Inflammatory and immunological biomarkers are not related to survival in adults with Cystic Fibrosis

Key pointsr The epithelial Na + channel (ENaC) is hyperactive in cystic fibrosis (CF) airway epithelia, and contributes to excessive Na + absorption and dehydration of the airway surface liquid (ASL) that lines the lungs -a major cause of CF lung disease.r The CF gene product (CFTR) is a cAMP-regulated anion channel and how CFTR dysfunction contributes to ENaC hyperactivity is poorly understood. Of note, ENaC must be proteolytically cleaved to be active.r CF ASL is moderately acidic, due to the absence of HCO 3 − secretion through CFTR. The acid protease cathepsin B is present in the apical membrane of airway epithelia and is secreted into the ASL, suggesting that this protease may be active in the acidic CF environment.r We have found that cathepsin B induces activation of ENaC in both Xenopus laevis oocytes and in airway epithelia. Cathepsin B is also highly expressed in airway epithelia derived from patients with CF.r Inhibition of cathepsin B prevents Na + /ASL hyperabsorption in CF airway cultures, suggesting a hitherto unrecognized role for this protease in CF pathogenesis. Treatments directed at normalizing CF ASL pH or inhibiting cathepsin B may be useful in the treatment of CF lung disease.Abstract In cystic fibrosis (CF) lung disease, the absence of functional CF transmembrane conductance regulator results in Cl − /HCO 3 − hyposecretion and triggers Na + hyperabsorption through the epithelial Na + channel (ENaC), which contribute to reduced airway surface liquid (ASL) pH and volume. Prostasin, a membrane-anchored serine protease with trypsin-like substrate specificity has previously been shown to activate ENaC in CF airways. However, prostasin is typically inactive below pH 7.0, suggesting that it may be less relevant in acidic CF airways. Cathepsin B (CTSB) is present in both normal and CF epithelia and is secreted into ASL, but little is known about its function in the airways. We hypothesized that the acidic ASL seen in CF airways may stimulate CTSB to activate ENaC, contributing to Na + hyperabsorption and depletion of CF ASL volume. In Xenopus laevis oocytes, CTSB triggered α-and γENaC cleavage and induced an increase in ENaC activity. In bronchial epithelia from both normal and CF donor lungs, CTSB localized to the apical membrane. In normal and CF human bronchial epithelial cultures, CTSB was detected at the apical plasma membrane and in the ASL. CTSB activity was significantly elevated in acidic ASL, which correlated with increased abundance of ENaC in the plasma membrane and a reduction in ASL volume. This acid/CTSB-dependent activation of ENaC was ameliorated with the cell impermeable, CTSB-selective inhibitor CA074, suggesting that CTSB inhibition may have therapeutic relevance. Taken together, our data suggest that CTSB is a pathophysiologically relevant protease that activates ENaC in CF airways.

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“…; Moffitt et al . ), we observed CTSB staining in mucus plugs that were adherent to CF luminal surfaces (Fig. C ).…”

Section: Resultsmentioning

confidence: 68%

Cathepsin B contributes to Na⁺ hyperabsorption in cystic fibrosis airway epithelial cultures

Tan

Hobbs

Sameni

et al. 2014

The Journal of Physiology

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“…It is the most common species colonizing the CF respiratory tract. Moreover, chronic Pseudomonas aeruginosa pulmonary infection is associated with a decline in lung function, increased exacerbations and reduced survival in people with CF [ 18 , 19 ]. Pseudomonas aeruginosa can induce an inflammatory response that leads to tissue breakdown and severe lung damage.…”

Section: Discussionmentioning

confidence: 99%

Elevated IgG4 serum levels in patients with cystic fibrosis

et al. 2017

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ObjectiveSerum immunoglobulin (Ig) G4 elevation has been associated with several pathological conditions other than IgG4-related disease (IgG4-RD). In cystic fibrosis (CF), an elevation of specific IgG4 has been associated with colonization and infection by Pseudomonas aeruginosa. IgG4 elevation may be a marker of chronic infection or inflammatory stimulation. The aim of this study was to explore the prevalence of elevated IgG4 levels in CF and its correlation with the major clinical and microbiological features found in CF patients.MethodsIn a cross-sectional study, we analyzed data from a large cohort of adult CF patients attending the CF center of Lyon University Hospital. An elevated IgG4 level was defined as being above the cut-off value of 135 mg/dL.ResultsOne hundred and sixty-five CF patients were analyzed. An IgG4 elevation was detected in 43 patients (26%). Compared with the control group (≤ 135 mg/dL), high IgG4 patients exhibited a greater prevalence of Staphylococcus aureus colonization and higher IgG, IgG1, IgG2 and IgE levels. No significant differences were observed in terms of pulmonary function, colonization with Pseudomonas aeruginosa, or the annual rate of bronchial exacerbations.ConclusionAn elevated IgG4 serum level was frequently detected in adult CF patients and did not appear to be associated with poor lung function. We suggest that IgG4 elevation is a marker of the activation of tolerance. Its clinical significance remains to be demonstrated.

