Epithelial cell damage is induced by neutrophil-derived, not pseudomonas-derived, proteases in cystic fibrosis sputum

Venaille, T.; Ryan, Gerard; Robinson, Bruce

doi:10.1016/s0954-6111(98)90101-9

Cited by 49 publications

(26 citation statements)

References 21 publications

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“…NE induces hypersecretion of two major respiratory tract mucins, MUC5AC and MUC5B, by activation of protein kinase Cδ, causing translocation of PKCδ from the cytoplasm to the plasma membrane and associated transient activation of myristoylated alanine-rich C-kinase substrate (MARCKS), a key secretory granule chaperone during stimulated exocytosis . Finally, NE slows ciliary beat frequency (Amitani et al, 1991) and causes epithelial disruption (Venaille et al, 1998). Together, these airway epithelial changes result in abundant mucin production and failure of adequate ciliary clearance.…”

Section: Neutrophil Elastase and Mucins Mucus Secretion And Mucocilmentioning

confidence: 99%

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Proteases and cystic fibrosis

Voynow

Fischer

Zheng

2008

The International Journal of Biochemistry & Cell Biology

175

159

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Cystic fibrosis is the most common, inherited fatal disease in Caucasians. The major cause of morbidity and mortality is chronic lung disease due to infection and inflammation in the airways leading to bronchiectasis and respiratory failure. The signature pathologic features of CF lung disease including abnormal mucus obstructing airways, chronic infection with S. aureus, P. aeruginosa and other gram negative bacteria, and a robust neutrophil-dominant airway inflammation, are exacerbated by unopposed proteases present at high concentrations in the ASL. There is strong evidence that proteases, particularly neutrophil elastase, contribute to the pathology of CF by impairing mucociliary clearance, interfering with innate immune functions, and perpetuating neutrophilic inflammation. The mechanisms employed by proteases to impact airway function in CF will be reviewed.

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Section: Neutrophil Elastase and Mucins Mucus Secretion And Mucocilmentioning

confidence: 99%

“…NE has been reported to cause epithelial disruption, an effect that is concentration and time-dependent (Amitani et al, 1991, Venaille et al, 1998. Importantly, following NE exposure, epithelial cells enter a cell cycle arrest associated with increased expression of the cyclin kinase inhibitor, p27 .…”

Section: Ne and Airway Remodelingmentioning

confidence: 99%

Proteases and cystic fibrosis

Voynow

Fischer

Zheng

2008

The International Journal of Biochemistry & Cell Biology

175

159

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“…This early acquisition of P. aeruginosa in relatively normal lungs is unique to CF. Much of the lung damage that occurs in CF is thought to be due to ineffective host factors [2]. Bacterial virulence factors undoubtedly also contribute to lung damage, but they have been poorly characterised in vivo.…”

mentioning

confidence: 99%

Bacterial cyanogenesis occurs in the cystic fibrosis lung

Sanderson¹,

Wescombe²,

Kirov³

et al. 2008

Eur Respir J

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The cystic fibrosis (CF) lung environment is poorly defined, but data suggest that bacteria may encounter reduced oxygen tensions and possibly an anaerobic environment. Pseudomonas aeruginosa produces the potent toxin cyanide under strictly microaerobic conditions. Evidence of bacterial cyanogenesis in the CF lung was investigated in the present study by measuring sputum cyanide concentrations.Sputum cyanide was measured in seven stable CF patients, as well as before and after intravenous antibiotic therapy during a hospital admission in a further eight patients experiencing acute exacerbations. All patients were chronically infected with P. aeruginosa. Comparative sputum data were obtained from nine CF patients with no documented P. aeruginosa infection and 10 healthy, nonsmoking normal controls.High levels of cyanide were detected in all the P. aeruginosa-infected stable CF patients (median (range) 0.56 (0.37-2.81) mg?mL -1 ), and in seven out of eight acute sputum samples (0.73 (0-1.43) mg?mL -1 ). In contrast, cyanide was not detectable in sputum from eight out of nine CF patients without P. aeruginosa infection or in any of the normal controls. Intravenous antibiotic treatment significantly reduced sputum cyanide levels (median 0.73 to median 0.0 mg?mL -1 ).The cyanide detected indicates that the cystic fibrosis lung provides a predominantly microaerobic environment for Pseudomonas aeruginosa. Cyanide is likely to be a potentially important virulence factor in Pseudomonas aeruginosa-infected cystic fibrosis patients.

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“…Furthermore, CF patients are more sensitive to provocation with high salt concentrations than healthy individuals [26]. Because of airway inflammation in CF patients, epithelial damage is common in their respiratory tract [27], even if this is not a primary feature of the disease.…”

Section: Discussionmentioning

confidence: 99%

Effect of luminal osmolarity on ion content of connective tissue in rat trachea after epithelial damage

Relova¹,

Roomans²

2001

European Respiratory Journal

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Effect of luminal osmolarity on ion content of connective tissue in rat trachea after epithelial damage. A.J. Relova, G.M. Roomans. #ERS Journals Ltd 2001. ABSTRACT: The authors investigated the physical role of the airway epithelium in response to changes in the airway surface fluid9s composition by superperfusing the lumen with nonisotonic solutions. Morphological studies and measurements of changes in ion content in the underlying connective tissue (CT) were carried out.The study used an experimental model of isolated rat trachea. The trachea was mounted in an extraluminal organ bath with Ringer9s solution, whereas the lumen was perfused with a fluid in which the NaCl concentration was varied. The tissue was fixed for electron microscopy or frozen for X-ray microanalysis.X-ray microanalysis showed that the Na and Cl content of the CT increased with increasing luminal NaCl concentrations. This increase was significantly larger when the tight junctions had been damaged by exposure to ethylene glycol tetra-acetic acid. At high luminal NaCl concentrations, electron microscopy showed that a significant influx of fluid into the CT had occurred in tracheae with damaged epithelia. Damage to the epithelium also resulted in ultrastructural changes in myofibroblasts, increased diameter of capillaries, and thickening of the basement membrane.The epithelium evidently plays a crucial role in the regulation of the ion content of the connective tissue in the airway wall, and epithelial damage may explain the greater sensitivity to provocation with hypersomolar sodium chloride solutions or airway dehydration observed in patients with asthma or cystic fibrosis.

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Epithelial cell damage is induced by neutrophil-derived, not pseudomonas-derived, proteases in cystic fibrosis sputum

Cited by 49 publications

References 21 publications

Proteases and cystic fibrosis

Proteases and cystic fibrosis

Bacterial cyanogenesis occurs in the cystic fibrosis lung

Effect of luminal osmolarity on ion content of connective tissue in rat trachea after epithelial damage

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