Corr4A and VRT325 do not Reduce the Inflammatory Response to &lt;i&gt;P. aeruginosa&lt;/i&gt; in Human Cystic Fibrosis Airway Epithelial Cells

Talebian, Laleh; Coutermarsh, Bonita; Channon, Jacqueline Y.

doi:10.1159/000204108

Cited by 12 publications

(13 citation statements)

References 30 publications

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“…CFBE41o-cells treated with either VRT-325 or Corr4a, two investigational compounds that increase F508del-CFTR chloride secretion, failed to show improvement in IL-6 or IL-8 concentrations after exposure to P aeruginosa. 50 In a subsequent study, neither to stimulate phagocytosis and killing of P aeruginosa by macrophages. 54 The fact that the inflammatory response in cells isolated from people with CF and studied ex vivo was attenuated by the administration of CFTR modulators indicates that CF inflammation is not entirely effective or beneficial, but it may be related to the underlying basic defect.…”

Section: S33mentioning

confidence: 90%

“…Studies in CF cell models have attempted to determine whether pharmacologic improvement of CFTR function alters the inflammatory response. CFBE41o‐cells treated with either VRT‐325 or Corr4a, two investigational compounds that increase F508del‐CFTR chloride secretion, failed to show improvement in IL‐6 or IL‐8 concentrations after exposure to P aeruginosa . In a subsequent study, neither VX‐809 (lumacaftor) nor VX‐809 in combination with VX‐770 (lumacaftor/ivacaftor) reduced IL‐8 or IL‐6 secretion in CFBE41o‐ or CF‐human bronchial epithelial cells (HBE) cells at baseline or after stimulation with P aeruginosa .…”

Section: Associations Between Abnormal Cftr and Airway Inflammationmentioning

confidence: 99%

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Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

198

221

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Inflammation plays a critical role in cystic fibrosis (CF) lung pathology and disease progression making it an active area of research and important therapeutic target. In this review, we explore the most recent research on the major contributors to the exuberant inflammatory response seen in CF as well as potential therapeutics to combat this response. Absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) alters anion transport across CF airway epithelial cells and ultimately results in dehydration of the airway surface liquid. The dehydrated airway surface liquid in combination with abnormal mucin secretion contributes to airway obstruction and subsequent infection that may serve as a trigger point for inflammation. There is also evidence to suggest that airway inflammation may be excessive and sustained relative to the infectious stimuli. Studies have shown dysregulation of both pro-inflammatory mediators such as IL-17 and pro-resolution mediators including metabolites of the eicosanoid pathway. Recently, CFTR potentiators and correctors have garnered much attention in the CF community. Although these modulators address the underlying defect in CF, their impact on downstream consequences such as inflammation are not known. Here, we review pre-clinical and clinical data on the impact of CFTR modulators on inflammation. In addition, we examine other cell types including neutrophils, macrophages, and T-lymphocytes that express CFTR and contribute to the CF inflammatory response. Finally, we address challenges in developing anti-inflammatory therapies and highlight some of the most promising anti-inflammatory drugs under development for CF.

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Section: S33mentioning

confidence: 90%

Section: Associations Between Abnormal Cftr and Airway Inflammationmentioning

confidence: 99%

Inflammation in cystic fibrosis: An update

Roesch

Nichols

Chmiel

2018

Pediatric Pulmonology

198

221

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“…It was shown to have an effect on stabilizing ΔF508-CFTR, leading to increased channel function [58]. Although, Talebian et al have recently shown that VRT-532, and another potential corrector drug, Corr4A, do not reduce the IL-6 and IL-8 inflammatory response in CFBE41o- cells [59]. Thus, these drugs will likely have little effect on reversing the chronic lung disease.…”

Section: Pharmacological Therapeutic Strategies To Correct Cftr Protementioning

confidence: 99%

Protein Processing and Inflammatory Signaling in Cystic Fibrosis: Challenges and Therapeutic Strategies

Belcher¹,

Vij²

2010

CMM

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Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) that regulates epithelial surface fluid secretion in respiratory and gastrointestinal tracts. The deletion of phenylalanine at position 508 (ΔF508) in CFTR is the most common mutation that results in a temperature sensitive folding defect, retention of the protein in the endoplasmic reticulum (ER), and subsequent degradation by the proteasome. ER associated degradation (ERAD) is a major quality control pathway of the cell. The majority (99%) of the protein folding, ΔF508-, mutant of CFTR is known to be degraded by this pathway to cause CF. Recent studies have revealed that inhibition of ΔF508-CFTR ubiquitination and proteasomal degradation can increase its cell surface expression and may provide an approach to treat CF. The finely tuned balance of ER membrane interactions determine the cytosolic fate of newly synthesized CFTR. These ER membrane interactions induce ubiquitination and proteasomal targeting of ΔF508- over wild type- CFTR. We discuss here challenges and therapeutic strategies targeting protein processing of ΔF508-CFTR with the goal of rescuing functional ΔF508-CFTR to the cell surface. It is evident from recent studies that CFTR plays a critical role in inflammatory response in addition to its well-described ion transport function. Previous studies in CF have focused only on improving chloride efflux as a marker for promising treatment. We propose that methods quantifying the therapeutic efficacy and recovery from CF should not include only changes in chloride efflux, but also recovery of the chronic inflammatory signaling, as evidenced by positive changes in inflammatory markers (in vitro and ex vivo), lung function (pulmonary function tests, PFT), and chronic lung disease (state of the art molecular imaging, in vivo). This will provide novel therapeutics with greater opportunities of potentially attenuating the progression of the chronic CF lung disease.

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“…Ussing chamber measurements of Phe508del-CFTR Cl Ϫ currents. As described in detail elsewhere (31,32,35), cells on Snapwell filters were mounted in Ussing chambers. CF HBEC or CFBE cells were treated with vehicle, HP␤CD (5 mM), or M␤CD (5 mM) (Sigma) on the apical side or basolateral side of monolayers.…”

Section: Methodsmentioning

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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Corr4A and VRT325 do not Reduce the Inflammatory Response to <i>P. aeruginosa</i> in Human Cystic Fibrosis Airway Epithelial Cells

Cited by 12 publications

References 30 publications

Inflammation in cystic fibrosis: An update

Inflammation in cystic fibrosis: An update

Protein Processing and Inflammatory Signaling in Cystic Fibrosis: Challenges and Therapeutic Strategies

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

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Corr4A and VRT325 do not Reduce the Inflammatory Response to <i>P. aeruginosa</i> in Human Cystic Fibrosis Airway Epithelial Cells

Cited by 12 publications

References 30 publications

Inflammation in cystic fibrosis: An update

Inflammation in cystic fibrosis: An update

Protein Processing and Inflammatory Signaling in Cystic Fibrosis: Challenges and Therapeutic Strategies

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

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Product

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