Ivacaftor modifies cystic fibrosis neutrophil phenotype in subjects with R117H residual function CFTR mutations

Hardisty, Gareth; Law, Sheonagh M.; Carter, Suzanne; Grogan, Brenda; Singh, Pradeep Kumar; McKone, Edward F.; Gray, Robert D.

doi:10.1183/13993003.02161-2020

Cited by 9 publications

(9 citation statements)

References 14 publications

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“…Activated neutrophils regulate CFTR distribution by mobilising it to the subcellular sites of activation, while neutrophils with the most common CFTR mutation, F508del, do not achieve this targeting and thus compromise host defence function [ 45 ]. In patients with CF with residual CFTR function, CFTR modulator therapy has been shown to bring about phenotypic changes in neutrophils, consistent with neutrophils becoming less activated [ 46 ]. Polymorphonuclear neutrophil (PMN)-dominated airway inflammation is a feature of CF.…”

Section: The Role Of Cftr In In Nonepithelial Cellsmentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

et al. 2022

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The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel for transport of chloride and bicarbonate anions. Functional roles of CFTR have been identified in a broad range of cell types including epithelial, endothelial, immune, and structural cells. While CFTR has been investigated largely in the context of inborn dysfunction in cystic fibrosis (CF), recent evidence shows CFTR is also affected by acquired dysfunction in chronic obstructive pulmonary disease (COPD). In patients with COPD and smokers, CFTR impairment has been demonstrated in the upper and lower airways, sweat glands and intestines, suggesting both pulmonary and systemic defects. Cigarette smoke, a key factor in COPD development, is the major cause of acquired CFTR dysfunction. Inflammation, bacterial by-products, and reactive oxygen species can further impair CFTR expression and function. CFTR dysfunction could directly contribute to disease manifestation and progression of COPD including disturbed airway surface liquid homeostasis, airway mucus obstruction, pathogen colonisation and inflammation. Mucus plugging and neutrophilic inflammation contribute to tissue destruction, development of dysfunction at the level of the small airways and COPD progression. Acquired CFTR dysfunction in extra-pulmonary organs could add to common co-morbidities and the disease burden. This review explores how CFTR dysfunction may be acquired and its potential effects on patients with COPD, particularly those with chronic bronchitis. The development of CFTR potentiators and the probable benefits of CFTR potentiation to improve tissue homeostasis, reduce inflammation, improve host defence, and potentially reduce remodelling in the lungs will be discussed.

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Section: The Role Of Cftr In In Nonepithelial Cellsmentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

et al. 2022

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“…In addition, studies have observed an increased abundance of neutrophils possessing a pro-survival phenotype within the CF lung [ 73 ]. These neutrophils exhibit reduced apoptosis contributing to the self-perpetuating cycle of inflammation and infection [ 74 , 75 , 76 ].…”

Section: Microbiome In Cfmentioning

confidence: 99%

The Effect of CFTR Modulators on Airway Infection in Cystic Fibrosis

Harvey

Weldon

Elborn

et al. 2022

IJMS

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The advent of Cystic fibrosis transmembrane receptor (CFTR) modulators in 2012 was a critical event in the history of cystic fibrosis (CF) treatment. Unlike traditional therapies that target downstream effects of CFTR dysfunction, CFTR modulators aim to correct the underlying defect at the protein level. These genotype-specific therapies are now available for an increasing number of CF patients, transforming the way we view the condition from a life-limiting disease to one that can be effectively managed. Several studies have demonstrated the vast improvement CFTR modulators have on normalization of sweat chloride, CFTR function, clinical endpoints, and frequency of pulmonary exacerbation. However, their impact on other aspects of the disease, such as pathogenic burden and airway infection, remain under explored. Frequent airway infections as a result of increased susceptibility and impaired innate immune response are a serious problem within CF, often leading to accelerated decline in lung function and disease progression. Current evidence suggests that CFTR modulators are unable to eradicate pathogenic organisms in those with already established lung disease. However, this may not be the case for those with relatively low levels of disease progression and conserved microbial diversity, such as young patients. Furthermore, it remains unknown whether the restorative effects exerted by CFTR modulators extend to immune cells, such as phagocytes, which have the potential to modulate the response of people with CF (pwCF) to infection. Throughout this review, we look at the potential impact of CFTR modulators on airway infection in CF and their ability to shape impaired pulmonary defences to pathogens.

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“…Several trials have proven its efficacy in patients with mild and more advanced disease [142]. More recently, CFTR modulator therapy has been added to the therapeutic repertoire and emerging evidence indicates that these drugs can modulate neutrophil function including beneficial changes in markers of activation [143] and increased bacterial killing [144].…”

Section: Cystic Fibrosismentioning

confidence: 99%

Our evolving view of neutrophils in defining the pathology of chronic lung disease

et al. 2021

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Neutrophils are critical components of the body's immune response to infection, being loaded with a potent arsenal of toxic mediators and displaying immense destructive capacity. Given the potential of neutrophils to impart extensive tissue damage, it is perhaps not surprising that when augmented these cells are also implicated in the pathology of inflammatory diseases. Prominent neutrophilic inflammation is a hallmark feature of patients with chronic lung diseases such as chronic obstructive pulmonary disease, severe asthma, bronchiectasis and cystic fibrosis, with their numbers frequently associating with worse prognosis. Accordingly, it is anticipated that neutrophils are central to the pathology of these diseases and represent an attractive therapeutic target. However, in many instances, evidence directly linking neutrophils to the pathology of disease has remained somewhat circumstantial and strategies that have looked to reduce neutrophilic inflammation in the clinic have proved largely disappointing. We have classically viewed neutrophils as somewhat crude, terminally differentiated, insular and homogeneous protagonists of pathology. However, it is now clear that this does not do the neutrophil justice, and we now recognize that these cells exhibit heterogeneity, a pronounced awareness of the localized environment and a remarkable capacity to interact with and modulate the behaviour of a multitude of cells, even exhibiting anti‐inflammatory, pro‐resolving and pro‐repair functions. In this review, we discuss evidence for the role of neutrophils in chronic lung disease and how our evolving view of these cells may impact upon our perceived assessment of their contribution to disease pathology and efforts to target them therapeutically.

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Ivacaftor modifies cystic fibrosis neutrophil phenotype in subjects with R117H residual function CFTR mutations

Abstract: CFTR modulation leads to changes in neutrophil phenotype even in patients with residual function CFTR mutations https://bit.ly/2EUk7xH

Cited by 9 publications

References 14 publications

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

The Effect of CFTR Modulators on Airway Infection in Cystic Fibrosis

Our evolving view of neutrophils in defining the pathology of chronic lung disease

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