scholarly journals Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation

Genes ◽  
2019 ◽  
Vol 10 (3) ◽  
pp. 183 ◽  
Author(s):  
Meraj A. Khan ◽  
Zubair Sabz Ali ◽  
Neil Sweezey ◽  
Hartmut Grasemann ◽  
Nades Palaniyar
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Lung Disease ◽  
Bacterial Infections ◽  
Neutrophil Infiltration ◽  
Extracellular Dna ◽  
Neutrophil Extracellular Trap ◽  
Medium Size ◽  
Positive Effects ◽  
Dnase Treatment

Genetic defects in cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene cause CF. Infants with CFTR mutations show a peribronchial neutrophil infiltration prior to the establishment of infection in their lung. The inflammatory response progressively increases in children that include both upper and lower airways. Infectious and inflammatory response leads to an increase in mucus viscosity and mucus plugging of small and medium-size bronchioles. Eventually, neutrophils chronically infiltrate the airways with biofilm or chronic bacterial infection. Perpetual infection and airway inflammation destroy the lungs, which leads to increased morbidity and eventual mortality in most of the patients with CF. Studies have now established that neutrophil cytotoxins, extracellular DNA, and neutrophil extracellular traps (NETs) are associated with increased mucus clogging and lung injury in CF. In addition to opportunistic pathogens, various aspects of the CF airway milieux (e.g., airway pH, salt concentration, and neutrophil phenotypes) influence the NETotic capacity of neutrophils. CF airway milieu may promote the survival of neutrophils and eventual pro-inflammatory aberrant NETosis, rather than the anti-inflammatory apoptotic death in these cells. Degrading NETs helps to manage CF airway disease; since DNAse treatment release cytotoxins from the NETs, further improvements are needed to degrade NETs with maximal positive effects. Neutrophil-T cell interactions may be important in regulating viral infection-mediated pulmonary exacerbations in patients with bacterial infections. Therefore, clarifying the role of neutrophils and NETs in CF lung disease and identifying therapies that preserve the positive effects of neutrophils, while reducing the detrimental effects of NETs and cytotoxic components, are essential in achieving innovative therapeutic advances.

scholarly journals Loss of Cftr function exacerbates the phenotype of Na+ hyperabsorption in murine airways

2013 ◽  
Vol 304 (7) ◽  
pp. L469-L480 ◽  
Author(s):  
Alessandra Livraghi-Butrico ◽  
Elizabeth J. Kelly ◽  
Kristen J. Wilkinson ◽  
Troy D. Rogers ◽  
Rodney C. Gilmore ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Neonatal Mortality ◽  
Bacterial Infections ◽  
Pulmonary Inflammation ◽  
Neutrophil Infiltration ◽  
Clara Cell ◽  
Lung Pathology ◽  
Cell Necrosis ◽  
Severe Lung

Airway surface hydration depends on the balance between transepithelial Na+ absorption and Cl− secretion. In adult mice, absence of functional cystic fibrosis transmembrane conductance regulator (Cftr) fails to recapitulate human cystic fibrosis (CF) lung disease. In contrast, overexpression of the epithelial Na+ channel β subunit in transgenic mice (βENaC-Tg) produces unregulated Na+ hyperabsorption and results in CF-like airway surface dehydration, mucus obstruction, inflammation, and increased neonatal mortality. To investigate whether the combination of airway Na+ hyperabsorption and absent Cftr-mediated Cl− secretion resulted in more severe lung pathology, we generated double-mutant ΔF508 CF/βENaC-Tg mice. Survival of ΔF508 CF/βENaC-Tg mice was reduced compared with βENaC-Tg or ΔF508 CF mice. Absence of functional Cftr did not affect endogenous or transgenic ENaC currents but produced reduced basal components of Cl− secretion and tracheal cartilaginous defects in both ΔF508 CF and ΔF508 CF/βENaC-Tg mice. Neonatal ΔF508 CF/βENaC-Tg mice exhibited higher neutrophilic pulmonary inflammation and club cell (Clara cell) necrosis compared with βENaC-Tg littermates. Neonatal ΔF508 CF/βENaC-Tg mice also exhibited spontaneous bacterial infections, but the bacterial burden was similar to that of βENaC-Tg littermates. Adult ΔF508 CF/βENaC-Tg mice exhibited pathological changes associated with eosinophilic crystalline pneumonia, a phenotype not observed in age-matched βENaC-Tg mice. Collectively, these data suggest that the combined abnormalities in Na+ absorption and Cl− secretion produce more severe lung disease than either defect alone. Airway cartilage abnormalities, airway cell necrosis, and exaggerated neutrophil infiltration likely interact with defective mucus clearance caused by βENaC overexpression and absent CFTR-mediated Cl− secretion to produce the increased neonatal mortality observed in ΔF508 CF/βENaC-Tg mice.

