Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D

Hoppe, Jordana E.; Wagner, Brandie D.; Harris, J. Kirk; Rowe, Steven M.; Heltshe, Sonya L.; DeBoer, Emily M.; Sagel, Scott D.

doi:10.1016/j.jcf.2022.03.012

Cited by 11 publications

(8 citation statements)

References 59 publications

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“…The CF airway contains large numbers of neutrophils and increased concentrations of pro‐inflammatory mediators, including tumor necrosis factor‐α (TNF‐α), interleukin (IL)‐1β, IL‐6, IL‐8, IL‐17, IL‐33 and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) 7 . Systemic inflammation is also increased in people with CF (pwCF), particularly pro‐inflammatory cytokines and neutrophils 1,8–11 . The relationship between abnormal CFTR function and either inflammation or infection is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Impact of elexacaftor–tezacaftor–ivacaftor on bacterial colonization and inflammatory responses in cystic fibrosis

Sheikh

Britt

Ryan‐Wenger

et al. 2022

Pediatric Pulmonology

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Background Cystic fibrosis (CF) is a multisystem disease with progressive deterioration. Recently, CF transmembrane conductance regulator (CFTR) modulator therapies were introduced that repair underlying protein defects. Objective of this study was to determine the impact of elexacaftor–tezacaftor–ivacaftor (ETI) on clinical parameters and inflammatory responses in people with CF (pwCF). Methods Lung function (FEV1), body mass index (BMI) and microbiologic data were collected at initiation and 3‐month intervals for 1 year. Blood was analyzed at baseline and 6 months for cytokines and immune cell populations via flow cytometry and compared to non‐CF controls. Results Sample size was 48 pwCF, 28 (58.3%) males with a mean age of 28.8 ± 10.7 years. Significant increases in %predicted FEV1 and BMI were observed through 6 months of ETI therapy with no change thereafter. Changes in FEV1 and BMI at 3 months were significantly correlated (r = 57.2, p < 0.01). There were significant reductions in Pseudomonas and Staphylococcus positivity (percent of total samples) in pwCF through 12 months of ETI treatment. Healthy controls (n = 20) had significantly lower levels of circulating neutrophils, interleukin (IL)‐6, IL‐8, and IL‐17A and higher levels of IL‐13 compared to pwCF at baseline (n = 48). After 6 months of ETI, pwCF had significant decreases in IL‐8, IL‐6, and IL‐17A levels and normalization of peripheral blood immune cell composition. Conclusions In pwCF, ETI significantly improved clinical outcomes, reduced systemic pro‐inflammatory cytokines, and restored circulating immune cell composition after 6 months of therapy.

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Section: Introductionmentioning

confidence: 99%

“…7 Systemic inflammation is also increased in people with CF (pwCF), particularly proinflammatory cytokines and neutrophils. 1,[8][9][10][11] The relationship between abnormal CFTR function and either inflammation or infection is not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Impact of elexacaftor–tezacaftor–ivacaftor on bacterial colonization and inflammatory responses in cystic fibrosis

Sheikh

Britt

Ryan‐Wenger

et al. 2022

Pediatric Pulmonology

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“…The effect of ivacaftor was investigated also on monocyte/macrophage by several studies that made use of modern proteomics and transcriptomics techniques. [ 125 , 126 , 127 , 128 ]. Hisert et al performed a proteomic analysis of the plasma membrane of monocytes from 12 patients with CFTR -G551D mutations before, 2, and 7 days after treatment with ivacaftor finding a marked increase in levels of proteins implicated in cell migration [ 125 ].…”

Section: Cftr Modulators and Their Impact On Phagocytesmentioning

confidence: 99%

“…Another similar study was recently conducted by Hoppe and colleagues who analyzed inflammatory and growth-related proteins at baseline, 1, and 6 months after ivacaftor initiation in 64 CF subjects with G551D mutation [ 127 ]. After 1 month of treatment authors reported both significant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A (SAA), and granulocyte colony-stimulating factor (G-CSF), markers of inflammation, and an increase in insulin-like growth factor (IGF-1), implicated in linear growth; moreover, through 6 months of therapy, the decreased levels of HMGB-1 and calprotectin were confirmed.…”

Section: Cftr Modulators and Their Impact On Phagocytesmentioning

confidence: 99%

“…Based on the obtained results and considering the conflicting findings of the aforementioned proteomics studies, authors speculated that, although in innate immune cells a CFTR dysfunction predisposes to a pro-inflammatory status, in vivo the CF plasma milieu is able to override the inflammatory balance leading to an immune-suppressed (or tolerant) state. In these conditions, ivacaftor would exert both a pro-inflammatory and anti-inflammatory action on CF immune cells [ 125 , 126 , 127 , 128 , 131 ].…”

Section: Cftr Modulators and Their Impact On Phagocytesmentioning

confidence: 99%

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Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease

Meoli

Eickmeier

Pisi

et al. 2022

IJMS

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Cystic fibrosis (CF), the most common genetically inherited disease in Caucasian populations, is a multi-systemic life-threatening autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In 2012, the arrival of CFTR modulators (potentiators, correctors, amplifiers, stabilizers, and read-through agents) revolutionized the therapeutic approach to CF. In this review, we examined the physiopathological mechanism of chronic dysregulated innate immune response in the lungs of CF patients with pulmonary involvement with particular reference to phagocytes, critically analyzing the role of CFTR modulators in influencing and eventually restoring their function. Our literature review highlighted that the role of CFTR in the lungs is crucial not only for the epithelial function but also for host defense, with particular reference to phagocytes. In macrophages and neutrophils, the CFTR dysfunction compromises both the intricate process of phagocytosis and the mechanisms of initiation and control of inflammation which then reverberates on the epithelial environment already burdened by the chronic colonization of pathogens leading to irreversible tissue damage. In this context, investigating the impact of CFTR modulators on phagocytic functions is therefore crucial not only for explaining the underlying mechanisms of pleiotropic effects of these molecules but also to better understand the physiopathological basis of this disease, still partly unexplored, and to develop new complementary or alternative therapeutic approaches.

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Ivacaftor therapy post myocardial infarction augments systemic inflammation and evokes contrasting effects with respect to tissue inflammation in brain and lung

Vanherle¹,

Matthes²,

Uhl³

et al. 2023

Biomedicine & Pharmacotherapy

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Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D

Cited by 11 publications

References 59 publications

Impact of elexacaftor–tezacaftor–ivacaftor on bacterial colonization and inflammatory responses in cystic fibrosis

Impact of elexacaftor–tezacaftor–ivacaftor on bacterial colonization and inflammatory responses in cystic fibrosis

Impact of CFTR Modulators on the Impaired Function of Phagocytes in Cystic Fibrosis Lung Disease

Ivacaftor therapy post myocardial infarction augments systemic inflammation and evokes contrasting effects with respect to tissue inflammation in brain and lung

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