The use of the peroxisome proliferator-activated receptors γ agonist rosiglitazone to treat airway hyperreactivity

Sandhu, Manbir S.; Dimov, Vesselin; Sandhu, Arveen Kaur; Walters, Ryan W.; Wichman, Tammy; Casale, Thomas B.

doi:10.1016/j.anai.2012.05.001

Cited by 10 publications

(5 citation statements)

References 10 publications

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“…A placebo controlled randomized study of 32 patients also found a modest decrease in late phase asthma reactivity to allergen challenge after four weeks of treatment with rosiglitazone [19]. A separate study of 16 asthmatic patients found a similar decrease in airway bronchoconstriction with methacholine challenge after 12 weeks of treatment with rosiglitazone [20]. Comparing rosiglitazone with inhaled corticosteroid treatment, a randomized trial of 46 patients with asthma showed improvement in FEV 1 and FEF 25–75% among patients treated with rosiglitazone [21].…”

Section: Discussionmentioning

confidence: 99%

Thiazolidinediones and the risk of asthma exacerbation among patients with diabetes: a cohort study

Rinne

Feemster

Collins

et al. 2014

All Asth Clin Immun

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BackgroundThiazolidinediones are oral diabetes medications that selectively activate peroxisome proliferator-activated receptor gamma and have potent anti-inflammatory properties. While a few studies have found improvements in pulmonary function with exposure to thiazolidinediones, there are no studies of their impact on asthma exacerbations. Our objective was to assess whether exposure to thiazolidinediones was associated with a decreased risk of asthma exacerbation.MethodsWe performed a cohort study of diabetic Veterans who had a diagnosis of asthma and were taking oral diabetes medications during the period of 10/1/2005 – 9/30/2006. The risk of asthma exacerbations and oral steroid use during 10/1/2006 – 9/30/2007 was compared between patients who were prescribed thiazolidinediones and patients who were on alternative oral diabetes medications. Multivariable logistic regression and negative binomial regression analyses were used to characterize this risk. A sensitivity analysis was performed, restricting our evaluation to patients who were adherent to diabetes therapy.ResultsWe identified 2,178 patients who were on thiazolidinediones and 10,700 who were not. Exposure to thiazolidinediones was associated with significant reductions in the risk of asthma exacerbation (OR = 0.79, 95% CI, 0.62 – 0.99) and oral steroid prescription (OR = 0.73, 95% CI 0.63 – 0.84). Among patients who were adherent to diabetes medications, there were more substantial reductions in the risks for asthma exacerbation (OR = 0.64, 95% CI 0.47 – 0.85) and oral steroid prescription (OR = 0.68, 95% CI 0.57 – 0.81).ConclusionsThiazolidinediones may provide a novel anti-inflammatory approach to asthma management by preventing exacerbations and decreasing the use of oral steroids.

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Section: Discussionmentioning

confidence: 99%

Thiazolidinediones and the risk of asthma exacerbation among patients with diabetes: a cohort study

Rinne

Feemster

Collins

et al. 2014

All Asth Clin Immun

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“…More recently, treatment with RGZ (4 mg, twice daily for 28 days, oral) was associated with a modest (15%) reduction in the late asthmatic reaction in the allergen challenge model of asthma (28). Of note, a 12-wk treatment with progressively increasing oral doses of RGZ (2 mg for 4 wk, then 4 mg for 4 wk, then 8 mg for 4 wk) decreased responsiveness to MCh (2.5-fold increase in PC 20 ), albeit without effects on exhaled NO or FEV 1 (29). However, these findings have yet to be extended to assess responses to acute inhalation of PPAR␥ agonists.…”

