Anti-Inflammatory Influences of Cystic Fibrosis Transmembrane Conductance Regulator Drugs on Lung Inflammation in Cystic Fibrosis

Harwood, Kiera H.; McQuade, Rachel M.; Jarnicki, Andrew G.; Schneider‐Futschik, Elena K.

doi:10.3390/ijms22147606

Cited by 17 publications

(15 citation statements)

References 79 publications

(126 reference statements)

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“…In normal homeostatic conditions, neutrophils are short-lived and undergo spontaneous apoptosis to guarantee the termination of the inflammatory insult but, similarly to macrophages, are also characterized by remarkable plasticity. Indeed, although when they leave the bone marrow neutrophils have already a default pro-apoptotic program, it can be modified by stimuli received in the target tissue including IL-8 and GM-CSF, that promote their persistence and longevity [ 71 , 74 , 75 ]. IL-8, also known as CXCL8, is mainly produced by AECs and macrophages, and one of its major functions is to attract and activate neutrophils and delay their apoptosis via their IL-8 receptor (mainly CXCR2) [ 76 , 77 ].…”

Section: The Role Of Cftr Dysfunction In Phagocyte...mentioning

confidence: 99%

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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Section: The Role Of Cftr Dysfunction In Phagocyte...mentioning

confidence: 99%

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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show abstract

“…However, none of the studies described looked at the influence of CFTR modulators upon alveolar macrophage surface receptors or phagocytic signaling pathways. Other studies examined the influence of CFTR modulators on inflammatory signaling in monocytes and macrophages and were reviewed elsewhere [ 181 , 182 ].…”

Section: Cftr Modulators/other Therapeutics and Cf Phagocytosismentioning

confidence: 99%

Emerging Concepts in Defective Macrophage Phagocytosis in Cystic Fibrosis

Jaganathan

Bruscia

Kopp

2022

IJMS

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Cystic fibrosis (CF) is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Chronic inflammation and decline in lung function are major reasons for morbidity in CF. Mutant CFTR expressed in phagocytic cells such as macrophages contributes to persistent infection, inflammation, and lung disease in CF. Macrophages play a central role in innate immunity by eliminating pathogenic microbes by a process called phagocytosis. Phagocytosis is required for tissue homeostasis, balancing inflammation, and crosstalk with the adaptive immune system for antigen presentation. This review focused on (1) current understandings of the signaling underlying phagocytic mechanisms; (2) existing evidence for phagocytic dysregulation in CF; and (3) the emerging role of CFTR modulators in influencing CF phagocytic function. Alterations in CF macrophages from receptor initiation to phagosome formation are linked to disease progression in CF. A deeper understanding of macrophages in the context of CFTR and phagocytosis proteins at each step of phagosome formation might contribute to the new therapeutic development of dysregulated innate immunity in CF. Therefore, the review also indicates future areas of research in the context of CFTR and macrophages.

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“…Some studies have suggested that CFTR modulators may also decrease the inflammatory response in CF airways, an effect that would further contribute to improved disease outcomes [ 57 ]; however, to date conflicting results have been reported and data still remain inconclusive (reviewed in [ 58 , 59 ]). Furthermore, it remains to be defined whether these drugs are capable of restoring dysfunctional CFTR in immune cells that may contribute to the exaggerated inflammatory process and the impaired clearance of pathogens in CF airways [ 60 , 61 ].…”

Section: Airway Infections In Cystic Fibrosismentioning

confidence: 99%

CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis

Saluzzo

Riberi

Messore

et al. 2022

Cells

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Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding for the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, expressed on the apical surface of epithelial cells. CFTR absence/dysfunction results in ion imbalance and airway surface dehydration that severely compromise the CF airway microenvironment, increasing infection susceptibility. Recently, novel therapies aimed at correcting the basic CFTR defect have become available, leading to substantial clinical improvement of CF patients. The restoration or increase of CFTR function affects the airway microenvironment, improving local defence mechanisms. CFTR modulator drugs might therefore affect the development of chronic airway infections and/or improve the status of existing infections in CF. Thus far, however, the full extent of these effects of CFTR-modulators, especially in the long-term remains still unknown. This review aims to provide an overview of current evidence on the potential impact of CFTR modulators on airway infections in CF. Their role in affecting CF microbiology, the susceptibility to infections as well as the potential efficacy of their use in preventing/decreasing the development of chronic lung infections and the recurrent acute exacerbations in CF will be critically analysed.

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Anti-Inflammatory Influences of Cystic Fibrosis Transmembrane Conductance Regulator Drugs on Lung Inflammation in Cystic Fibrosis

Cited by 17 publications

References 79 publications

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

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

Emerging Concepts in Defective Macrophage Phagocytosis in Cystic Fibrosis

CFTR Modulator Therapies: Potential Impact on Airway Infections in Cystic Fibrosis

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