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Target Dysfunctional Inflammation in Cystic Fibrosis Airway
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Target Dysfunctional Inflammation in Cystic Fibrosis Airway

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 June 2021) | Viewed by 25337

Special Issue Editor

Dr. Valerie Urbach

E-Mail Website
Guest Editor
INSERM, U955 - Institut Mondor de Recherche Biomédicale, Faculté de Médecine de Créteil, 8 rue du Général Sarrail, 94010 Créteil cedex, France
Interests: cystic fibrosis; ion transport; lipid mediators of inflammation

Special Issue Information

Dear Colleagues,

A major cause of morbidity and mortality in patients with cystic fibrosis (CF) is the exaggerated and dysfunctional airway inflammation, which contributes to irreversible airway destruction and fibrosis. Inflammation in the CF airways can occur very early in CF, independently of bacterial infection. This unresolved inflammation contributes to disease progression and determines life expectancy. This Special Issue will give an overview of the recent discovery of key immune processes involved in CF airway disease, the impact of CFTR dysfunction and CFTR modulators therapy on the CF inflammatory phenotype, and the therapeutic perspectives to target airway inflammation in patients with CF.

Dr. Valerie Urbach
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cystic fibrosis airway
  • inflammation
  • early inflammation in CF
  • resolution of inflammation
  • lipoxins
  • resolvins
  • leucotrienes
  • airway surface liquid pH
  • cannabinoid
  • protease
  • elastase
  • cathepsin
  • non-steroidal anti-inflammatory molecules

Published Papers (7 papers)

