Early alterations in airway mucociliary clearance and inflammation of the lamina propria in CF mice

Zahm, Jean‐Marie; Gaillard, Dominique; Dupuit, Florence; Hinnrasky, Jocelyne; Porteous, David J.; Dorin, Julia R.; Puchelle, Édith

doi:10.1152/ajpcell.1997.272.3.c853

Cited by 112 publications

(68 citation statements)

References 4 publications

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“…In a recent report, however, this group has reported normal MCC in both the upper and lower airways of CF mice [37]. ZAHM et al [38] reported slower tracheal MCC in CFTR tm1Unc CF mice, but also showed significant inflammation in the lamina propria. These mice had not been exposed to infection, supporting the possibility of primary inflammation.…”

Section: Discussionmentioning

confidence: 89%

Normal nasal mucociliary clearance in CF children: evidence against a CFTR‐related defect

McShane

Davies

Wodehouse³

et al. 2004

Eur Respir J

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Studies on mucociliary clearance (MCC) in cystic fibrosis (CF) have produced conflicting results. This study aimed to differentiate primary (ion transportrelated) from secondary (inflammatory) causes of delayed MCC in CF.Nasal MCC was measured in 50 children (CF, primary ciliary dyskinesia (PCD) and no respiratory disease). Nasal lavage fluid was analysed for interleukin (IL)-8 and tumour necrosis factor-a. Similar measurements were obtained in adult CF patients with and without chronic sinusitis (CS).Children with CF had neither delayed MCC nor increased levels of cytokines. Conversely, children with PCD had prolonged MCC times (all w30 min) and significantly raised levels of IL-8. CS-positive CF adults had significantly slower MCC than CS-negative subjects, but IL-8 levels were low and similar in both groups.Decreased airway surface liquid and delayed mucociliary clearance are the postulated primary mechanisms in cystic fibrosis. However, the current study reports that cystic fibrosis children have normal nasal mucociliary clearance. Abnormalities appeared in cystic fibrosis adults with symptoms of chronic sinus disease, suggesting a secondary rather than primary phenomenon. Studies to explore this mechanism in the distal, more sparsely-ciliated airways could aid an understanding of pathogenesis and the development of new treatments. Eur Respir J 2004; 24: 95-100.

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Section: Discussionmentioning

confidence: 89%

Normal nasal mucociliary clearance in CF children: evidence against a CFTR‐related defect

McShane

Davies

Wodehouse³

et al. 2004

Eur Respir J

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“…In this respect they dovetail with observations of mice carrying mutations in the CFTR gene. The mouse data show that airway mucus transport velocity is reduced in mutant mice prior to infection (29). Davidson et al (30) also showed that mutant mice had impaired mucociliary clearance from airways but no mucous cell metaplasia or mucus retention before infection.…”

Section: Resultsmentioning

confidence: 99%

Activation of NF-κB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa -induced mucin overproduction in epithelial cells

Feng

Gallup

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

315

264

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Cystic fibrosis (CF) is an autosomal recessive disorder, the most common lethal genetic disease in Caucasians. Respiratory disease is the major cause of morbidity and mortality. Indeed, 95% of CF patients die of respiratory failure. Pseudomonas aeruginosa, an opportunistic pathogen, chronically infects the lungs of over 85% of CF patients. It is ineradicable by antibiotics and responsible for airway mucus overproduction that contributes to airway obstruction and death. The molecular mechanisms underlying this pathology are unknown. Here we show that P. aeruginosa activates a c-Src-Ras-MEK1͞2-MAPK-pp90rsk signaling pathway that leads to activation of nuclear factor NF-B (p65͞p50). Activated NF-B binds to a B site in the 5-f lanking region of the MUC2 gene and activates MUC2 mucin transcription. These studies bring new insight into bacterialepithelial interactions and more specifically into the molecular pathogenesis of cystic fibrosis. Understanding these signaling and gene regulatory mechanisms opens up new therapeutic targets for cystic fibrosis.Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian population (1). The mutation responsible for the disease is in the gene encoding the cystic fibrosis transmembrane regulator (CFTR), a chloride channel. This mutation gives rise to a chain of events involving chronic bacterial lung infection and mucus overproduction. Although there have been significant clues regarding the link between the mutation and chronic infection (2-4), the nature of the link between the mutation and mucus overproduction is completely unknown.We recently showed that bacterial exoproducts up-regulate epithelial MUC2 mucin transcription (5). This suggests that CF-associated mucin overproduction occurs secondary to lung infection, a sine qua non of advanced disease. The molecular mechanisms underlying mucin induction are unknown. In the present study, we performed experiments to examine these mechanisms. Results showed that Pseudomonas aeruginosa, a common CF pathogen, activates the MUC2 mucin gene transcription by activation of a Src-dependent Ras-MEK1͞2-ERK1͞2-pp90rsk-NF-B pathway. These studies provide insight into bacterial-host epithelial interactions and open up new therapeutic targets for CF. MATERIALS AND METHODSReagents. P. aeruginosa lipopolysaccharide (LPS) from serotype 10 was purchased from Sigma. PP1, PD98059, and caffeic acid phenethyl ester (CAPE) were purchased from Calbiochem.Bacterial Strains and Culture Conditions. The P. aeruginosa strains used in these studies were grown in M9 medium with aeration at 37°C to late logarithmic phase. The broth cultures were then centrifuged at 10,000 rpm in a Sorvall RC5C for 50 min. The supernatants containing bacterial exoproducts were sterilized by passage through a 0.22-m polymer filter (Corning) and were then kept at Ϫ80°C until use. Bacterial culture supernatants were added to epithelial cell culture medium at a 1:4 dilution ratio.Cell Culture. Two MUC2-expressing epithelial cell lines were used in these...

