Hyperacidification in cystic fibrosis: links with lung disease and new prospects for treatment

Poschet, Jens F.; Perkett, Elizabeth A.; Deretic, Vojo

doi:10.1016/s1471-4914(02)02414-0

Cited by 69 publications

(77 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The only previous case of AAB isolation during CF has been reported from a respiratory tract infection caused by A. indonesiensis (3). Our report reinforces the hypothesis that AAB may specifically colonize and potentially infect the respiratory tract of CF patients by their propensity to grow in an acidic environment, which is a classic condition in the CF airway liquid (22). AAB were also implied or suspected to be responsible for other types of infections, including, in particular, bacteremia in patients for whom the probable source of infection was an indwelling device (1,12,17,27).…”

Section: Discussionsupporting

confidence: 85%

Gluconobacter as Well as Asaia Species, Newly Emerging Opportunistic Human Pathogens among Acetic Acid Bacteria

Alauzet¹,

Teyssier

Jumas‐Bilak

et al. 2010

J Clin Microbiol

View full text Add to dashboard Cite

Acetic acid bacteria (AAB) are broadly used in industrial food processing. Among them, members of the genera Asaia, Acetobacter, and Granulibacter were recently reported to be human opportunistic pathogens. We isolated AAB from clinical samples from three patients and describe here the clinical and bacteriological features of these cases. We report for the first time (i) the isolation of a Gluconobacter sp. from human clinical samples; (ii) the successive isolation of different AAB, i.e., an Asaia sp. and two unrelated Gluconobacter spp., from a cystic fibrosis patient; and (iii) persistent colonization of the respiratory tract by a Gluconobacter sp. in this patient. We reviewed the main clinical features associated with AAB isolation identified in the 10 documented reports currently available in the literature. Albeit rare, infections as well as colonization with AAB are increasingly reported in patients with underlying chronic diseases and/or indwelling devices. Clinicians as well as medical microbiologists should be aware of these unusual opportunistic pathogens, which are difficult to detect during standard medical microbiological investigations and which are multiresistant to antimicrobial agents. Molecular methods are required for identification of genera of AAB, but the results may remain inconclusive for identification to the species level.

show abstract

Section: Discussionsupporting

confidence: 85%

Gluconobacter as Well as Asaia Species, Newly Emerging Opportunistic Human Pathogens among Acetic Acid Bacteria

Alauzet¹,

Teyssier

Jumas‐Bilak

et al. 2010

J Clin Microbiol

View full text Add to dashboard Cite

show abstract

“…Furin is proteolytically processed into its mature form within the TGN (17) as a step necessary for its convertase action. Chloroquine corrects the hyperacidification of a subset of intracellular organelles that are abnormally acidic in CF lung epithelial cells (5,6). Chloroquine restored the pH of the TGN in IB3-1 mutant cells to levels matching those in CFTR-transfected S9 cells (Supplemental Figure 2).…”

Section: Resultsmentioning

confidence: 90%

“…Mutations in CFTR have pleiotropic effects on the function of other ion transporters (2,3). Of particular importance is the CFTR-dependent regulation of the amiloride-sensitive epithelial sodium channel in respiratory epithelial cells (2,3), causing electrolyte and fluid hyperabsorption in the CF lung (2,4) and hyperacidification of intracellular organelles of CF lung epithelial cells including trans-Golgi network (TGN) and endosomal compartments (5)(6)(7)(8)(9)(10). In addition, there is an abundance of proposed defects related to pathology in CF, including defective phagosomal acidification in macrophages (11), altered P. aeruginosa uptake by respiratory epithelial cells (12), impaired glycosylation (13), enhanced Toll-like receptor activation (14), reduced levels of iNOS (15), and disrupted cholesterol transport (16).…”

