scholarly journals Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches

2021 ◽  
Vol 22 (4) ◽  
pp. 1952
Author(s):  
Alessandra Ghigo ◽  
Giulia Prono ◽  
Elisa Riccardi ◽  
Virginia De Rose
Keyword(s):  
Cystic Fibrosis ◽  
Critical Role ◽  
Airway Epithelial Cells ◽  
Lung Damage ◽  
Molecular Defect ◽  
Apical Surface ◽  
Therapeutic Approaches ◽  
Beneficial Effects ◽  
Anti Inflammatory ◽  
Novel Therapeutic

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.

scholarly journals Restoration of Chloride Efflux by Azithromycin in Airway Epithelial Cells of Cystic Fibrosis Patients

2011 ◽  
Vol 55 (4) ◽  
pp. 1792-1793 ◽  
Author(s):  
Vinciane Saint-Criq ◽  
Carine Rebeyrol ◽  
Manon Ruffin ◽  
Telma Roque ◽  
Loïc Guillot ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Airway Epithelial Cells ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Respiratory Condition ◽  
Beneficial Effects ◽  
Chronic Obstructive Pulmonary Diseases ◽  
Anti Inflammatory ◽  
Inflammatory Effect ◽  
Airway Cells

ABSTRACTAzithromycin (AZM) has shown promising anti-inflammatory properties in chronic obstructive pulmonary diseases, and clinical studies have presented an improvement in the respiratory condition of cystic fibrosis (CF) patients. The aim of this study was to investigate, in human airway cells, the mechanism by which AZM has beneficial effects in CF. We demonstrated that AZM did not have any anti-inflammatory effect on CF airway cells but restored Cl−efflux.

scholarly journals Airway Epithelium Dysfunction in Cystic Fibrosis and COPD

2018 ◽  
Vol 2018 ◽  
pp. 1-20 ◽  
Author(s):  
Virginia De Rose ◽  
Kevin Molloy ◽  
Sophie Gohy ◽  
Charles Pilette ◽  
Catherine M. Greene
Keyword(s):  
Cystic Fibrosis ◽  
Airway Epithelium ◽  
Critical Role ◽  
Airflow Obstruction ◽  
Alveolar Epithelium ◽  
Airway Epithelial Cells ◽  
Lung Damage ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Epithelial Dysfunction

Cystic fibrosis is a genetic disease caused by mutations in the CFTR gene, whereas chronic obstructive pulmonary disease (COPD) is mainly caused by environmental factors (mostly cigarette smoking) on a genetically susceptible background. Although the etiology and pathogenesis of these diseases are different, both are associated with progressive airflow obstruction, airway neutrophilic inflammation, and recurrent exacerbations, suggesting common mechanisms. The airway epithelium plays a crucial role in maintaining normal airway functions. Major molecular and morphologic changes occur in the airway epithelium in both CF and COPD, and growing evidence suggests that airway epithelial dysfunction is involved in disease initiation and progression in both diseases. Structural and functional abnormalities in both airway and alveolar epithelium have a relevant impact on alteration of host defences, immune/inflammatory response, and the repair process leading to progressive lung damage and impaired lung function. In this review, we address the evidence for a critical role of dysfunctional airway epithelial cells in chronic airway inflammation and remodelling in CF and COPD, highlighting the common mechanisms involved in the epithelial dysfunction as well as the similarities and differences of the two diseases.

scholarly journals Activity and inhibition of prostasin and matriptase on apical and basolateral surfaces of human airway epithelial cells

2012 ◽  
Vol 303 (2) ◽  
pp. L97-L106 ◽  
Author(s):  
Shilpa Nimishakavi ◽  
Marina Besprozvannaya ◽  
Wilfred W. Raymond ◽  
Charles S. Craik ◽  
Dieter C. Gruenert ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Cell Surface ◽  
Selective Inhibition ◽  
Airway Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Apical Surface ◽  
Airway Epithelial ◽  
Wild Type ◽  
Bronchial Epithelial