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“…Different models do, however, present components of the phenotype (9,10). For example, Kent et al (11) produced a congenic Cftr tm1UNC mouse strain in C57BL/6J (B6) background and showed the lung disease measured in these mice to include clinical attributes such as a perpetual neutrophil influx (12)(13)(14), patchy inflammation (15), mucus accumulation, and interstitial fibrosis in the lower airways (1).…”

Section: †mentioning

confidence: 99%

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

Bazett

Stefanov

Paun

et al. 2012

The Journal of Immunology

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We previously observed the lungs of naive BALB/cJ Cftrtm1UNC mice to have greater numbers of lymphocytes, by immunohistochemical staining, than did BALB wild type littermates or C57BL/6J Cftrtm1UNC mice. In the present study, we initially investigated whether this mutation in Cftr alters the adaptive immunity phenotype by measuring the lymphocyte populations in the lungs and spleens by FACS and by evaluating CD3-stimulated cytokine secretion, proliferation, and apoptosis responses. Next, we assessed a potential influence of this lymphocyte phenotype on lung function through airway resistance measures. Finally, we mapped the phenotype of pulmonary lymphocyte counts in BALB × C57BL/6J F2 Cftrtm1UNC mice and reviewed positional candidate genes. By FACS analysis, both the lungs and spleens of BALB Cftrtm1UNC mice had more CD3+ (both CD4+ and CD8+) cells than did littermates or C57BL/6J Cftrtm1UNC mice. Cftrtm1UNC and littermate mice of either strain did not differ in anti-CD3–stimulated apoptosis or proliferation levels. Lymphocytes from BALB Cftrtm1UNC mice produced more IL-4 and IL-5 and reduced levels of IFN-γ than did littermates, whereas lymphocytes from C57BL/6J Cftrtm1UNC mice demonstrated increased Il-17 secretion. BALB Cftrtm1UNC mice presented an enhanced airway hyperresponsiveness to methacholine challenge compared with littermates and C57BL/6J Cftrtm1UNC mice. A chromosome 7 locus was identified to be linked to lymphocyte numbers, and genetic evaluation of the interval suggests Itgal and Il4ra as candidate genes for this trait. We conclude that the pulmonary phenotype of BALB Cftrtm1UNC mice includes airway hyperresponsiveness and increased lymphocyte numbers, with the latter trait being influenced by a chromosome 7 locus.

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Early alterations in airway mucociliary clearance and inflammation of the lamina propria in CF mice

Cited by 112 publications

References 4 publications

Normal nasal mucociliary clearance in CF children: evidence against a CFTR‐related defect

Normal nasal mucociliary clearance in CF children: evidence against a CFTR‐related defect

Activation of NF-κB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa -induced mucin overproduction in epithelial cells

Strain-Dependent Airway Hyperresponsiveness and a Chromosome 7 Locus of Elevated Lymphocyte Numbers in Cystic Fibrosis Transmembrane Conductance Regulator-Deficient Mice

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