Section: Introductionmentioning

confidence: 99%

Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Ornatowski¹,

Poschet²,

Perkett³

et al. 2007

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Progressive pulmonary disease and infections with Pseudomonas aeruginosa remain an intractable problem in cystic fibrosis (CF). At the cellular level, CF is characterized by organellar hyperacidification, which results in altered protein and lipid glycosylation. Altered pH of the trans-Golgi network (TGN) may further disrupt the protein processing and packaging that occurs in this organelle. Here we measured activity of the major TGN endoprotease furin and demonstrated a marked upregulation in human CF cells. Increased furin activity was linked to elevated production in CF of the immunosuppressive and tissue remodeling cytokine TGF-β and its downstream effects, including macrophage deactivation and augmented collagen secretion by epithelial cells. As furin is responsible for the proteolytic processing of a range of endogenous and exogenous substrates including growth factors and bacterial toxins, we determined that elevated furin-dependent activation of exotoxin A caused increased cell death in CF respiratory epithelial cells compared with genetically matched CF transmembrane conductance regulator-corrected cells. Thus elevated furin levels in CF respiratory epithelial cells contributes to bacterial toxin-induced cell death, fibrosis, and local immunosuppression. These data suggest that the use of furin inhibitors may represent a strategy for pharmacotherapy in CF.

show abstract

“…Additionally, potential interest in PDE5 inhibitors to treat CF might be raised by the assumption that PDE5 inhibitors have a possible anti-inflammatory action [28][29][30]. In fact, it has been shown that application of sildenafil for 24 h to cultured CF bronchial epithelial cells exposed to Pseudomonas aeruginosa, a crucial pathogen responsible for the progressive loss of lung function in CF, reduced secretion of interleukin-8, a cytokine abnormally elevated in CF and responsible for neutrophil infiltrate and subsequent inflammatory cascade [29].…”

Section: Discussionmentioning

confidence: 99%

Inhaled phosphodiesterase type 5 inhibitors restore chloride transport in cystic fibrosis mice

Lubamba

Lebacq²,

Reychler³

et al. 2010

European Respiratory Journal

View full text Add to dashboard Cite

Sildenafil and vardenafil, two selective inhibitors of phosphodiesterase type 5 (PDE5) are able, when applied by intraperitoneal injection, to activate chloride transport in cystic fibrosis (CF) mice homozygous for the F508del mutation. Oral treatment with the drugs may be associated with adverse haemodynamic effects. We hypothesised that inhaled PDE5 inhibitors are able to restore ion transport in F508del CF airway epithelium.We developed a restraint-free mouse chamber for inhalation studies. PDE5 inhibitors were nebulised for 15 min at concentrations adjusted from recommended therapeutic oral doses for male erectile dysfunction. We measured in vivo nasal transepithelial potential difference 1 h after a single inhalation of sildenafil, vardenafil or tadalafil in F508del CF and normal homozygous mice.After nebulisation with the drugs in F508del mice, chloride transport, evaluated by perfusing the nasal mucosa with chloride-free buffer containing amiloride followed by forskolin, was normalised; the forskolin response was increased, with the largest values being observed with tadalafil and intermediate values with vardenafil. No detectable effect was observed on sodium conductance.Our results confirm the role of PDE5 inhibitors in restoring chloride transport function of F508del CF transmembrane conductance regulator protein and highlight the potential of inhaled sildenafil, vardenafil and tadalafil as a therapy for CF.

show abstract

Hyperacidification in cystic fibrosis: links with lung disease and new prospects for treatment

Cited by 69 publications

References 56 publications

Gluconobacter as Well as Asaia Species, Newly Emerging Opportunistic Human Pathogens among Acetic Acid Bacteria

Gluconobacter as Well as Asaia Species, Newly Emerging Opportunistic Human Pathogens among Acetic Acid Bacteria

Elevated furin levels in human cystic fibrosis cells result in hypersusceptibility to exotoxin A–induced cytotoxicity

Inhaled phosphodiesterase type 5 inhibitors restore chloride transport in cystic fibrosis mice

Contact Info

Product

Resources

About