scholarly journals Targeting of cathepsin S reduces cystic fibrosis-like lung disease

2019 ◽  
Vol 53 (3) ◽  
pp. 1801523 ◽  
Author(s):  
Donna M. Small ◽  
Ryan R. Brown ◽  
Declan F. Doherty ◽  
Anthony Abladey ◽  
Zhe Zhou-Suckow ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Pulmonary Inflammation ◽  
Lung Damage ◽  
Cathepsin S ◽  
Lung Pathology ◽  
Wild Type ◽  
Mucin Expression ◽  
Protease Activated Receptor 2 ◽  
Lung Remodelling

Cathepsin S (CatS) is upregulated in the lungs of patients with cystic fibrosis (CF). However, its role in CF lung disease pathogenesis remains unclear.In this study, β-epithelial Na+ channel-overexpressing transgenic (βENaC-Tg) mice, a model of CF-like lung disease, were crossed with CatS null (CatS−/−) mice or treated with the CatS inhibitor VBY-999.Levels of active CatS were elevated in the lungs of βENaC-Tg mice compared with wild-type (WT) littermates. CatS−/−βENaC-Tg mice exhibited decreased pulmonary inflammation, mucus obstruction and structural lung damage compared with βENaC-Tg mice. Pharmacological inhibition of CatS resulted in a significant decrease in pulmonary inflammation, lung damage and mucus plugging in the lungs of βENaC-Tg mice. In addition, instillation of CatS into the lungs of WT mice resulted in inflammation, lung remodelling and upregulation of mucin expression. Inhibition of the CatS target, protease-activated receptor 2 (PAR2), in βENaC-Tg mice resulted in a reduction in airway inflammation and mucin expression, indicating a role for this receptor in CatS-induced lung pathology.Our data indicate an important role for CatS in the pathogenesis of CF-like lung disease mediated in part by PAR2 and highlight CatS as a therapeutic target.

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 Pseudomonas aeruginosa Exoenzyme S Induces Transcriptional Expression of Proinflammatory Cytokines and Chemokines

2000 ◽  
Vol 68 (8) ◽  
pp. 4811-4814 ◽  
Author(s):  
Slava Epelman ◽  
Tony F. Bruno ◽  
Graham G. Neely ◽  
Donald E. Woods ◽  
Christopher H. Mody
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Proinflammatory Cytokines ◽  
Pulmonary Inflammation ◽  
Lung Damage ◽  
Gene Probe ◽  
Necrosis Factor Alpha ◽  
Exoenzyme S ◽  
Cytokines And Chemokines ◽  
Immunoregulatory Cytokines

ABSTRACT Pseudomonas aeruginosa infection of cystic fibrosis patients causes lung damage that is substantially orchestrated by cytokines. In this study, multi-gene probe analysis was used to characterize the ability of the P. aeruginosamitogen, exoenzyme S, to induce proinflammatory and immunoregulatory cytokines and chemokines. Exoenzyme S strongly induced transcription of proinflammatory cytokines and chemokines (tumor necrosis factor alpha, interleukin-1α [IL-1α], IL-1β, IL-6, IL-8, MIP-1α, MIP-1β, MCP-1, RANTES, and I-309), modest transcription of immunoregulatory cytokines (IL-10 and IL-12p40), and weak transcription of Th1 cytokines (IL-2 and gamma interferon). The response occurred early and subsided without evolving over time. These data suggest that cells responding to exoenzyme S would rapidly express proinflammatory cytokines and chemokines that may contribute to pulmonary inflammation in cystic fibrosis.

scholarly journals Aspergillus-related lung disease in people with cystic fibrosis: can imaging help us to diagnose disease?

2021 ◽  
Vol 30 (162) ◽  
pp. 210103
Author(s):  
Qianting Lv ◽  
Bernadette B.L.J. Elders ◽  
Adilia Warris ◽  
Daan Caudri ◽  
Pierluigi Ciet ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Computed Tomography ◽  
Cystic Fibrosis ◽  
Lung Disease ◽  
Lung Damage ◽  
Current Evidence ◽  
Resonance Imaging ◽  
Chronic Infections ◽  
Chest Computed Tomography ◽  
Different Types

In people with cystic fibrosis (PwCF), viscous sputum and dysfunction of the mucociliary escalator leads to early and chronic infections. The prevalence of Aspergillus fumigatus in sputum is high in PwCF and the contribution of A. fumigatus to the progression of structural lung disease has been reported. However, overall, relatively little is known about the contribution of A. fumigatus to CF lung disease. More knowledge is needed to aid clinical decisions on whether to start antifungal treatment. In this review, we give an overview of A. fumigatus colonisation and infection in PwCF and the different types of pulmonary disease caused by it. Furthermore, we discuss the current evidence for structural lung damage associated with A. fumigatus in PwCF on chest computed tomography and magnetic resonance imaging. We conclude that radiological outcomes to identify disease caused by A. fumigatus can be important for clinical studies and management.

scholarly journals Scnn1b-Transgenic BALB/c Mice as a Model of Pseudomonas aeruginosa Infections of the Cystic Fibrosis Lung