Prostasin is a membrane-anchored protease expressed in airway epithelium, where it stimulates salt and water uptake by cleaving the epithelial Na+ channel (ENaC). Prostasin is activated by another transmembrane tryptic protease, matriptase. Because ENaC-mediated dehydration contributes to cystic fibrosis (CF), prostasin and matriptase are potential therapeutic targets, but their catalytic competence on airway epithelial surfaces has been unclear. Seeking tools for exploring sites and modulation of activity, we used recombinant prostasin and matriptase to identify substrate t-butyloxycarbonyl-l-Gln-Ala-Arg-4-nitroanilide (QAR-4NA), which allowed direct assay of proteases in living cells. Comparisons of bronchial epithelial cells (CFBE41o−) with and without functioning cystic fibrosis transmembrane conductance regulator (CFTR) revealed similar levels of apical and basolateral aprotinin-inhibitable activity. Although recombinant matriptase was more active than prostasin in hydrolyzing QAR-4NA, cell surface activity resisted matriptase-selective inhibition, suggesting that prostasin dominates. Surface biotinylation revealed similar expression of matriptase and prostasin in epithelial cells expressing wild-type vs. ΔF508-mutated CFTR. However, the ratio of mature to inactive proprostasin suggested surface enrichment of active enzyme. Although small amounts of matriptase and prostasin were shed spontaneously, prostasin anchored to the cell surface by glycosylphosphatidylinositol was the major contributor to observed QAR-4NA-hydrolyzing activity. For example, the apical surface of wild-type CFBE41o− epithelial cells express 22% of total, extractable, aprotinin-inhibitable, QAR-4NA-hydrolyzing activity and 16% of prostasin immunoreactivity. In conclusion, prostasin is present, mature and active on the apical surface of wild-type and CF bronchial epithelial cells, where it can be targeted for inhibition via the airway lumen.

scholarly journals Microbial interaction: Prevotella spp. reduce P.aeruginosa induced inflammation in Cystic Fibrosis bronchial epithelial cells

2020 ◽  
Author(s):  
Anne Bertelsen ◽  
Stuart J Elborn ◽  
Bettina Schock
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Bacterial Species ◽  
Airway Epithelial Cells ◽  
Lung Damage ◽  
Airway Epithelial ◽  
Lung Function Decline ◽  
Mapk Signalling ◽  
Microbial Environment

Abstract Background: In Cystic Fibrosis (CF) airways, mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) lead to dehydrated, thick mucus which promotes the establishment of persistent polymicrobial infections and drives chronic airways inflammation. This also predisposes the airways to further infections, a vicious, self-perpetuating cycle causing lung damage and progressive lung function decline. The airways are a poly-microbial environment, containing both aerobic and anaerobic bacterial species. Pseudomonas aeruginosa (P.aeruginosa) infections contribute to the excessive inflammatory response in CF, but the role of anaerobic Prevotella spp., frequently found in CF airways, is not known.Materials: We assessed innate immune signalling in CF airway epithelial cells in response to clinical strains of P.histicola, P.nigresens and P.aeruginosa. CFBE41o- cells were infected with P.aeruginosa (MOI 100, 2h) followed by infection with P.histicola or P.nigrescens (MOI 100, 2h). Cells were incubated under anaerobic conditions for the duration of the experiments.Results: Our study shows that P.histicola and P.nigresens can reduce the growth of P.aeruginosa and dampen the inflammatory response in airway epithelial cells. We specifically illustrate that the presence of Prevotella spp. reduces Toll-like-receptor (TLR)-4, MAPK, NF-kB(p65) signalling and cytokine release (Interleukin (IL)-6, IL-8) in mixed infections. Conclusion: Our work, for the first time, strongly indicates a relationship between P. aeruginosa and anaerobe Prevotella spp. The observed modified NF-kB and MAPK signalling provides some mechanisms of this interaction that could offer a novel therapeutic approach to combat chronic P.aeruginosa infection in people with CF.

scholarly journals Flagellin From Pseudomonas aeruginosa Modulates SARS-CoV-2 Infectivity in Cystic Fibrosis Airway Epithelial Cells by Increasing TMPRSS2 Expression

2021 ◽  
Vol 12 ◽  
Author(s):  
Manon Ruffin ◽  
Jeanne Bigot ◽  
Claire Calmel ◽  
Julia Mercier ◽  
Maëlle Givelet ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Critical Role ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Health Crisis ◽  
Chronic Respiratory Diseases ◽  
Cf Transmembrane Conductance Regulator ◽  
Main Component

In the coronavirus disease 2019 (COVID-19) health crisis, one major challenge is to identify the susceptibility factors of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in order to adapt the recommendations for populations, as well as to reduce the risk of COVID-19 development in the most vulnerable people, especially patients with chronic respiratory diseases such as cystic fibrosis (CF). Airway epithelial cells (AECs) play a critical role in the modulation of both immune responses and COVID-19 severity. SARS-CoV-2 infects the airway through the receptor angiotensin-converting enzyme 2, and a host protease, transmembrane serine protease 2 (TMPRSS2), plays a major role in SARS-CoV-2 infectivity. Here, we show that Pseudomonas aeruginosa increases TMPRSS2 expression, notably in primary AECs with deficiency of the ion channel CF transmembrane conductance regulator (CFTR). Further, we show that the main component of P. aeruginosa flagella, the protein flagellin, increases TMPRSS2 expression in primary AECs and Calu-3 cells, through activation of Toll-like receptor-5 and p38 MAPK. This increase is particularly seen in Calu-3 cells deficient for CFTR and is associated with an intracellular increased level of SARS-CoV-2 infection, however, with no effect on the amount of virus particles released. Considering the urgency of the COVID-19 health crisis, this result may be of clinical significance for CF patients, who are frequently infected with and colonized by P. aeruginosa during the course of CF and might develop COVID-19.

