Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation

Ortiz-Muñoz, Guadalupe; Yu, Michelle; Lefrançais, Emma; Mallavia, Beñat; Valet, Colin; Tian, Jennifer J.; Ranucci, Serena; Wang, Kristin M.; Zhe, Liu; Kwaan, Nicholas; Dawson, Diana; Kleinhenz, Mary Ellen; Khasawneh, Fadi T.; Haggie, Peter M.; Verkman, A. S.; Looney, Mark R.

doi:10.1172/jci129635

Cited by 47 publications

(60 citation statements)

References 69 publications

(72 reference statements)

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“…The existing data that we have summarised in this review shed light on the multiple mechanisms by which CFTR modulators may attenuate the hyperinflammatory CF airway environment. Ex vivo studies have revealed direct effects of CFTR modulators on the function of neutrophils [ 69 , 109 , 124 , 125 ], macrophages [ 126 , 127 , 130 ], lymphocytes [ 131 , 132 , 133 ], epithelial cells [ 134 , 135 ], and their signalling pathways [ 124 , 128 , 132 ]. There have been additional effects of CFTR modulators demonstrating improvements in MCC including LCI, mucus plugging, and air trapping [ 117 , 121 , 122 ], as well as effects on ciliary function [ 143 ].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, alterations in the pattern of the adaptive immune response were not determined. To our knowledge, the only study considering the effect of CFTR modulators on lymphocyte subsets has been reported as an abstract by Kopp and colleagues [ 132 ]. The investigators compared peripheral blood lymphocyte subsets of PWCF receiving the CFTR modulators IVA, LUM/IVA, TEZ/IVA, or no treatments with healthy controls [ 132 ].…”

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

“…To our knowledge, the only study considering the effect of CFTR modulators on lymphocyte subsets has been reported as an abstract by Kopp and colleagues [ 132 ]. The investigators compared peripheral blood lymphocyte subsets of PWCF receiving the CFTR modulators IVA, LUM/IVA, TEZ/IVA, or no treatments with healthy controls [ 132 ]. Compared to PWCF on other CFTR modulators, those with IVA-responsive genotypes exhibited a resolution of T helper cell, cytotoxic T cell, and B-lymphocyte deficits, but there was little change in the number of regulatory T cells [ 132 ].…”

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

“…The investigators compared peripheral blood lymphocyte subsets of PWCF receiving the CFTR modulators IVA, LUM/IVA, TEZ/IVA, or no treatments with healthy controls [ 132 ]. Compared to PWCF on other CFTR modulators, those with IVA-responsive genotypes exhibited a resolution of T helper cell, cytotoxic T cell, and B-lymphocyte deficits, but there was little change in the number of regulatory T cells [ 132 ]. The data from this study has yet to be published, but the preliminary finding of restoration of adaptive immune cell deficits highlights the insights that can be gleaned from differentiating between lymphocyte subsets.…”

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

Section: Effects Of Cftr Modulators On Inflammationmentioning

confidence: 99%

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Airway Inflammation and Host Responses in the Era of CFTR Modulators

Keown

Brown

Doherty

et al. 2020

IJMS

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“…Although in bronchial epithelial cells ensifentrine elicited similar anti-inflammatory effects to selective PDE4 inhibitors, CF pathology and inflammation also involve other cell types that express PDE3. For instance, recent reports have indicated that CFTR dysfunction in platelets contribute to the excessive inflammation in CF airways (Ortiz-Munoz et al, 2020). PDE3 inhibition can modulate platelet function (Gresele et al, 2011), therefore PDE3 inhibitors may exert anti-inflammatory effects in CF platelets rather than directly on bronchial epithelium.…”

Section: Discussionmentioning

confidence: 99%

The Phosphodiesterase Inhibitor Ensifentrine Reduces Production of Proinflammatory Mediators in Well Differentiated Bronchial Epithelial Cells by Inhibiting PDE4

Turner

Dauletbaev

Lands

et al. 2020

J Pharmacol Exp Ther

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Cystic fibrosis (CF) is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) anion channel that impair airway salt and fluid secretion. Excessive release of pro-inflammatory cytokines and chemokines by CF bronchial epithelium during airway infection leads to chronic inflammation and a slow decline in lung function, thus there is much interest in finding safe and effective treatments that reduce inflammation in CF. We showed previously that the cyclic nucleotide phosphodiesterase (PDE) inhibitor ensifentrine (RPL554; Verona Pharma) stimulates the channel function of CFTR mutants with abnormal gating and also those with defective trafficking that are partially rescued using a clinically approved corrector drug. PDE inhibitors also have known anti-inflammatory effects, therefore we examined whether ensifentrine alters the production of pro-inflammatory cytokines in CF bronchial epithelial cells. Ensifentrine reduced the production of monocyte chemoattractant protein-1 (MCP-1) and granulocyte monocyte colony stimulating factor (GM-CSF) during challenge with Interleukin-1β. Comparing the effect of ensifentrine with milrinone and roflumilast, selective PDE3 and PDE4 inhibitors respectively, demonstrated that the anti-inflammatory effect of ensifentrine was mainly due to inhibition of PDE4. Beneficial modulation of GM-CSF was further enhanced when ensifentrine was combined with low concentrations of the β 2adrenergic agonist isoproterenol or the corticosteroid dexamethasone. The results indicate ensifentrine may have beneficial anti-inflammatory effects in CF airways particularly when used in combination with β 2-adrenergic agonists or corticosteroids.

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