scholarly journals The CFTR and ENaC debate: how important is ENaC in CF lung disease?

2012 ◽  
Vol 302 (11) ◽  
pp. L1141-L1146 ◽  
Author(s):  
James F. Collawn ◽  
Ahmed Lazrak ◽  
Zsuzsa Bebok ◽  
Sadis Matalon
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Bacterial Infections ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Ongoing Debate ◽  
The Subject ◽  
Cystic Fibrosis Transmembrane ◽  
Epithelial Sodium Channel Enac

Cystic fibrosis (CF) is caused by the loss of the cystic fibrosis transmembrane conductance regulator (CFTR) function and results in a respiratory phenotype that is characterized by dehydrated mucus and bacterial infections that affect CF patients throughout their lives. Much of the morbidity and mortality in CF results from a failure to clear bacteria from the lungs. What causes the defect in the bacterial clearance in the CF lung has been the subject of an ongoing debate. Here we discuss the arguments for and against the role of the epithelial sodium channel, ENaC, in the development of CF lung disease.

scholarly journals Intrinsic Abnormalities of Cystic Fibrosis Airway Connective Tissue Revealed by an In Vitro 3D Stromal Model

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1371
Author(s):  
Claudia Mazio ◽  
Laura S. Scognamiglio ◽  
Rossella De Cegli ◽  
Luis J. V. Galietta ◽  
Diego Di Bernardo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Bacterial Infections ◽  
Inflammatory Cells ◽  
Lung Model ◽  
Lung Dysfunction ◽  
Novel Therapeutic Strategies ◽  
And Function

Cystic fibrosis is characterized by lung dysfunction involving mucus hypersecretion, bacterial infections, and inflammatory response. Inflammation triggers pro-fibrotic signals that compromise lung structure and function. At present, several in vitro cystic fibrosis models have been developed to study epithelial dysfunction but none of these focuses on stromal alterations. Here we show a new cystic fibrosis 3D stromal lung model made up of primary fibroblasts embedded in their own extracellular matrix and investigate its morphological and transcriptomic features. Cystic fibrosis fibroblasts showed a high proliferation rate and produced an abundant and chaotic matrix with increased protein content and elastic modulus. More interesting, they had enhanced pro-fibrotic markers and genes involved in epithelial function and inflammatory response. In conclusion, our study reveals that cystic fibrosis fibroblasts maintain in vitro an activated pro-fibrotic state. This abnormality may play in vivo a role in the modulation of epithelial and inflammatory cell behavior and lung remodeling. We argue that the proposed bioengineered model may provide new insights on epithelial/stromal/inflammatory cells crosstalk in cystic fibrosis, paving the way for novel therapeutic strategies.

scholarly journals Update on Respiratory Fungal Infections in Cystic Fibrosis Lung Disease and after Lung Transplantation