scholarly journals Exocytosis is not involved in activation of Cl− secretion via CFTR in Calu-3 airway epithelial cells

1998 ◽  
Vol 275 (4) ◽  
pp. C913-C920 ◽  
Author(s):  
Johannes Loffing ◽  
Bryan D. Moyer ◽  
David McCoy ◽  
Bruce A. Stanton
Keyword(s):  
Cystic Fibrosis ◽  
Plasma Membrane ◽  
Epithelial Cells ◽  
Critical Role ◽  
Airway Epithelial Cells ◽  
Cell Phenotype ◽  
Apical Plasma Membrane ◽  
Airway Epithelial ◽  
Intracellular Pool ◽  
Airway Function

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl−channel, which mediates transepithelial Cl− transport in a variety of epithelia, including airway, intestine, pancreas, and sweat duct. In some but not all epithelial cells, cAMP stimulates Cl− secretion in part by increasing the number of CFTR Cl− channels in the apical plasma membrane. Because the mechanism whereby cAMP stimulates CFTR Cl− secretion is cell-type specific, our goal was to determine whether cAMP elevates CFTR-mediated Cl− secretion across serous airway epithelial cells by stimulating the insertion of CFTR Cl− channels from an intracellular pool into the apical plasma membrane. To this end we studied Calu-3 cells, a human airway cell line with a serous cell phenotype. Serous cells in human airways, such as Calu-3 cells, express high levels of CFTR, secrete antibiotic-rich fluid, and play a critical role in airway function. Moreover, dysregulation of CFTR-mediated Cl− secretion in serous cells is thought to contribute to the pathophysiology of cystic fibrosis lung disease. We report that cAMP activation of CFTR-mediated Cl− secretion across human serous cells involves stimulation of CFTR channels present in the apical plasma membrane and does not involve the recruitment of CFTR from an intracellular pool to the apical plasma membrane.

Direct interaction of a small-molecule modulator with G551D-CFTR, a cystic fibrosis-causing mutation associated with severe disease

2009 ◽  
Vol 418 (1) ◽  
pp. 185-190 ◽  
Author(s):  
Stan Pasyk ◽  
Canhui Li ◽  
Mohabir Ramjeesingh ◽  
Christine E. Bear
Keyword(s):  
Cystic Fibrosis ◽  
Atpase Activity ◽  
Small Molecule ◽  
Mechanism Of Action ◽  
Severe Disease ◽  
Atp Binding ◽  
Molecular Defect ◽  
Apical Surface ◽  
Channel Activity ◽  
Small Molecule Modulator

CF (cystic fibrosis) is caused by mutations in CFTR (CF transmembrane conductance regulator), which cause its mistrafficking and/or dysfunction as a regulated chloride channel on the apical surface of epithelia. CFTR is a member of the ABC (ATP-binding-cassette) superfamily of membrane proteins and a disease-causing missense mutation within the ABC signature sequence; G551D-CFTR exhibits defective phosphorylation and ATP-dependent channel gating. Studies of the purified and reconstituted G551D-CFTR protein revealed that faulty gating is associated with defective ATP binding and ATPase activity, reflecting the key role of G551 in these functions. Recently, high-throughput screens of chemical libraries led to identification of modulators that enhance channel activity of G551D-CFTR. However, the molecular target(s) for these modulators and their mechanism of action remain unclear. In the present study, we evaluated the mechanism of action of one small-molecule modulator, VRT-532, identified as a specific modulator of CF-causing mutants. First, we confirmed that VRT-532 causes a significant increase in channel activity of G551D-CFTR using a novel assay of CFTR function in inside-out membrane vesicles. Biochemical studies of purified and reconstituted G551D-CFTR revealed that potentiation of the ATPase activity of VRT-532 is mediated by enhancing the affinity of the mutant for ATP. Interestingly, VRT-532 did not affect the ATPase activity of the Wt (wild-type) CFTR, supporting the idea that this compound corrects the specific molecular defect in this mutant. To summarize, these studies provide direct evidence that this compound binds to G551D-CFTR to rescue its specific defect in ATP binding and hydrolysis.

scholarly journals Therapeutic Potential of Resveratrol in COVID-19-Associated Hemostatic Disorders

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 856
Author(s):  
Roberta Giordo ◽  
Angelo Zinellu ◽  
Ali Hussein Eid ◽  
Gianfranco Pintus
Keyword(s):  
Therapeutic Potential ◽  
Coagulation Cascade ◽  
Low Molecular Weight ◽  
Coagulation Disorders ◽  
Therapeutic Approaches ◽  
Beneficial Effects ◽  
Primary Hemostasis ◽  
Anti Inflammatory ◽  
Hemostatic Disorders ◽  
Different Levels