2020 ◽  
Vol 88 (9) ◽  
Author(s):  
Kristen J. Brao ◽  
Brendan P. Wille ◽  
Joshua Lieberman ◽  
Robert K. Ernst ◽  
Mark E. Shirtliff ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Immune Cell ◽  
Opportunistic Pathogen ◽  
Sodium Absorption ◽  
Lung Pathology ◽  
Wild Type ◽  
Content Type ◽  
Lung Infections ◽  
Content Modeling

ABSTRACT The opportunistic pathogen Pseudomonas aeruginosa is responsible for much of the morbidity and mortality associated with cystic fibrosis (CF), a condition that predisposes patients to chronic lung infections. P. aeruginosa lung infections are difficult to treat because P. aeruginosa adapts to the CF lung, can develop multidrug resistance, and can form biofilms. Despite the clinical significance of P. aeruginosa, modeling P. aeruginosa infections in CF has been challenging. Here, we characterize Scnn1b-transgenic (Tg) BALB/c mice as P. aeruginosa lung infection models. Scnn1b-Tg mice overexpress the epithelial Na+ channel (ENaC) in their lungs, driving increased sodium absorption that causes lung pathology similar to CF. We intranasally infected Scnn1b-Tg mice and wild-type littermates with the laboratory P. aeruginosa strain PAO1 and CF clinical isolates and then assessed differences in bacterial clearance, cytokine responses, and histological features up to 12 days postinfection. Scnn1b-Tg mice carried higher bacterial burdens when infected with biofilm-grown rather than planktonic PAO1; Scnn1b-Tg mice also cleared infections more slowly than their wild-type littermates. Infection with PAO1 elicited significant increases in proinflammatory and Th17-linked cytokines on day 3. Scnn1b-Tg mice infected with nonmucoid early CF isolates maintained bacterial burdens and mounted immune responses similar to those of PAO1-infected Scnn1b-Tg mice. In contrast, Scnn1b-Tg mice infected with a mucoid CF isolate carried high bacterial burdens, produced significantly more interleukin 1β (IL-1β), IL-13, IL-17, IL-22, and KC, and showed severe immune cell infiltration into the bronchioles. Taken together, these results show the promise of Scnn1b-Tg mice as models of early P. aeruginosa colonization in the CF lung.

scholarly journals Cystic fibrosis–adaptedPseudomonas aeruginosaquorum sensinglasRmutants cause hyperinflammatory responses

2015 ◽  
Vol 1 (6) ◽  
pp. e1500199 ◽  
Author(s):  
Shantelle L. LaFayette ◽  
Daniel Houle ◽  
Trevor Beaudoin ◽  
Gabriella Wojewodka ◽  
Danuta Radzioch ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Opportunistic Pathogen ◽  
Respiratory Epithelial Cells ◽  
Adaptive Mutations ◽  
Cystic Fibrosis Lung Disease ◽  
Airway Infections ◽  
Respiratory Epithelial

Cystic fibrosis lung disease is characterized by chronic airway infections with the opportunistic pathogenPseudomonas aeruginosaand severe neutrophilic pulmonary inflammation.P. aeruginosaundergoes extensive genetic adaptation to the cystic fibrosis (CF) lung environment, and adaptive mutations in the quorum sensing regulator genelasRcommonly arise. We sought to define how mutations inlasRalter host-pathogen relationships. We demonstrate thatlasRmutants induce exaggerated host inflammatory responses in respiratory epithelial cells, with increased accumulation of proinflammatory cytokines and neutrophil recruitment due to the loss of bacterial protease–dependent cytokine degradation. In subacute pulmonary infections,lasRmutant–infected mice show greater neutrophilic inflammation and immunopathology compared with wild-type infections. Finally, we observed that CF patients infected withlasRmutants have increased plasma interleukin-8 (IL-8), a marker of inflammation. These findings suggest that bacterial adaptive changes may worsen pulmonary inflammation and directly contribute to the pathogenesis and progression of chronic lung disease in CF patients.

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 Best practices in the treatment of early cystic fibrosis lung disease

2016 ◽  
Vol 11 (2) ◽  
pp. 97-104 ◽  
Author(s):  
Marijke Proesmans
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Current Knowledge ◽  
Young Patients ◽  
Symptomatic Treatment ◽  
Lung Infection ◽  
Lung Damage ◽  
Model Studies ◽  
Cystic Fibrosis Lung Disease ◽  
Chronic Lung Infection

For many years, management of cystic fibrosis (CF) lung disease was focused on symptomatic treatment of chronic lung infection, which is characterized by cough and sputum production, leading to progressive lung damage. With increasing survival and better knowledge of the pathogenesis of CF lung disease, it has become clear that treatment has to start very early because lung damage occurs in young patients, often before obvious symptoms appear. The arrival of new cystic fibrosis transmembrane conductance-regulator (CFTR)-correcting therapies will bring more opportunities to prevent the disease, apart from only treating chronic lung infection. In this review, a summary of the current knowledge of early CF lung disease is provided, based on animal model studies, as well as on data obtained from well structured follow-up programs after newborn screening (NBS). The most important clinical guidelines for treating young CF patients are also summarized.

Investigating the role of cathepsin S in the pathogenesis of cystic fibrosis-like lung disease

2015 ◽  
Author(s):  
Ryan Brown ◽  
Donna Small ◽  
Anthony Abladey ◽  
Leslie Holsinger ◽  
Robert Booth ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Cathepsin S
Sign in / Sign up

Export Citation Format

Share Document