Inhibitory effects of fluvastatin on cytokine and chemokine production by peripheral blood mononuclear cells in patients with allergic asthma

Samson, Karen Thursday; Minoguchi, Kenji; Tanaka, Akihiko; Oda, Naruhito; Yokoe, Takuya; Yamamoto, Yoshitaka; Yamamoto, Masahide; Ohta, Shin; Adachi, Mitsuru

doi:10.1111/j.1365-2222.2006.02470.x

Cited by 39 publications

(38 citation statements)

References 29 publications

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“…Statins also modulate monocyte-macrophage function and inflammatory responses (33,34), consistent with our finding of reduced BALF macrophage counts ( Figure 1D). Peripheral blood mononuclear cells from patients with asthma display reduced chemokine and cytokine production after fluvastatin treatment (35), antiinflammatory effects that may be mediated via GGPP depletion (Scheme 1) (36). Clearly, there is mechanistic precedence that supports the central role of the MA pathway in modulating the simvastatin inhibition of OVAinduced airway inflammation.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin Inhibits Airway Hyperreactivity

Zeki

Franzi

Kenyon

2009

Am J Respir Crit Care Med

109

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Rationale: Statin use has been linked to improved lung health in asthma and chronic obstructive pulmonary disease. We hypothesize that statins inhibit allergic airway inflammation and reduce airway hyperreactivity via a mevalonate-dependent mechanism. Objectives: To determine whether simvastatin attenuates airway inflammation and improves lung physiology by mevalonate pathway inhibition. Methods: BALB/c mice were sensitized to ovalbumin over 4 weeks and exposed to 1% ovalbumin aerosol over 2 weeks. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) was injected intraperitoneally before each ovalbumin exposure. Measurements and Main Results: Simvastatin reduced total lung lavage leukocytes, eosinophils, and macrophages (P , 0.05) in the ovalbumin-exposed mice. Cotreatment with mevalonate, in addition to simvastatin, reversed the antiinflammatory effects seen with simvastatin alone (P , 0.05). Lung lavage IL-4, IL-13, and tumor necrosis factor-a levels were all reduced by treatment with simvastatin (P , 0.05). Simvastatin treatment before methacholine bronchial challenge increased lung compliance and reduced airway hyperreactivity (P 5 0.0001). Conclusions: Simvastatin attenuates allergic airway inflammation, inhibits key helper T cell type 1 and 2 chemokines, and improves lung physiology in a mouse model of asthma. The mevalonate pathway appears to modulate allergic airway inflammation, while the beneficial effects of simvastatin on lung compliance and airway hyperreactivity may be independent of the mevalonate pathway. Simvastatin and similar agents that modulate the mevalonate pathway may prove to be treatments for inflammatory airway diseases, such as asthma.

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Section: Discussionmentioning

confidence: 99%

Simvastatin Inhibits Airway Hyperreactivity

Zeki

Franzi

Kenyon

2009

Am J Respir Crit Care Med

109

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“…26 The benefits of statin medications for asthma were thought to be dose-dependent, which may account for the apparently conflicting data in murine studies that tested the effects of statins at various doses. 18,25 A low dose of statins may inhibit chemotaxis of type 1 helper T cells, which cause proliferation and aggregation, whereas large doses of statins may inhibit cell death of dendritic cells that differentiate to T h 2 cells. 13,25 These hypotheses have been tested and verified in mice.…”

Section: Journal Of International Medical Research 41(2)mentioning

confidence: 99%

“…27 In contrast, it has been argued that although asthma may be controlled by ICS, the long-term use of ICS carries the risk of side-effects such as adrenal suppression, growth inhibition, and osteoporosis. 18 Statins may help improve the results of long-term ICS treatment and prevent the above-mentioned side-effects. An experiment was undertaken to verify whether statins could prevent and improve airway remodelling, according to regulation of the proliferation of goblet cells and the production of profibrogenic mediators; the authors concluded that statins should be used for asthma.…”

Section: Journal Of International Medical Research 41(2)mentioning

confidence: 99%

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Statin therapy does not improve lung function in asthma: A meta-analysis of randomized controlled trials

