Fluticasone Propionate Downregulates Nasal Fibroblast Functions Involved in Airway Inflammation and Remodeling

Silvestri, Michela; Sabatini, Federica; Scarso, Lucia; Cordone, Annalisa; Dašić, Gorana; Rossi, Giovanni A.

doi:10.1159/000058003

Cited by 38 publications

(41 citation statements)

References 33 publications

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“…These data are consistent with the current authors' previous findings, where a 91% increase in DNA synthesis above untreated fibroblasts isolated from subjects with mild asthma was demonstrated [7]. However, in a different model system by SILVESTRI et al [10], fluticasone at concentrations ranging from 0.1-100 nM was found to decrease proliferation and eotaxin expression from fibroblasts cultured from nasal polyps. In addition to the differences in the model system, fluticasone is also 10-100 times more potent than dexamethasone, which may explain the disparate results between these studies [28].…”

Section: Discussionsupporting

confidence: 92%

“…Dexamethasone increased DNA synthesis in cultured airway fibroblasts from asthmatics, an effect that was most prominent in cells from mild asthmatics. Whether this response is beneficial or detrimental is not clear; however, it does stand in contrast to the effects of corticosteroids on fibroblasts in other organ systems, where proliferation was either decreased or unchanged [8][9][10]. To further investigate the effects of corticosteroids on airway fibroblast function in asthma, the present authors also examined the effect of dexamethasone on cell cycle proteins and cell cycle progression in airway fibroblasts cultured from asthmatic individuals.…”

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confidence: 99%

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Dexamethasone can stimulate G1-S phase transition in human airway fibroblasts in asthma

Fouty

Moss

Solodushko

et al. 2006

European Respiratory Journal

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Corticosteroids are the first line of therapy for asthma. Whether they alter the progression of airway remodelling in asthma is, as yet, unknown.To determine whether corticosteroids could alter the fibroblast cell cycle the current authors studied the effect of dexamethasone on cultured airway fibroblasts obtained from nine mild-tomoderate, steroid-naïve asthmatics (forced expiratory volume in one second 78¡4% predicted), and seven normal controls. Fibroblasts were cultured from endobronchial biopsies obtained via bronchoscopy. Cells were exposed to dexamethasone (10 -9 -10 -7 M) and studied at 72 h to determine differences in progression through the cell cycle.In asthmatic fibroblasts, dexamethasone, at concentrations of 10 -8M and 10 -7 M, nearly doubled the number of cells in the S phase (17.8¡3.0% and 18.4¡3.1%, respectively) compared with untreated fibroblasts (10.3¡1.4%). There was no significant effect in normal control fibroblasts. Dexamethasone induced hyperphosphorylation of the tumour suppressor, retinoblastoma (RB) in asthmatic fibroblasts; fibroblasts from normal controls had significantly less hyperphosphorylation of RB. No difference in protein expression of the CCAAT/enhancer binding protein a between the two groups was detected. This study suggests that dexamethasone can stimulate G1-S phase cell cycle transition in human airway fibroblasts obtained from asthmatics. Whether this leads to enhanced airway remodelling in some individuals remains to be determined.

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Dexamethasone can stimulate G1-S phase transition in human airway fibroblasts in asthma

Fouty

Moss

Solodushko

et al. 2006

European Respiratory Journal

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“…This effect on NF-κB in nasal polyp fibroblasts had already been suggested by Silvestri et al 7 and by our group 21 , although this is the first in vitro study to confirm the effect of FP on NF-κB translocation for nasal polyps.…”

Section: Discussionsupporting

confidence: 82%

In vitro effect of glucocorticoids on nasal polyps

Valera¹,

Brassesco²,

Castro‐Gamero³

et al. 2011

Braz. j. otorhinolaryngol. (Impr.)