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Research

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16 pages, 2447 KiB  
Article
Identification of Potential Leukocyte Biomarkers Related to Drug Recovery of CFTR: Clinical Applications in Cystic Fibrosis
by Marco Pedrazzi, Silvia Vercellone, Elettra Barberis, Michela Capraro, Roberta De Tullio, Federico Cresta, Rosaria Casciaro, Carlo Castellani, Mauro Patrone, Emilio Marengo, Paola Lecca, Paola Melotti, Claudio Sorio, Marcello Manfredi and Monica Averna
Int. J. Mol. Sci. 2021, 22(8), 3928; https://doi.org/10.3390/ijms22083928 - 10 Apr 2021
Cited by 10 | Viewed by 2563
Abstract
The aim of this study was the identification of specific proteomic profiles, related to a restored cystic fibrosis transmembrane conductance regulator (CFTR) activity in cystic fibrosis (CF) leukocytes before and after ex vivo treatment with the potentiator VX770. We used leukocytes, isolated from [...] Read more.
The aim of this study was the identification of specific proteomic profiles, related to a restored cystic fibrosis transmembrane conductance regulator (CFTR) activity in cystic fibrosis (CF) leukocytes before and after ex vivo treatment with the potentiator VX770. We used leukocytes, isolated from CF patients carrying residual function mutations and eligible for Ivacaftor therapy, and performed CFTR activity together with proteomic analyses through micro-LC–MS. Bioinformatic analyses of the results obtained revealed the downregulation of proteins belonging to the leukocyte transendothelial migration and regulation of actin cytoskeleton pathways when CFTR activity was rescued by VX770 treatment. In particular, we focused our attention on matrix metalloproteinase 9 (MMP9), because the high expression of this protease potentially contributes to parenchyma lung destruction and dysfunction in CF. Thus, the downregulation of MMP9 could represent one of the possible positive effects of VX770 in decreasing the disease progression, and a potential biomarker for the prediction of the efficacy of therapies targeting the defect of Cl− transport in CF. Full article
(This article belongs to the Special Issue Target Dysfunctional Inflammation in Cystic Fibrosis Airway)
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15 pages, 2818 KiB  
Article
Functional and Transcriptional Adaptations of Blood Monocytes Recruited to the Cystic Fibrosis Airway Microenvironment In Vitro
by Bijean D. Ford, Diego Moncada Giraldo, Camilla Margaroli, Vincent D. Giacalone, Milton R. Brown, Limin Peng and Rabindra Tirouvanziam
Int. J. Mol. Sci. 2021, 22(5), 2530; https://doi.org/10.3390/ijms22052530 - 3 Mar 2021
Cited by 5 | Viewed by 2428
Abstract
Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung [...] Read more.
Cystic fibrosis (CF) lung disease is dominated by the recruitment of myeloid cells (neutrophils and monocytes) from the blood which fail to clear the lung of colonizing microbes. In prior in vitro studies, we showed that blood neutrophils migrated through the well-differentiated lung epithelium into the CF airway fluid supernatant (ASN) mimic the dysfunction of CF airway neutrophils in vivo, including decreased bactericidal activity despite an increased metabolism. Here, we hypothesized that, in a similar manner to neutrophils, blood monocytes undergo significant adaptations upon recruitment to CFASN. To test this hypothesis, primary human blood monocytes were transmigrated in our in vitro model into the ASN from healthy control (HC) or CF subjects to mimic in vivo recruitment to normal or CF airways, respectively. Surface phenotype, metabolic and bacterial killing activities, and transcriptomic profile by RNA sequencing were quantified post-transmigration. Unlike neutrophils, monocytes were not metabolically activated, nor did they show broad differences in activation and scavenger receptor expression upon recruitment to the CFASN compared to HCASN. However, monocytes recruited to CFASN showed decreased bactericidal activity. RNASeq analysis showed strong effects of transmigration on monocyte RNA profile, with differences between CFASN and HCASN conditions, notably in immune signaling, including lower expression in the former of the antimicrobial factor ISG15, defensin-like chemokine CXCL11, and nitric oxide-producing enzyme NOS3. While monocytes undergo qualitatively different adaptations from those seen in neutrophils upon recruitment to the CF airway microenvironment, their bactericidal activity is also dysregulated, which could explain why they also fail to protect CF airways from infection. Full article
(This article belongs to the Special Issue Target Dysfunctional Inflammation in Cystic Fibrosis Airway)
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13 pages, 2003 KiB  
Article
Cellular Redox State Acts as Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells
by Maria Favia and Anna Atlante
Int. J. Mol. Sci. 2021, 22(2), 967; https://doi.org/10.3390/ijms22020967 - 19 Jan 2021
Cited by 4 | Viewed by 2123
Abstract
The redox states of NAD and NADP are linked to each other in the mitochondria thanks to the enzyme nicotinamide nucleotide transhydrogenase (NNT) which, by utilizing the mitochondrial membrane potential (mΔΨ), catalyzes the transfer of redox potential between these two coenzymes, reducing one [...] Read more.
The redox states of NAD and NADP are linked to each other in the mitochondria thanks to the enzyme nicotinamide nucleotide transhydrogenase (NNT) which, by utilizing the mitochondrial membrane potential (mΔΨ), catalyzes the transfer of redox potential between these two coenzymes, reducing one at the expense of the oxidation of the other. In order to define NNT reaction direction in CF cells, NNT activity under different redox states of cell has been investigated. Using spectrophotometric and western blotting techniques, the presence, abundance and activity level of NNT were determined. In parallel, the levels of NADPH and NADH as well as of mitochondrial and cellular ROS were also quantified. CF cells showed a 70% increase in protein expression compared to the Wt sample; however, regarding NNT activity, it was surprisingly lower in CF cells than healthy cells (about 30%). The cellular redox state, together with the low mΔΨ, pushes to drive NNT reverse reaction, at the expense of its antioxidant potential, thus consuming NADPH to support NADH production. At the same time, the reduced NNT activity prevents the NADH, produced by the reaction, from causing an explosion of ROS by the damaged respiratory chain, in accordance with the reduced level of mitochondrial ROS in NNT-loss cells. This new information on cellular bioenergetics represents an important building block for further understanding the molecular mechanisms responsible for cellular dysfunction in cystic fibrosis. Full article
(This article belongs to the Special Issue Target Dysfunctional Inflammation in Cystic Fibrosis Airway)
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Review