Section: Discussionmentioning

confidence: 99%

Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease

Donovan

Bailey

Tran

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor-␥ (PPAR␥) ligand, is a novel dilator of small airways in mouse precision cut lung slices (PCLS). In this study, relaxation to RGZ and ␤-adrenoceptor agonists were compared in trachea from naïve mice and guinea pigs and trachea and PCLS from a mouse model of chronic allergic airways disease (AAD). Airways were precontracted with methacholine before addition of PPAR␥ ligands [RGZ, ciglitazone (CGZ), or 15-deoxy-⌬12,14 -prostaglandin J2 (15-deoxy-PGJ2)] or ␤-adrenoceptor agonists (isoprenaline and salbutamol). The effects of T0070907 and GW9662 (PPAR␥ antagonists) or epithelial removal on relaxation were assessed. Changes in force of trachea and lumen area in PCLS were measured using preparations from saline-challenged mice and mice sensitized (days 0 and 14) and challenged with ovalbumin (3 times/wk, 6 wk). RGZ and CGZ elicited complete relaxation with greater efficacy than ␤-adrenoceptor agonists in mouse airways but not guinea pig trachea, while 15-deoxy-PGJ2 did not mediate bronchodilation. Relaxation to RGZ was not prevented by T0070907 or GW9662 or by epithelial removal. RGZ-induced relaxation was preserved in the trachea and increased in PCLS after ovalbumin-challenge. Although RGZ was less potent than ␤-adrenoceptor agonists, its effects were additive with salbutamol and isoprenaline and only RGZ maintained potency and full efficacy in maximally contracted airways or after allergen challenge. Acute PPAR␥-independent, epithelial-independent airway relaxation to RGZ is resistant to functional antagonism and maintained in both trachea and PCLS from a model of chronic AAD. These novel efficacious actions of RGZ support its therapeutic potential in asthma when responsiveness to ␤-adrenoceptor agonists is limited. allergic airways disease; bronchodilation; lung slice; peroxisome proliferator-activated receptor-␥; rosiglitazone THERE IS INCREASING EVIDENCE that rosiglitazone (RGZ) and other agonists of peroxisome proliferator-activated receptor-␥ (PPAR␥) may offer therapeutic benefit in asthma. Numerous studies suggest that PPAR␥ ligands can inhibit allergen-induced inflammation and the development of airway remodeling and airway hyperresponsiveness (AHR) in vivo (reviewed in Ref. 8), as well as exert direct dilator effects on airway smooth muscle (ASM) in vitro (3, 12).PPAR␥ expression is increased in bronchial biopsies from patients with asthma, including in the epithelial and ASM layers (2). In vitro, human ASM cytokine secretion and proliferation have been shown to be suppressed by the PPAR␥ agonists RGZ and ciglitazone (CGZ) (10,27,30,34,37). However, only some of these anti-inflammatory and antiremodeling activities were inhibited by the selective PPAR␥ antagonist GW9662, suggesting both PPAR␥-dependent and -independent mechanisms (30, 34).The effects of chronic treatment with PPAR␥ ligands have also been examined in mouse models of allergic airway disease (AAD), where sensitization and nebulization with ovalbumin (OVA) causes airway inflamma...

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“…The 1070 CpG sites annotated to 885 genes, of which 569 have not been reported in previous asthma EWAS or GWAS (including PDE4B and PPARG ). In ChEMBL [ 28 ], PPARG is a target of a candidate asthma drug (Rosiglitazone) [ 36 , 37 ] ( supplementary table E14 ).…”

Section: Resultsmentioning

confidence: 99%

Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study

Hoang

Sikdar

et al. 2020

Eur Respir J

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Epigenome-wide studies of methylation in children support a role for epigenetic mechanisms in asthma. Studies in adults are rare, and few have examined non-atopic asthma. We conducted the largest epigenome-wide association study of blood DNA methylation in adults in relation to non-atopic and atopic asthma.We measured DNA methylation in blood using the Illumina MethylationEPIC array among 2286 participants in a case-control study of current adult asthma nested within a U.S. agricultural cohort. Atopy was defined by serum specific immunoglobulin E. Participants were categorised as atopy without asthma (n=185), non-atopic asthma (n=673), atopic asthma (n=271), or a reference group of neither atopy nor asthma (n=1157). Analyses were conducted using logistic regression.No associations were observed with atopy without asthma. Numerous CpGs were differentially methylated in non-atopic asthma (8 at family-wise error rate [FWER] p<9×10−8; 524 at False Discovery Rate [FDR]<0.05) and implicated 382 novel genes. More CpGs were identified in atopic asthma (181 at FWER; 1086 at FDR) and implicated 569 novel genes. 104 FDR CpGs overlapped. 35% of CpGs in non-atopic asthma and 91% in atopic asthma replicated in studies of whole blood, eosinophils, airway epithelium, or nasal epithelium. Implicated genes were enriched in pathways related to the nervous system or inflammation.We identified numerous, distinct differentially methylated CpGs in non-atopic and atopic asthma. Many CpGs from blood replicated in asthma-relevant tissues. These circulating biomarkers reflect risk and sequelae of disease and implicate novel genes associated with non-atopic and atopic asthma.

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The use of the peroxisome proliferator-activated receptors γ agonist rosiglitazone to treat airway hyperreactivity

Cited by 10 publications

References 10 publications

Thiazolidinediones and the risk of asthma exacerbation among patients with diabetes: a cohort study

Thiazolidinediones and the risk of asthma exacerbation among patients with diabetes: a cohort study

Rosiglitazone elicits in vitro relaxation in airways and precision cut lung slices from a mouse model of chronic allergic airways disease

Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study

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