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Glucocorticoids are considered the main treatment option for nasal polyps, but their effect is only recently being understood. Aim To evaluate whether fluticasone propionate (FP) inhibits the inflammatory process induced by TNF-alpha in vitro , and to assess if NF-kappaB is associated to this inhibition. Study Design Experimental in vitro study. Materials and Methods Nasal polyp fibroblasts were cultured during 24 hours. Three different concentrations of FP (1, 10 and 100 nM, added to TNF-alpha) were compared to negative (without additive) and positive (TNF-alpha) controls. Gene expression (RTQ-PCR) and protein concentration (ELISA) of VCAM-1, ICAM-1, eotaxin and RANTES were measured, as well as the nuclear translocation of NF-kappaB. Results TNF-alpha significantly increased protein concentration and RNA expression of all the studied molecules, as well as the nuclear translocation of NF-kappaB, when compared to the negative control. FP decreased these parameters in a dose-dependent manner, statistically different from positive control up to 100nM. Conclusions FP extensively inhibited inflammatory recruiters, at both protein and RNA levels, confirming the ability of glucocorticoids to modulate the inflammatory process in nasal polyps. This inhibition was associated to decreased NF-kappaB nuclear translocation, demonstrating that this is an important mechanism of glucocorticoids action for nasal polyps.

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“…Varela et al reported a similar finding in cultivating fibroblasts from nasal polyps, which, upon exposure to this steroid, inhibit the synthesis of cellular adhesion molecules [33]. In a similar model, Silvestri et al reported a decrease in the expression of ICAM-1, but not VCAM-1, in the presence of TNF-α [34]. Together, these mechanisms lead to an improvement in pulmonary function and a decrease in the degree of nasal polyposis [35].…”

Section: Discussionmentioning

confidence: 75%

Single Nucleotide Polymorphisms in TNF are Associated with Susceptibility to Aspirin-exacerbated Respiratory Disease but not to Cytokine Levels: a Study in Mexican Mestizo Population

et al. 2017

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Aim:To evaluate the association of three single nucleotide polymorphisms in TNF and one in LTA in Mexican patients with aspirin-exacerbated respiratory disease (AERD) and the correlation of those single nucleotide polymorphisms with serum levels of TNF-α. Patients & methods: Case-control study including 133 patients with AERD, 135 patients with asthma (aspirin-tolerant asthmatics) and 182 healthy subjects. Results: GA genotype of rs1800629 in TNF was found to be associated with the risk of developing AERD (p < 0.05; odds ratio = 2.36) and by dominant model (p < 0.05; odds ratio = 2.51). Furthermore, there was a difference in the serum levels between the aspirin-tolerant asthmatics group and the other groups (p < 0.001). Conclusion: The GA genotype of rs1800629 is associated with genetic susceptibility to AERD, but it does not correlate to protein serum levels. Aspirin-exacerbated respiratory disease (AERD) is a clinical disease characterized by hypersensitivity to aspirin, asthma and chronic rhinosinusitis with nasal polyps. It affects 10% of the population with asthma; however, its prevalence increases to 21% when provocation tests are used [1]. AERD is a disease characterized by restructuring of the airway [2] and the presence of extensive hyperplastic eosinophilic sinusitis with the formation of nasal polyps [3]. The most important clinical characteristic is bronchoconstriction after the administration of aspirin (ASA) or other nonsteroidal anti-inflammatory drugs (NSAIDs) [2,4]. The physiopathology involves a block in the cyclooxygenase pathway that promotes a diversion of arachidonic acid metabolism toward the lipoxygenase pathway, inducing the synthesis of leukotrienes such as LTC4, LTD4 and LTE4 [5,6], proteins that induce inflammatory cell chemotaxis, and the release of cytokines such as TNF-α [7] and lymphotoxin. TNF-α is a critical molecule in the regulation of inflammation because it induces a cascade of other inflammatory cytokines, chemokines and growth factors [8]. The results of various in vivo and in vitro studies indicate that the increase in their production is involved in the severity of the inflammation, due to their participation in restructuring the airway and in the pro-oxidative response [9]. In relation to single nucleotide polymorphisms (SNPs), it has been reported that rs1800629 (G→A change in position -308) increases transcriptional activity [10,11], in addition to being associated with different pulmonary pathological diseases such as chronic obstructive pulmonary disease and asthma [9,12,13]. However, no SNPs have been reported in TNF or LTA that are associated with AERD.

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Fluticasone Propionate Downregulates Nasal Fibroblast Functions Involved in Airway Inflammation and Remodeling

Cited by 38 publications

References 33 publications

Dexamethasone can stimulate G1-S phase transition in human airway fibroblasts in asthma

Dexamethasone can stimulate G1-S phase transition in human airway fibroblasts in asthma

In vitro effect of glucocorticoids on nasal polyps

Single Nucleotide Polymorphisms in TNF are Associated with Susceptibility to Aspirin-exacerbated Respiratory Disease but not to Cytokine Levels: a Study in Mexican Mestizo Population

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