Terminal sialylation is altered in airway cells with impaired CFTR-mediated chloride transport

Kube, Dianne; Adams, Lynn M.; Perez, Aura; Davis, Pamela B.

doi:10.1152/ajplung.2001.280.3.l482

Cited by 26 publications

(23 citation statements)

References 30 publications

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“…These alterations result in higher membrane levels of the ganglioside asialo-GM 1 , an epithelial cell receptor that has been reported to bind P. aeruginosa via bacterial pili (57,69,118,265). However, a recent report indicates that no increased expression of asialo-GM 1 was detected in cells overexpressing the R domain portion of CFTR if an asialo-GM 1 -specific lectin was used for detection (165). Moreover, these studies have been carried out principally using laboratory strains of P. aeruginosa and not clinical isolates from patients.…”

Section: Downloaded Frommentioning

confidence: 99%

Lung Infections Associated with Cystic Fibrosis

2002

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While originally characterized as a collection of related syndromes, cystic fibrosis (CF) is now recognized as a single disease whose diverse symptoms stem from the wide tissue distribution of the gene product that is defective in CF, the ion channel and regulator, cystic fibrosis transmembrane conductance regulator (CFTR). Defective CFTR protein impacts the function of the pancreas and alters the consistency of mucosal secretions. The latter of these effects probably plays an important role in the defective resistance of CF patients to many pathogens. As the modalities of CF research have changed over the decades from empirical histological studies to include biophysical measurements of CFTR function, the clinical management of this disease has similarly evolved to effectively address the ever-changing spectrum of CF-related infectious diseases. These factors have led to the successful management of many CF-related infections with the notable exception of chronic lung infection with the gram-negative bacterium Pseudomonas aeruginosa. The virulence of P. aeruginosa stems from multiple bacterial attributes, including antibiotic resistance, the ability to utilize quorum-sensing signals to form biofilms, the destructive potential of a multitude of its microbial toxins, and the ability to acquire a mucoid phenotype, which renders this microbe resistant to both the innate and acquired immunologic defenses of the host

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Section: Downloaded Frommentioning

confidence: 99%

Lung Infections Associated with Cystic Fibrosis

2002

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“…Cells transfected with the R domain of CFTR, pCEP-R, retain expression of endogenous CFTR mRNA (12) but have completely inhibited cAMP-stimulated chloride transport while retaining Ca 2ϩ -stimulated chloride transport. These cells display increased levels of aGM1, increased P. aeruginosa binding, and increased cytokine production in response to PAO1 (4,12,13,19). Cells Fig.…”

Section: /Hteo ϫ Pcep and Pcep-r Cell Linesmentioning

confidence: 99%

CFTR inhibition mimics the cystic fibrosis inflammatory profile

Perez¹,

Issler²,

Cotton³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Primary airway epithelial cells grown in air-liquid interface differentiate into cultures that resemble native epithelium morphologically, express ion transport similar to those in vivo, and secrete cytokines in response to stimuli. Comparisons of cultures derived from normal and cystic fibrosis (CF) individuals are difficult to interpret due to genetic differences besides CFTR. The recently discovered CFTR inhibitor, CFTRinh-172, was used to create a CF model with its own control to test if loss of CFTR-Cl− conductance alone was sufficient to initiate the CF inflammatory response. Continuous inhibition of CFTR-Cl− conductance for 3–5 days resulted in significant increase in IL-8 secretion at basal ( P = 0.006) and in response to 109 Pseudomonas ( P = 0.0001), a fourfold decrease in Smad3 expression ( P = 0.02), a threefold increase in RhoA expression, and increased NF-κB nuclear translocation upon TNF-α/IL-1β stimulation ( P < 0.000001). CFTR inhibition by CFTRinh-172 over this period does not increase epithelial sodium channel activity, so lack of Cl− conductance alone can mimic the inflammatory CF phenotype. CFTRinh-172 does not affect IL-8, IL-6, or granulocyte/macrophage colony-stimulating factor secretion in two CF phenotype immortalized cell lines: 9/HTEo− pCEP-R and 16HBE14o− AS, or IL-8 secretion in primary CF cells, and inhibitor withdrawal abolishes the increased response, so CFTRinh-172 effects on cytokines are not direct. Five-day treatment with CFTRinh-172 does not affect cells deleteriously as evidenced by lactate dehydrogenase, trypan blue, ciliary activity, electron micrograph histology, and inhibition reversibility. Our results support the hypothesis that lack of CFTR activity is responsible for the onset of the inflammatory cascade in the CF lung.

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“…Activation of epithelial proinflammatory responses, whether stimulated by S. aureus or P. aeruginosa, appears to be handled predominantly by TLR2 presented at the surfaces of airway cells within the context of an asialoganglioside/lipid raft microdomain or caveolae. In diseases such as cystic fibrosis (CF), in which there is a CF transmembrane conductance regulator-associated increase in asialylated glycolipids such as asialoGM1 (35)(36)(37), there is likely to be enhanced TLR2 signaling, as suggested by the excessive epithelial IL-8 expression characteristic of CF epithelial cells (38)(39)(40). Strategies to ameliorate excessive proinflammatory responses to bacterial airway infection should include consideration of the role of TLR2 and asialoGM1-mediated signaling, even in the context of a Gram-negative infection.…”

Section: Figurementioning

confidence: 99%