Quantitative cytokine gene expression in CF airway

Muhlebach, Marianne S.; Reed, William; Noah, Terry L.

doi:10.1002/ppul.20010

Cited by 57 publications

(34 citation statements)

References 30 publications

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“…Although additional mechanisms likely contribute to Nrf2 dysregulation, diminished antioxidant capacity, and related excessive inflammatory signaling in CF epithelia, inhibition of cAMP-mediated signaling significantly corrects these abnormalities. Notably, this mechanism links a response to CFTR dysfunction (e.g., altered cAMP-mediated signaling) to the clinically relevant manifestations of excessive inflammation (3,11,29) and diminished antioxidant and anti-inflammatory signaling present in CF (6,7,39,41).…”

Section: Discussionmentioning

confidence: 99%

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Interaction with CREB binding protein modulates the activities of Nrf2 and NF-κB in cystic fibrosis airway epithelial cells

Ziady

Sokolow

Shank

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cystic fibrosis (CF) is characterized by inflammatory lung disease that significantly contributes to morbidity and mortality. Airway epithelial cells play a role in the inflammatory signaling in CF and have been reported to exhibit a number of dysfunctions in signaling cascades that modulate inflammation. Previously, we reported that the activity of nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor that regulates antioxidant and cytoprotective protein expression, is diminished in CF epithelia ( 7 ). In this report, we examined the mechanism of Nrf2 dysregulation in vitro in human airway epithelial cell lines and primary cells and in vivo in nasal epithelia excised from ΔF508 CF mutant mice. We found that cAMP-mediated signaling markedly reduces Nrf2 activity in CF vs. non-CF cells. Rp-cAMPS, a cAMP competitor, significantly corrected Nrf2 activity in CF cells, predominantly by increasing the nuclear accumulation of the transcription factor. Furthermore, we found that Rp-cAMPS significantly decreased NF-κB activation following inflammatory stimulation of CF cells. Further investigation revealed that Nrf2 and NF-κB compete for the transcriptional coactivator cAMP responsive element-binding protein (CREB) binding protein (CBP) and that Rp-cAMPS shifts CBP association in favor of Nrf2. Thus our findings provide a link between feedback to CF transmembrane regulator dysfunction and dysregulation of an inflammatory signaling pathway that modulates the coordinated activities of Nrf2 and NF-κB. Furthermore, our studies suggest that strategies that shift CBP association away from NF-κB and toward Nrf2 could have potential therapeutic efficacy for reducing inflammation in patients with CF.

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Section: Discussionmentioning

confidence: 99%

“…Excessive inflammatory responses have been reported in patients with CF (29) and CF mice (11). Furthermore, there is evidence that resolution of inflammation in CF is impaired (17,27).…”

mentioning

confidence: 99%

Interaction with CREB binding protein modulates the activities of Nrf2 and NF-κB in cystic fibrosis airway epithelial cells

Ziady

Sokolow

Shank

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Clinical measures of lung inflammation (e.g., assessment of proinflammatory cytokines in bronchoalveolar lavage fluid) consistently demonstrate more robust inflammation in patients with CF chronically infected with bacteria compared with patients without CF with similar lung infections (7,25,33), leaving little doubt that the infected CF airway as a whole is more inflamed than an infected non-CF airway. Although it is generally assumed that CF airway epithelial cells are hyperinflammatory in response to P. aeruginosa compared with non-CF airway epithelial cells, human CF airway cells in culture often fail to show a hyperinflammatory phenotype compared with airway epithelial cells expressing wild-type (wt)-CFTR (16,21,35).…”

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confidence: 99%

Does the ΔF508-CFTR mutation induce a proinflammatory response in human airway epithelial cells?