2020 ◽  
Vol 6 (4) ◽  
pp. 381
Author(s):  
Sabine Renner ◽  
Edith Nachbaur ◽  
Peter Jaksch ◽  
Eleonora Dehlink
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Bacterial Infections ◽  
Fungal Infections ◽  
Chloride Transport ◽  
Lung Damage ◽  
Western World ◽  
Detection Rates ◽  
Airway Infections ◽  
The Impact

Cystic fibrosis is the most common autosomal-recessive metabolic disease in the Western world. Impaired trans-membrane chloride transport via the cystic fibrosis transmembrane conductance regulator (CFTR) protein causes thickened body fluids. In the respiratory system, this leads to chronic suppurative cough and recurrent pulmonary infective exacerbations, resulting in progressive lung damage and respiratory failure. Whilst the impact of bacterial infections on CF lung disease has long been recognized, our understanding of pulmonary mycosis is less clear. The range and detection rates of fungal taxa isolated from CF airway samples are expanding, however, in the absence of consensus criteria and univocal treatment protocols for most respiratory fungal conditions, interpretation of laboratory reports and the decision to treat remain challenging. In this review, we give an overview on fungal airway infections in CF and CF-lung transplant recipients and focus on the most common fungal taxa detected in CF, Aspergillus fumigatus, Candida spp., Scedosporium apiospermum complex, Lomentospora species, and Exophiala dermatitidis, their clinical presentations, common treatments and prophylactic strategies, and clinical challenges from a physician’s point of view.

scholarly journals Novel Neutrophil-Derived Proteins in Bronchoalveolar Lavage Fluid Indicate an Exaggerated Inflammatory Response in Pediatric Cystic Fibrosis Patients

2007 ◽  
Vol 53 (10) ◽  
pp. 1782-1791 ◽  
Author(s):  
Brendan J McMorran ◽  
Severine A Ouvry Patat ◽  
John B Carlin ◽  
Keith Grimwood ◽  
Alun Jones ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
Airway Inflammation ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Respiratory Pathogens ◽  
Tissue Destruction ◽  
Tof Ms

Abstract Background: Airway inflammation in cystic fibrosis (CF) is exaggerated and characterized by neutrophil-mediated tissue destruction, but its genesis and mechanisms remain poorly understood. To further define the pulmonary inflammatory response, we conducted a proteome-based screen of bronchoalveolar lavage fluid (BALF) collected from young children with and without CF experiencing endobronchial infection. Methods: We collected BALF samples from 45 children younger than 5 years and grouped them according to the presence of respiratory pathogens: ≥1 × 105 colony-forming units (CFU)/mL BALF (18 and 12 samples with and without CF, respectively) and <1 × 105 CFU/mL (23 and 15 samples). BALF proteins were analyzed with SELDI-TOF mass spectrometry (MS) and H4 ProteinChips®. Proteins were identified and characterized using trypsin digestion, tandem MS, Fourier transform ion cyclotron resonance MS, immunoblotting, and ELISA. Results: The SELDI-TOF MS BALF profiles contained 53 unique, reliably detected proteins. Peak intensities of 24 proteins differed significantly between the CF and non-CF samples. They included the neutrophil proteins, α-defensin 1 and 2, S100A8, S100A9, and S100A12, as well as novel forms of S100A8 and S100A12 with equivalent C-terminal deletions. Peak intensities of these neutrophil proteins and immunoreactive concentrations of selected examples were significantly higher in CF than non-CF samples. Conclusions: Small neutrophil-derived BALF proteins, including novel C-terminal truncated forms of S100A proteins, are easily detected with SELDI-TOF MS. Concentrations of these molecules are abnormally high in early CF lung disease. The data provide new insights into CF lung disease and identify novel proteins strongly associated with CF airway inflammation.

scholarly journals The Balance of Neutrophil Extracellular Trap Formation and Nuclease Degradation: an Unknown Role of Bacterial Coinfections in COVID-19 Patients?