Zhang

Huo

et al. 2013

J Int Med Res

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Objective: To assess the efficacy of statins in the treatment of asthma. Methods: Electronic databases were searched to identify randomized controlled trials that measured the efficacy of statins in the treatment of asthma, and a meta-analysis of the pooled data was performed. Results: Five trials were identified; four met the inclusion criteria (total number of patients 200). Compared with controls, patients in the statin groups had higher forced expiratory volume in 1 s (FEV 1 ) values before inhaled corticosteroids (0.09 l, 95% confidence interval [CI] À0.06, 0.23), higher FEV 1 values after inhaled corticosteroids (0.06 l, 95% CI À0.09, 0.22), and higher morning peak expiratory flow rates (9.87 l, 95% CI À15.66, 35.40). These results were not statistically significant and, furthermore, publication bias was detected. Conclusion: In conclusion, there is currently insufficient evidence to show that statins improve lung function in patients with asthma.

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“…Preclinical in vitro and in vivo studies, including experimental models of allergic [146] and tobacco-smokeinduced lung inflammation [147] found that statins reduce components of airway inflammation potentially relevant to the pathogenesis of asthma and smoke-induced airway diseases. Statins may also restore corticosteroid sensitivity in asthma [148,149]. In smokers with asthma the effects of atorvastatin alone and in combination with inhaled corticosteroid 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 27 was investigated on the ability to suppress the concentration of a range of cytokines, chemokines and growth factors in sputum [150,151] in patients with stable COPD [152].…”

Section: Statinsmentioning

confidence: 99%

Addressing corticosteroid insensitivity in adults with asthma

Thomson

2016

Expert Review of Respiratory Medicine

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Corticosteroids are the most effective treatment for asthma, but the therapeutic response varies markedly between individuals, with up to one third of patients showing evidence of insensitivity to corticosteroids. This article summarizes information on genetic, environmental and asthma-related factors as well as demographic and pharmacokinetic variables associated with corticosteroid insensitivity in asthma. Molecular mechanisms proposed to explain corticosteroid insensitivity are reviewed including alterations in glucocorticoid receptor subtype, binding and nuclear translocation, increased proinflammatory transcription factors and defective histone acetylation. Current therapies and future interventions that may restore corticosteroid sensitivity in asthma are discussed, including small molecule drugs and biological agents. In the future, biomarkers may be used in the clinic to predict corticosteroid sensitivity in patients with poorly controlled asthma. Word count: 120 wordsKey words: Adherence; asthma; biological agents; biomarkers; cigarette smoking; corticosteroids; corticosteroid insensitivity; corticosteroid resistance; small molecule drugs. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 IntroductionAsthma is a chronic inflammatory disease of the airways that affects 300 million people worldwide. Both national and international guidelines recommend daily inhaled corticosteroid as the preferred controller treatment for adults and adolescents with asthma who have poor symptom control or who at risk of exacerbations [201, 202]. Inhaled corticosteroid use in asthma reduces symptoms, improves quality of life and increases lung function as well as decreases the rate of exacerbations [201, 202]. The majority of the therapeutic benefits of inhaled corticosteroids are achieved at low to medium doses [1], although higher doses are often required in patients with more severe asthma [2] [202]. Short courses of oral corticosteroids are administered to treat severe exacerbations and daily oral corticosteroids are used in the lowest dose providing adequate control to treat patients with severe asthma when symptoms are uncontrolled despite maximal therapy [201, 202].Guideline recommendations for inhaled and oral corticosteroid use in asthma are based on average therapeutic responses from clinical trial populations that may not be representative of 'real-life' patients [3]. Numerous studies in adults and children with asthma have noted a considerable patient-to-patient variability in improvements in lung function and airway hyperreactivity with inhaled and oral corticosteroid treatment in patients with apparently similar levels of disease severity [4][5][6] (Figure 1). The findings from these studies suggest that corticosteroid insensitivity may be present in approximately one third of patients with asthma.Inhaled corticosteroids exhib...

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Inhibitory effects of fluvastatin on cytokine and chemokine production by peripheral blood mononuclear cells in patients with allergic asthma

Abstract: Fluvastatin has inhibitory effects on cytokine and chemokine production, and thus might be used as a potential therapeutic agent in severe asthma.

Cited by 39 publications

References 29 publications

Simvastatin Inhibits Airway Hyperreactivity

Simvastatin Inhibits Airway Hyperreactivity

Statin therapy does not improve lung function in asthma: A meta-analysis of randomized controlled trials

Addressing corticosteroid insensitivity in adults with asthma

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