Coagulation disorders, endotheliopathy and inflammation are the most common hallmarks in SARS-CoV-2 infection, largely determining COVID-19’s outcome and severity. Dysfunctions of endothelial cells and platelets are tightly linked in contributing to the systemic inflammatory response that appears to be both a cause and a consequence of COVID-19-associated coagulation disorders and thrombotic events. Indeed, elevated levels of circulating inflammatory cytokines are often associated with abnormal coagulation parameters in COVID-19 patients. Although treatments with low molecular weight heparin (LMWH) have shown beneficial effects in decreasing patient mortality with severe COVID-19, additional therapeutic strategies are urgently needed. Utilizing the anti-inflammatory and anti-thrombotic properties of natural compounds may provide alternative therapeutic approaches to prevent or reduce the risk factors associated with pre-existing conditions and comorbidities that can worsen COVID-19 patients’ outcomes. In this regard, resveratrol, a natural compound found in several plants and fruits such as grapes, blueberries and cranberries, may represent a promising coadjuvant for the prevention and treatment of COVID-19. By virtue of its anti-thrombotic and anti-inflammatory properties, resveratrol would be expected to lower COVID-19-associated mortality, which is well known to be increased by thrombosis and inflammation. This review analyzes and discusses resveratrol’s ability to modulate vascular hemostasis at different levels targeting both primary hemostasis (interfering with platelet activation and aggregation) and secondary hemostasis (modulating factors involved in coagulation cascade).

scholarly journals PGD Synthase and PGD2in Immune Resposne

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Myungsoo Joo ◽  
Ruxana T. Sadikot
Keyword(s):  
Arachidonic Acid ◽  
Inflammatory Response ◽  
Inflammatory Diseases ◽  
Disease Process ◽  
Therapeutic Approaches ◽  
Enzyme Reactions ◽  
Common Precursor ◽  
Anti Inflammatory ◽  
Novel Therapeutic

PGD2is formed from arachidonic acid by successive enzyme reactions: oxygenation of arachidonic acid to PGH2, a common precursor of various prostanoids, catalyzed by cyclooxygenase, and isomerization of PGH2to PGD2by PGD synthases (PGDSs). PGD2can be either pro- or anti-inflammatory depending on disease process and etiology. The anti-inflammatory and immunomodulatory attributes of PGDS/PGD2provide opportunities for development of novel therapeutic approaches for resistant infections and refractory inflammatory diseases. This paper highlights the role of PGD synthases and PGD2 in immune inflammatory response.

scholarly journals Nonclassical Pathway of Pseudomonas aeruginosa DNA-Induced Interleukin-8 Secretion in Cystic Fibrosis Airway Epithelial Cells

2006 ◽  
Vol 74 (5) ◽  
pp. 2975-2984 ◽  
Author(s):  
Mónica A. Delgado ◽  
Jens F. Poschet ◽  
Vojo Deretic
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Epithelial Cells ◽  
Neutrophil Infiltration ◽  
Airway Epithelial Cells ◽  
Interleukin 8 ◽  
Lung Damage ◽  
Cystic Fibrosis Lung ◽  
Toll Like Receptor ◽  
Chronic Infections

ABSTRACT Pseudomonas aeruginosa is a critical colonizer of the respiratory tract in cystic fibrosis. The chronic infections with this microorganism contribute to excessive inflammation and progressive lung damage in cystic fibrosis patients. The full repertoire of Pseudomonas products that promote inflammation in the cystic fibrosis lung is not known. Here we show that P. aeruginosa DNA released from the bacterium, but not human DNA from epithelial cells or Escherichia coli DNA, displays proinflammatory properties and induces human respiratory epithelial cells to secrete interleukin-8 (IL-8), a key chemokine causing excessive neutrophil infiltration in the cystic fibrosis lung. IL-8 secretion was not due to an increase in NF-κB- or activator protein-1-dependent IL-8 promoter transcription, but instead depended on p38 and Erk mitogen-activated protein kinases. No secretion of IL-8 was observed using conventional Toll-like receptor 9 ligands (CpG oligonucleotides), although it could be demonstrated that parts of the Toll-like receptor 9-signaling pathway were functional, since class B and C CpG oligonucleotide ligands stimulated production of RANTES chemokine. The IL-8 secretion in response to P. aeruginosa DNA was decreased by treatments that inhibit acidification of intracellular organelles, using chloroquine, a pH-neutralizing compound, or bafilomycin A1, an inhibitor of vacuolar H+-ATPase. These data indicate that DNA released from P. aeruginosa during chronic infections may significantly contribute to the proinflammatory processes in cystic fibrosis. Our findings also show that treatments with drugs diminishing organellar acidification may reduce the inflammatory response in cystic fibrosis.

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