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nicole de Buhr ◽  
Maren von Köckritz-Blickwede
Keyword(s):  
Treatment Strategies ◽  
Extracellular Dna ◽  
Neutrophil Extracellular Trap ◽  
Host Defense Peptides ◽  
Antimicrobial Substances ◽  
Dnase Treatment ◽  
Severity Of The Disease ◽  
Vascular Occlusions ◽  
Nuclease Degradation

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is leading to public health crises worldwide. An understanding of the pathogenesis and the development of treatment strategies is of high interest. Recently, neutrophil extracellular traps (NETs) have been identified as a potential driver of severe SARS-CoV-2 infections in humans. NETs are extracellular DNA fibers released by neutrophils after contact with various stimuli and accumulate antimicrobial substances or host defense peptides. When massively released, NETs are described to contribute to immunothrombosis in acute respiratory distress syndrome and in vascular occlusions. Based on the increasing evidence that NETs contribute to severe COVID-19 cases, DNase treatment of COVID-19 patients to degrade NETs is widely discussed as a potential therapeutic strategy. Here, we discuss potential detrimental effects of NETs and their nuclease degradation, since NET fragments can boost certain bacterial coinfections and thereby increase the severity of the disease.

scholarly journals Ceramide in Cystic Fibrosis: A Potential New Target for Therapeutic Intervention

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Gabriella Wojewodka ◽  
Juan B. De Sanctis ◽  
Danuta Radzioch
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Inflammatory Response ◽  
Therapeutic Intervention ◽  
Bacterial Infections ◽  
Potential Role ◽  
Cell Signalling ◽  
Membrane Microdomains ◽  
Molecular Processes

Patients with cystic fibrosis (CF) are afflicted with many symptoms but the greatest challenge is the fight against chronic bacterial infections, leading to decreased lung function and ultimately death. Our group has recently found reduced levels of ceramides in CF patients and mice. Ceramides are sphingolipids involved in the structure of cell membranes but also participate in the inflammatory response, in cell signalling through membrane microdomains (lipid rafts), and in apoptosis. These characteristics of ceramides make them strong candidates for therapeutic intervention in CF. As more studies have come to evaluate the role of ceramide in CF, conflicting results have been described. This paper discusses various views regarding the potential role of ceramide in CF, summarizes methods of ceramide detection and their role in the regulation of cellular and molecular processes.

scholarly journals Esc peptides as novel potentiators of defective cystic fibrosis transmembrane conductance regulator: an unprecedented property of antimicrobial peptides

2021 ◽  
Author(s):  
Loretta Ferrera ◽  
Floriana Cappiello ◽  
Maria Rosa Loffredo ◽  
Elena Puglisi ◽  
Bruno Casciaro ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Antimicrobial Peptides ◽  
Lung Disease ◽  
Bacterial Infections ◽  
Wound Repair ◽  
Direct Interaction ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Advanced Stages ◽  
Cf Transmembrane Conductance Regulator

AbstractMutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein lead to persistent lung bacterial infections, mainly due to Pseudomonas aeruginosa, causing loss of respiratory function and finally death of people affected by CF. Unfortunately, even in the era of CFTR modulation therapies, management of pulmonary infections in CF remains highly challenging especially for patients with advanced stages of lung disease. Recently, we identified antimicrobial peptides (AMPs), namely Esc peptides, with potent antipseudomonal activity. In this study, by means of electrophysiological techniques and computational studies we discovered their ability to increase the CFTR-controlled ion currents, by direct interaction with the F508del-CFTR mutant. Remarkably, this property was not explored previously with any AMPs or peptides in general. More interestingly, in contrast with clinically used CFTR modulators, Esc peptides would give particular benefit to CF patients by combining their capability to eradicate lung infections and to act as promoters of airway wound repair with their ability to ameliorate the activity of the channel with conductance defects. Overall, our findings not only highlighted Esc peptides as the first characterized AMPs with a novel property, that is the potentiator activity of CFTR, but also paved the avenue to investigate the functions of AMPs and/or other peptide molecules, for a new up-and-coming pharmacological approach to address CF lung disease.

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