scholarly journals Update on Calcium Signaling in Cystic Fibrosis Lung Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Alessandro Rimessi ◽  
Veronica A. M. Vitto ◽  
Simone Patergnani ◽  
Paolo Pinton
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Immune Cells ◽  
Cell Function ◽  
Autosomal Recessive Disorder ◽  
Airway Epithelial ◽  
Cystic Fibrosis Lung Disease ◽  
Relevant Role ◽  
Intracellular Organelles

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by mutations in the cystic fibrosis transmembrane conductance regulator gene, which causes multifunctional defects that preferentially affect the airways. Abnormal viscosity of mucus secretions, persistent pathogen infections, hyperinflammation, and lung tissue damage compose the classical pathological manifestation referred to as CF lung disease. Among the multifunctional defects associated with defective CFTR, increasing evidence supports the relevant role of perturbed calcium (Ca2+) signaling in the pathophysiology of CF lung disease. The Ca2+ ion is a critical player in cell functioning and survival. Its intracellular homeostasis is maintained by a fine balance between channels, transporters, and exchangers, mediating the influx and efflux of the ion across the plasma membrane and the intracellular organelles. An abnormal Ca2+ profile has been observed in CF cells, including airway epithelial and immune cells, with heavy repercussions on cell function, viability, and susceptibility to pathogens, contributing to proinflammatory overstimulation, organelle dysfunction, oxidative stress, and excessive cytokines release in CF lung. This review discusses the role of Ca2+ signaling in CF and how its dysregulation in airway epithelial and immune cells contributes to hyperinflammation in the CF lung. Finally, we provide an outlook on the therapeutic options that target the Ca2+ signaling to treat the CF lung disease.

scholarly journals A molecular atlas of proximal airway identifies subsets of known airway cell types revealing details of the unique molecular pathogenesis of Cystic Fibrosis

2020 ◽  
Author(s):  
Gianni Carraro ◽  
Justin Langerman ◽  
Shan Sabri ◽  
Zareeb Lorenzana ◽  
Arunima Purkayastha ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Autosomal Recessive Disorder ◽  
Cell Types ◽  
Airway Disease ◽  
Transmembrane Conductance Regulator ◽  
Basal Cells ◽  
Airway Epithelial ◽  
Polarized Epithelia ◽  
End Stage

Introduction/AbstractCystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts in excess of 70,000 people globally. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most significant determinant of morbidity and mortality. In this study we report results from a multi-institute consortium in which single cell transcriptomics were applied to define disease-related changes to the proximal airway of CF donors (n=19) undergoing transplantation for end-stage lung disease compared to the proximal airway of previously healthy lung donors (n=19). We found that all major airway epithelial cell types were conserved between control and CF donors. Disease-dependent differences were observed, including an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subtypes coupled with an unexpected decrease in cycling basal cells. This study developed a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.

scholarly journals Role of Neutrophils in Cystic Fibrosis Lung Disease

10.5772/67798 ◽  
2017 ◽  
Author(s):  
Massimo Conese ◽  
Stefano Castellani ◽  
Susanna D’Oria ◽  
Sante Di Gioia ◽  
Pasqualina Montemurro
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Cystic Fibrosis Lung ◽  
Cystic Fibrosis Lung Disease

scholarly journals CXCR4+ granulocytes reflect fungal cystic fibrosis lung disease

2015 ◽  
Vol 46 (2) ◽  
pp. 395-404 ◽  
Author(s):  
Melanie Carevic ◽  
Anurag Singh ◽  
Nikolaus Rieber ◽  
Olaf Eickmeier ◽  
Matthias Griese ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Immune Cells ◽  
Therapeutic Target ◽  
Cystic Fibrosis Lung ◽  
Fungal Colonisation ◽  
Cystic Fibrosis Lung Disease ◽  
Potential Biomarker ◽  
Healthy Control

Cystic fibrosis airways are frequently colonised with fungi. However, the interaction of these fungi with immune cells and the clinical relevance in cystic fibrosis lung disease are incompletely understood.We characterised granulocytes in airway fluids and peripheral blood from cystic fibrosis patients with and without fungal colonisation, non-cystic fibrosis disease controls and healthy control subjects cross-sectionally and longitudinally and correlated these findings with lung function parameters.Cystic fibrosis patients with chronic fungal colonisation by Aspergillus fumigatus were characterised by an accumulation of a distinct granulocyte subset, expressing the HIV coreceptor CXCR4. Percentages of airway CXCR4+ granulocytes correlated with lung disease severity in patients with cystic fibrosis.These studies demonstrate that chronic fungal colonisation with A. fumigatus in cystic fibrosis patients is associated with CXCR4+ airway granulocytes, which may serve as a potential biomarker and therapeutic target in fungal cystic fibrosis lung disease.

scholarly journals Cystic Fibrosis Lung Disease Modifiers and Their Relevance in the New Era of Precision Medicine

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 562
Author(s):  
Afsoon Sepahzad ◽  
Deborah J. Morris-Rosendahl ◽  
Jane C. Davies
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Response To Treatment ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
New Era ◽  
Genome Wide ◽  
Cystic Fibrosis Lung Disease ◽  
Genomic Tools

Our understanding of cystic fibrosis (CF) has grown exponentially since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989. With evolving genetic and genomic tools, we have come to better understand the role of CFTR genotypes in the pathophysiology of the disease. This, in turn, has paved the way for the development of modulator therapies targeted at mutations in the CFTR, which are arguably one of the greatest advances in the treatment of CF. These modulator therapies, however, do not target all the mutations in CFTR that are seen in patients with CF and, furthermore, a variation in response is seen in patients with the same genotype who are taking modulator therapies. There is growing evidence to support the role of non-CFTR modifiers, both genetic and environmental, in determining the variation seen in CF morbidity and mortality and also in the response to existing therapies. This review focusses on key findings from studies using candidate gene and genome-wide approaches to identify CF modifier genes of lung disease in cystic fibrosis and considers the interaction between modifiers and the response to modulator therapies. As the use of modulator therapies expands and we gain data around outcomes, it will be of great interest to investigate this interaction further. Going forward, it will also be crucial to better understand the relative influence of genomic versus environmental factors. With this understanding, we can truly begin to deliver personalised care by better profiling the likely disease phenotype for each patient and their response to treatment.

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