Clinically approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia

Borcherding, Dana C.; Siefert, Matthew; Lin, Shibin; Brewington, John J.; Sadek, Hesham A.; Clancy, John; Plafker, Scott M.; Ziady, Assem G.

doi:10.1172/jci96273

Cited by 31 publications

(36 citation statements)

References 72 publications

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“…Amongst factors that increase Nrf2 transcripts is Nrf2 itself (Suzuki et al, 2013), possibly contributing to the overall significant decrease in Nrf2 levels following CFTR inhibition. Of interest, is the recent observation that clinically approved CFTR modulators rescue Nrf2 dysfunction in CF airway epithelial cells (Borcherding et al, 2019). The effect of CFTR modulators on endothelial Nrf-2 expression and activity remains to be investigated.…”

Section: Nrf2 As a Therapeutic Targetmentioning

confidence: 99%

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Human Lung Microvascular Endothelial Cells Controls Oxidative Stress, Reactive Oxygen-Mediated Cell Signaling and Inflammatory Responses

et al. 2020

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Background: Perturbation of endothelial function in people with cystic fibrosis (CF) has been reported, which may be associated with endothelial cell expression of the cystic fibrosis transmembrane conductance regulator (CFTR). Previous reports indicate that CFTR activity upregulates endothelial barrier function, endothelial nitric oxide synthase (eNOS) expression and NO release, while limiting interleukin-8 (IL-8) release, in human umbilical vein endothelial cells (HUVECs) in cell culture. In view of reported microvascular dysfunction in people with CF we investigated the role of CFTR expression and activity in the regulation of oxidative stress, cell signaling and inflammation in human lung microvascular endothelial cells (HLMVECs) in cell culture. Methods: HLMVECs were cultured in the absence and presence of the CFTR inhibitor GlyH-101 and CFTR siRNA. CFTR expression was analyzed using qRT-PCR, immunocytochemistry (IHC) and western blot, and function by membrane potential assay. IL-8 expression was analyzed using qRT-PCR and ELISA. Nrf2 expression, and NF-κB and AP-1 activation were determined using IHC and western blot. The role of the epidermal growth factor receptor (EGFR) in CFTR signaling was investigated using the EGFR tyrosine kinase inhibitor AG1478. Oxidative stress was measured as intracellular ROS and hydrogen peroxide (H 2 O 2) concentration. VEGF and SOD-2 were measured in culture supernatants by ELISA. Results: HLMVECs express low levels of CFTR that increase following inhibition of CFTR activity. Inhibition of CFTR, significantly increased intracellular ROS and H 2 O 2 levels over 30 min and significantly decreased Nrf2 expression by 70% while increasing SOD-2 expression over 24 h. CFTR siRNA significantly increased constitutive expression of IL-8 by HLMVECs. CFTR inhibition activated the AP-1 pathway and increased IL-8

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Section: Nrf2 As a Therapeutic Targetmentioning

confidence: 99%

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Human Lung Microvascular Endothelial Cells Controls Oxidative Stress, Reactive Oxygen-Mediated Cell Signaling and Inflammatory Responses

et al. 2020

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“…The PI3K/Akt pathway is activated in lung epithelial cells during pyocyanin exposure, and the increased transcription of antioxidants may protect these cells from death[ 236 ]. It has been suggested that defective Nrf-2 in CF cells causes enhanced oxidative stress that increases inflammatory cytokine production[ 237 ], and Nrf-2 function is restored when mutant CFTR function is enhanced by small molecule therapeutics[ 238 ]. Alterations of Nrf-2 signaling in CF may also be tied to alterations in cAMP signaling and the CREB binding protein[ 239 ].…”

Section: Potential Roles Of the Phosphoinositide-3-kinase/akt Pathwaymentioning

confidence: 99%

Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

Gopallawa¹,

Lee²

2020

WJBC

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The airway innate immune system maintains the first line of defense against respiratory infections. The airway epithelium and associated immune cells protect the respiratory system from inhaled foreign organisms. These cells sense pathogens via activation of receptors like toll-like receptors and taste family 2 receptors (T2Rs) and respond by producing antimicrobials, inflammatory cytokines, and chemokines. Coordinated regulation of fluid secretion and ciliary beating facilitates clearance of pathogens via mucociliary transport. Airway cells also secrete antimicrobial peptides and radicals to directly kill microorganisms and inactivate viruses. The phosphoinositide-3-kinase/protein kinase B (Akt) kinase pathway regulates multiple cellular targets that modulate cell survival and proliferation. Akt also regulates proteins involved in innate immune pathways. Akt phosphorylates endothelial nitric oxide synthase (eNOS) enzymes expressed in airway epithelial cells. Activation of eNOS can have anti-inflammatory, anti-bacterial, and anti-viral roles. Moreover, Akt can increase the activity of the transcription factor nuclear factor erythroid 2 related factor-2 that protects cells from oxidative stress and may limit inflammation. In this review, we summarize the recent findings of non-cancerous functions of Akt signaling in airway innate host defense mechanisms, including an overview of several known downstream targets of Akt involved in innate immunity.

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“…Indeed, patients with the G551D mutation showed marked improvements in whole lung, central, and peripheral MCC at 1 and 3 months after starting treatment with IVA, which correlated with lung function [ 117 ]. Other studies have shown reductions in lung clearance index (LCI) with CFTR modulation [ 120 ], indicating reduced mucus plugging and improved air trapping [ 121 , 122 ]. A large multicentre study assessing inflammatory and clinical outcomes in Kaftrio (known as Trikafta in the United States; ivacaftor/tezacaftor/elexacaftor) treated patients is underway, which should give a clearer picture of the modulator effects on inflammation [ 123 ].…”

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

Airway Inflammation and Host Responses in the Era of CFTR Modulators

Keown

Brown

Doherty

et al. 2020

IJMS

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The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

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Clinically approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia

Cited by 31 publications

References 72 publications

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Human Lung Microvascular Endothelial Cells Controls Oxidative Stress, Reactive Oxygen-Mediated Cell Signaling and Inflammatory Responses

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Human Lung Microvascular Endothelial Cells Controls Oxidative Stress, Reactive Oxygen-Mediated Cell Signaling and Inflammatory Responses

Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity

Airway Inflammation and Host Responses in the Era of CFTR Modulators

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