Hampton

Ballok

Bomberger

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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In the clinical setting, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene enhance the inflammatory response in the lung to Pseudomonas aeruginosa ( P. aeruginosa ) infection. However, studies on human airway epithelial cells in vitro have produced conflicting results regarding the effect of mutations in CFTR on the inflammatory response to P. aeruginosa, and there are no comprehensive studies evaluating the effect of P. aeruginosa on the inflammatory response in airway epithelial cells with the ΔF508/ΔF508 genotype and their matched CF cell line rescued with wild-type (wt)-CFTR. CFBE41o- cells (ΔF508/ΔF508) and CFBE41o- cells complemented with wt-CFTR (CFBE-wt-CFTR) have been used extensively as an experimental model to study CF. Thus the goal of this study was to examine the effect of P. aeruginosa on gene expression and cytokine/chemokine production in this pair of cells. P. aeruginosa elicited a more robust increase in cytokine and chemokine expression (e.g., IL-8, CXCL1, CXCL2 and TNF-α) in CFBE-wt-CFTR cells compared with CFBE-ΔF508-CFTR cells. These results demonstrate that CFBE41o- cells complemented with wt-CFTR mount a more robust inflammatory response to P. aeruginosa than CFBE41o-ΔF508/ΔF508-CFTR cells. Taken together with other published studies, our data demonstrate that there is no compelling evidence to support the view that mutations in CFTR induce a hyperinflammatory response in human airway epithelial cells in vivo . Although the lungs of patients with CF have abundant levels of proinflammatory cytokines and chemokines, because the lung is populated by immune cells and epithelial cells there is no way to know, a priori, whether airway epithelial cells in the CF lung in vivo are hyperinflammatory in response to P. aeruginosa compared with non-CF lung epithelial cells. Thus studies on human airway epithelial cell lines and primary cells in vitro that propose to examine the effect of mutations in CFTR on the inflammatory response to P. aeruginosa have uncertain clinical significance with regard to CF.

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“…1 CF is characterized by the dysfunction of the CF transmembrane regulator chloride channel and by abnormal inflammatory signaling, 2,3 excessive inflammatory responses, 4 and impairment in the resolution of inflammation, 5,6 leading to diminishing lung function and increased mortality. Infections with respiratory viruses (eg, influenza and rhinoviruses) are associated with exacerbation of pulmonary problems, disease progression, and increase in bacterial adherence in CF airways, which predisposes to secondary bacterial infection.…”

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confidence: 99%

Safety of Live-Attenuated Influenza Vaccination in Cystic Fibrosis

et al. 2014

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OBJECTIVES: Given the improved efficacy of the nasal live-attenuated influenza virus vaccine (LAIV) compared with the injectable vaccine in children, we aimed to determine its safety in individuals with cystic fibrosis (CF). METHODS: A cohort of 168 study participants, aged 2 to 18 years with CF, vaccinated with LAIV between October 1, 2012, and January 30, 2013, was followed prospectively for 56 days after initial vaccination in 3 pediatric CF clinics across the province of Quebec. Days 0 to 28 post-LAIV were considered the at-risk period for all outcomes of interest, and days 29 to 56 post-LAIV were considered the non–at-risk period. Incident respiratory deteriorations were defined as an unscheduled medical visit, hospitalization, or a new course of oral antibiotics for respiratory complaints. Using a self-controlled design, incidence rate ratios (IRR) were used to compare at-risk and non–at-risk periods. RESULTS: Comparing at-risk to non–at-risk periods, there was no significant increase in the rate of incident respiratory deteriorations (IRR, 0.72; 95% confidence interval, 0.11–4.27) or all-cause hospitalizations (IRR, 1.16; 95% confidence interval, 0.30–4.81). A greater proportion of participants reported experiencing at least 1 minor respiratory and/or systemic adverse event after immunization during the at-risk period compared with the non–at-risk period (77% vs 54%, respectively). During the first week after LAIV, 13 of 168 (8%) children reported some wheezing, with the vast majority, 9 of 13 (69%), on the day of vaccination. CONCLUSIONS: There was no increased risk of respiratory deterioration or all-cause hospitalization associated with LAIV in our study population. LAIV seems well tolerated in children and adolescents with CF.

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Quantitative cytokine gene expression in CF airway

Cited by 57 publications

References 30 publications

Interaction with CREB binding protein modulates the activities of Nrf2 and NF-κB in cystic fibrosis airway epithelial cells

Interaction with CREB binding protein modulates the activities of Nrf2 and NF-κB in cystic fibrosis airway epithelial cells

Does the ΔF508-CFTR mutation induce a proinflammatory response in human airway epithelial cells?

Safety of Live-Attenuated Influenza Vaccination in Cystic Fibrosis

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