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“…As a ubiquitous endopeptidase and ectodipeptidase, CB has a clear association with neutrophils and several inflammation markers especially TNF-a. [42][43][44] Overexpression of TNF-a in the rat lungs led to severe pulmonary inflammation followed by accumulation of ECM, which was mediated by secondary upregulation of TGF-b. 45 TNF-a acts as a mediator of inflammation and cellular immune responses produced mainly by activated macrophages.…”

Section: Discussionmentioning

confidence: 99%

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

Zhang

et al. 2015

Laboratory Investigation

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Cathepsin B (CB) is involved in the turnover of proteins and has various roles in maintaining the normal metabolism of cells. In our recent study, CB is increased in the muscles of polymyositis/dermatomyositis (PM/DM). However, the role of CB in interstitial lung disease (ILD) has not been reported. ILD is a frequent complication of PM/DM, which is the leading cause of death in PM/DM. It carries high morbidity and mortality in connective tissue diseases, characterized by an overproduction of inflammatory cytokines and induced fibrosis, resulting in respiratory failure. The etiology and pathogenesis of ILD remain incompletely understood. This study investigated whether treatment with CA-074Me, a specific inhibitor of CB, attenuates ILD in PM. CB expression, inflammation, and fibrosis were analyzed in the lung tissues from patients with PM/DM. The animal model of PM was induced in guinea pigs with Coxsackie virus B1 (CVB1). CA-074Me was given 24 h after CVB1 injection for 7 consecutive days. At the end of the experiment, the animals were killed and lung tissues were collected for the following analysis. Inflammation, fibrosis and apoptosis cells, and cytokines were assessed by histological examinations and immunohistochemical analyses, western blot analysis and transferasemediated dUTP nick-end labeling assay. In patients with PM/DM, the protein levels of CB were significantly elevated in lung tissues compared with healthy controls, which correlated with increases in inflammation and fibrosis. Similarly, the expression of CB, inflammation and fibrosis, CD8 þ T cell, CD68 þ cell, tumor necrosis factor-alpha, transforming growth factor-beta1 infiltrations, and apoptotic cell death were significantly increased in lung tissues of the guinea-pig model of CVB1-induced PM. These changes were attenuated by the administration of CA-074Me. In conclusion, this study demonstrates that PM/DM increases CB expression in lung tissues and inhibition of CB reduces ILD in a guinea-pig model of CVB1-induced PM. This finding suggests that CB may be a potential therapeutic target for ILD.

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Inflammatory and immunological biomarkers are not related to survival in adults with Cystic Fibrosis

Abstract: These data indicate that biomarkers of inflammation are not independent predictors of survival in people with CF.

Cited by 12 publications

References 33 publications

Cathepsin B contributes to Na⁺ hyperabsorption in cystic fibrosis airway epithelial cultures

Cathepsin B contributes to Na⁺ hyperabsorption in cystic fibrosis airway epithelial cultures

Elevated IgG4 serum levels in patients with cystic fibrosis

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

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Inflammatory and immunological biomarkers are not related to survival in adults with Cystic Fibrosis

Abstract: These data indicate that biomarkers of inflammation are not independent predictors of survival in people with CF.

Cited by 12 publications

References 33 publications

Cathepsin B contributes to Na+ hyperabsorption in cystic fibrosis airway epithelial cultures

Cathepsin B contributes to Na+ hyperabsorption in cystic fibrosis airway epithelial cultures

Elevated IgG4 serum levels in patients with cystic fibrosis

Treatment with CA-074Me, a Cathepsin B inhibitor, reduces lung interstitial inflammation and fibrosis in a rat model of polymyositis

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Product

Resources

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Cathepsin B contributes to Na⁺ hyperabsorption in cystic fibrosis airway epithelial cultures

Cathepsin B contributes to Na⁺ hyperabsorption in cystic fibrosis airway epithelial cultures