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15 pages, 3279 KiB  
Review
Anti-Inflammatory Influences of Cystic Fibrosis Transmembrane Conductance Regulator Drugs on Lung Inflammation in Cystic Fibrosis
by Kiera H. Harwood, Rachel M. McQuade, Andrew Jarnicki and Elena K. Schneider-Futschik
Int. J. Mol. Sci. 2021, 22(14), 7606; https://doi.org/10.3390/ijms22147606 - 16 Jul 2021
Cited by 16 | Viewed by 3863
Abstract
Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) which instigates a myriad of respiratory complications including increased vulnerability to lung infections and lung inflammation. The extensive influx of pro-inflammatory cells and production of mediators [...] Read more.
Cystic fibrosis (CF) is caused by a defect in the cystic fibrosis transmembrane conductance regulator protein (CFTR) which instigates a myriad of respiratory complications including increased vulnerability to lung infections and lung inflammation. The extensive influx of pro-inflammatory cells and production of mediators into the CF lung leading to lung tissue damage and increased susceptibility to microbial infections, creates a highly inflammatory environment. The CF inflammation is particularly driven by neutrophil infiltration, through the IL-23/17 pathway, and function, through NE, NETosis, and NLRP3-inflammasome formation. Better understanding of these pathways may uncover untapped therapeutic targets, potentially reducing disease burden experienced by CF patients. This review outlines the dysregulated lung inflammatory response in CF, explores the current understanding of CFTR modulators on lung inflammation, and provides context for their potential use as therapeutics for CF. Finally, we discuss the determinants that need to be taken into consideration to understand the exaggerated inflammatory response in the CF lung. Full article
(This article belongs to the Special Issue Target Dysfunctional Inflammation in Cystic Fibrosis Airway)
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22 pages, 947 KiB  
Review
Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches
by Alessandra Ghigo, Giulia Prono, Elisa Riccardi and Virginia De Rose
Int. J. Mol. Sci. 2021, 22(4), 1952; https://doi.org/10.3390/ijms22041952 - 16 Feb 2021
Cited by 15 | Viewed by 6708
Abstract
Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport [...] Read more.
Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients. Full article
(This article belongs to the Special Issue Target Dysfunctional Inflammation in Cystic Fibrosis Airway)
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21 pages, 789 KiB  
Review
Airway Inflammation and Host Responses in the Era of CFTR Modulators
by Karen Keown, Ryan Brown, Declan F. Doherty, Claire Houston, Michael C. McKelvey, Shannice Creane, Dermot Linden, Daniel F. McAuley, Joseph C. Kidney, Sinéad Weldon, Damian G. Downey and Clifford C. Taggart
Int. J. Mol. Sci. 2020, 21(17), 6379; https://doi.org/10.3390/ijms21176379 - 2 Sep 2020
Cited by 34 | Viewed by 4640
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Target Dysfunctional Inflammation in Cystic Fibrosis Airway)
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Other

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12 pages, 2353 KiB  
Case Report
Two Siblings Homozygous for F508del-CFTR Have Varied Disease Phenotypes and Protein Biomarkers
by Zhihong Zhang, Jin Wang, Yanhui H. Zhang, Tonia E. Gardner, Elizabeth A. Fitzpatrick and Weiqiang Zhang
Int. J. Mol. Sci. 2021, 22(5), 2631; https://doi.org/10.3390/ijms22052631 - 5 Mar 2021
Viewed by 2198
Abstract
Two siblings with CF are homozygous for F508del (referred to as Subject A and Subject B). Despite having the same CFTR genotype and similar environment, these two subjects exhibited different disease phenotypes. We analyzed their medical records and CF Foundation Registry data and [...] Read more.
Two siblings with CF are homozygous for F508del (referred to as Subject A and Subject B). Despite having the same CFTR genotype and similar environment, these two subjects exhibited different disease phenotypes. We analyzed their medical records and CF Foundation Registry data and measured inflammatory protein mediators in their sputum samples. Then, we examined the longitudinal relationships between inflammatory markers and disease severity for each subject and compared between them. Subject A presented a more severe disease than Subject B. During the study period, Subject A had two pulmonary exacerbations (PEs) whereas Subject B had one mild PE. The forced expiratory volume in 1 s (FEV1, % predicted) values for Subject A were between 34–45% whereas for Subject B varied between 48–90%. Inflammatory protein mediators associated with neutrophils, Th1, Th2, and Th17 responses were elevated in sputum of Subject A compared with Subject B, and also in samples collected prior to and during PEs for both subjects. Neutrophilic elastase (NE) seemed to be the most informative biomarkers. The infectious burden between these two subjects was different. Full article
(This article belongs to the Special Issue Target Dysfunctional Inflammation in Cystic Fibrosis Airway)
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