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Background: Besides being highly effective in the treatment of allergic and nonallergic rhinitis with eosinophilia, intranasal corticosteroids appear to be useful in reducing nasal polypoid lesions and the likelihood of polyp recurrence after surgery. We evaluated the ability of fluticasone propionate to downregulate fibroblast functions related to nasal inflammation and remodeling. Methods: Primary nasal polyp tissue-derived fibroblasts were stimulated with tumor necrosis factor (TNF)-α or interleukin (IL)-4 or basic fibroblast growth factor (bFGF) in the presence of fluticasone propionate (0.1–100 nM). Fibroblast proliferation, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression and eotaxin release were then evaluated. Results: As compared with unstimulated cultures, a significant increase in fibroblast proliferation was observed when the cells were stimulated with bFGF (p < 0.05), but not with TNF-α or IL-4 (p > 0.05). TNF-α induced an upregulation of ICAM-1 expression (p < 0.05), which was not seen in fibroblasts cultured in the presence of IL-4 or bFGF. No changes in VCAM-1 expression were induced by TNF-α, IL-4 or bFGF, whereas both TNF-α and IL-4 increased eotaxin release (p < 0.05). Both bFGF-induced fibroblast proliferation and TNF-α-induced ICAM-1 expression were significantly reduced by fluticasone, starting at the dose of 1 and 10 nM, respectively (p < 0.05). Fluticasone at concentrations of 1–100 nM effectively inhibited eotaxin release by TNF-α- or IL-4-stimulated fibroblasts (p < 0.05). Conclusions: The pharmacologic activity of fluticasone in patients with chronic upper airway inflammatory disease may include inhibition of resident fibroblast functions involved in airway inflammation and remodeling.

b 2 -adrenoreceptor agonists have pharmacological properties that may suggest an inhibitory effect on various aspects of the inflammatory and repair processes that characterize asthma.Since fibroblasts express b 2 -adrenoreceptors, the effects of different concentrations (0.1 -100 nM) of fluticasone propionate (FP), salmeterol (S) and their combination (FPzS) on lung fibroblast proliferation and adhesion molecule expression were evaluated.Stimulation of human foetal lung fibroblasts with a fibrogenic cytokine, basic fibroblast growth factor (bFGF), resulted in a [methyl-3 H] thymidine ([ 3 H]TdR) uptake, four-fold higher than that of control cultures (p~0.0001) and was significantly inhibited by S, at all the concentrations tested (0.1 -100 nM; pv0.05). No changes in bFGFinduced cell proliferation were observed in the presence of FP (0.1 -100 nM; pw0.05, all comparisons). In addition, the association FPzS did not improve the inhibitory activity of S alone (pw0.05, each comparison). An upregulation of intercellular adhesion molecule-1 (ICAM-1) expression was induced by tumour necrosis factor-a (TNF-a) (p~0.0004), but not by interleukin-4 (IL-4) (pw0.05), while none of the two cytokines were able to increase hyaluronic-cellular adhesion molecule (H-CAM) expression by lung fibroblasts (pw0.05). A significant downregulation of ICAM-1 or H-CAM expression was demonstrated in the presence of FP or S, at all concentrations tested (0.1 -100 nM; pv0.01, each comparison). Interestingly, S (10 nM and 100 nM) was able to enhance the inhibitory activity of FP on ICAM-1 expression (pv0.01), but not on H-CAM expression (pw0.1).These results show that in human foetal lung fibroblasts, fluticasone propionate and salmeterol are effective in modulating in vitro, different lung fibroblast biological functions that are likely to be involved in airway remodelling.

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Asthma is characterized by an irreversible subepithelial fibrosis with the appearance of myofibroblasts, which can be now considered important early participants in inflammatory responses as well as potential targets for anti-inflammatory drugs. In this study, we show that fluticasone propionate (FP), a powerful inhaled corticosteroid (ICS), displays novel anti-inflammatory effects on human lung fibroblasts during their myofibroblastic differentiation. Indeed, FP inhibits in lung myofibroblasts, at a very early stage of differentiation, the activation of Janus kinase/STAT pathways induced by IL-13 (tyrosine kinase 2, STAT1, STAT3, STAT6, mitogen-activated protein kinase). Contrarily, in mildly or fully differentiated myofibroblastic cultures, FP still displays a potential anti-inflammatory activity even if it only inhibits tyrosine kinase 2 phosphorylation. Moreover, FP inhibits constitutive and TGF-β-induced expression of α-smooth muscle actin, the main marker of myofibroblastic differentiation, both in very early and in mild differentiated myofibroblasts. Finally, FP displays an additional powerful anti-inflammatory effect, decreasing nuclear translocation of NF-κB independent of the degree of myofibroblastic differentiation. These data 1) suggest that myofibroblasts are priority targets for ICS, which is able to revert them to a normal phenotype even if they appear to be already engaged in their differentiation, and 2) may help to explain why asthma is improved by an early ICS treatment, whereas advanced asthma is more resistant to these drugs.

