barnaby

Koeppen

2019

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pseudomonas aeruginosa secretes outer-membrane vesicles (OMVs) that fuse with cholesterol-rich lipid rafts in the apical membrane of airway epithelial cells and decrease wt-CFTR Cl− secretion. Herein, we tested the hypothesis that a reduction of the cholesterol content of CF human airway epithelial cells by cyclodextrins reduces the inhibitory effect of OMVs on VX-809 (lumacaftor)-stimulated Phe508del CFTR Cl− secretion. Primary CF bronchial epithelial cells and CFBE cells were treated with vehicle, hydroxypropyl-β-cyclodextrin (HPβCD), or methyl-β-cyclodextrin (MβCD), and the effects of OMVs secreted by P. aeruginosa on VX-809 stimulated Phe508del CFTR Cl− secretion were measured in Ussing chambers. Neither HPβCD nor MβCD were cytotoxic, and neither altered Phe508del CFTR Cl− secretion. Both cyclodextrins reduced OMV inhibition of VX-809-stimulated Phe508del-CFTR Cl− secretion when added to the apical side of CF monolayers. Both cyclodextrins also reduced the ability of P. aeruginosa to form biofilms and suppressed planktonic growth of P. aeruginosa. Our data suggest that HPβCD, which is in clinical trials for Niemann-Pick Type C disease, and MβCD, which has been approved by the U.S. Food and Drug Administration for use in solubilizing lipophilic drugs, may enhance the clinical efficacy of VX-809 in CF patients when added to the apical side of airway epithelial cells, and reduce planktonic growth and biofilm formation by P. aeruginosa. Both effects would be beneficial to CF patients.

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Pulmonary surfactant dysfunction in pediatric cystic fibrosis: Mechanisms and reversal with a lipid-sequestering drug

Abstract: We confirm that CF patients have impaired airway surfactant function which could be restored with MβCD. These findings have implications for improving lung function and mitigating inflammation in patients with CF.

Cited by 26 publications

References 29 publications

Cholesterol modulates the signaling of chemosensory bitter taste receptor T2R14 in human airway cells

Cholesterol modulates the signaling of chemosensory bitter taste receptor T2R14 in human airway cells

The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

Cyclodextrins reduce the ability of Pseudomonas aeruginosa outer-membrane vesicles to reduce CFTR Cl⁻ secretion

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Pulmonary surfactant dysfunction in pediatric cystic fibrosis: Mechanisms and reversal with a lipid-sequestering drug

Abstract: We confirm that CF patients have impaired airway surfactant function which could be restored with MβCD. These findings have implications for improving lung function and mitigating inflammation in patients with CF.

Cited by 26 publications

References 29 publications

Cholesterol modulates the signaling of chemosensory bitter taste receptor T2R14 in human airway cells

Cholesterol modulates the signaling of chemosensory bitter taste receptor T2R14 in human airway cells

The Implications for Cells of the Lipid Switches Driven by Protein–Membrane Interactions and the Development of Membrane Lipid Therapy

Cyclodextrins reduce the ability of Pseudomonas aeruginosa outer-membrane vesicles to reduce CFTR Cl− secretion

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Product

Resources

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Cyclodextrins reduce the ability of Pseudomonas aeruginosa outer-membrane vesicles to reduce CFTR Cl⁻ secretion