SUMMARYHantaviruses cause an important human illness, HFRS. Blood samples from 22 HFRS-positive, six seronegative patients and 15 healthy controls were examined in 1995, during the largest HFRS epidemic in Croatia. Results of double-and triple-colour immunofluorescence analysis showed an increased percentage of cytotoxic T cells (CD3 þ CD8 þ ) in seropositive patients compared with seronegatives and healthy controls. The majority of seropositive HFRS patients expressed activation and memory antigens on T and B lymphocytes. The percentage of CD23 þ and CD21 þ B lymphocytes was lower in seropositive patients. HFRS patients had elevated levels of sCD23 and five had elevated total IgE. The increased expression of both early and late T cell activation antigens, e.g. CD25, CD71 and HLA-DR, memory cells and sCD23 positively correlated with biochemical parameters (AST, ALT, urea, a 2 -globulin) during the acute phase of HFRS. The phenotypic changes observed, especially early and late T cell activation markers, as well as memory cells, could be useful parameters in the evaluation of HFRS course, and prognostic factors of HFRS severity. Additional attention should be paid to liver involvement in the pathogenesis of HFRS.

ObjectiveTo assess methotrexate (MTX) adherence using the Medication Event Monitoring System (MEMS) and characterize associations with adherence in patients with rheumatoid arthritis (RA).MethodsEligible patients participated in Forward, the National Databank for Rheumatic Diseases, and recently (12 months or sooner) initiated oral MTX. MEMS was used to compile MTX weekly dosing over 24 weeks. The Beliefs about Medicines Questionnaire (BMQ) was completed, and baseline demographics and disease characteristics obtained. MTX adherence (percentage of weeks dose taken correctly), implementation (percentage of weeks dose taken correctly from initiation until last dose), and persistence (duration from initiation to last dose) were calculated. Analyses measured associations between patient characteristics and adherence, modeled using logistic generalized estimating equations and censored Poisson regression, and persistence modeled using Cox regression.ResultsOverall, 60 of 119 eligible patients were included in the analysis. MTX adherence, implementation, and persistence were 75%, 80%, and 83%, respectively, at 24 weeks. Demographics and disease characteristics were generally similar between patients with 1 week or less and 2 weeks or more of missed MTX. Unemployment, less disability, higher Patient Global scores, and no prior disease‐modifying antirheumatic drug (DMARD) use were associated with correct dosing. No significant differences in adherence were observed between patients receiving concomitant MTX versus MTX monotherapy, and biologic DMARD‐experienced versus biologic DMARD‐naïve patients. Higher scores in BMQ Specific Necessity (indicating a greater belief in the necessity of the medication) was associated with a decreased likelihood of dosing at an interval shorter than prescribed (odds ratio 0.89).ConclusionEven in a participatory group over a short period, MTX adherence was suboptimal and associated with certain demographics, medication experience, and beliefs about medicines. This suggests a need for screening and alternative treatment opportunities in nonadherent MTX patients with RA.

CD23‐deficient and anti‐CD23 monoclonal antibody‐treated mice were used to investigate the role of the low‐affinity receptor for IgE (CD23) in allergic airway inflammation and airway hyperresponsiveness (AHR). While there were no significant differences in ovalbumin (OVA)‐specific IgE titers and tissue eosinophilia, evaluation of lung function demonstrated that CD23− / − mice showed an increased AHR to methacholine (MCh) when compared to wild‐type mice but were completely resistant to the OVA challenge. Anti‐CD23 Fab fragment treatment of wild‐type mice did not affect the MCh‐induced AHR but significantly reduced the OVA‐induced airway constriction. These results imply a novel role for CD23 in lung inflammation and suggest that anti‐CD23 Fab fragment treatment may be of therapeutic use in allergic asthma.