Bronchodilatory Effect of the PPAR-γ Agonist Rosiglitazone in Smokers With Asthma

Spears, Mark; Donnelly, Iona; Jolly, Lisa; Brannigan, Maureen; Ito, Kazuhiro; McSharry, Charles; Lafferty, Jane; Chaudhuri, Rekha; Braganza, Georgina; Bareille, Philippe; Sweeney, Lisa; Adcock, Ian M.; Barnes, Peter J.; Wood, Stuart F; Thomson, Neil C.

doi:10.1038/clpt.2009.41

Cited by 89 publications

(83 citation statements)

References 28 publications

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“…For example, ARVassociated cardiovascular disease and metabolic syndrome are thought to occur because of ARV-associated decreased expression of peroxisome-proliferator-activated receptor. This receptor is an important transcription factor in lipid and cytokine metabolism and provides an antiinflammatory effect in the lungs and airways; therefore, decreased levels might contribute to development of airway obstruction after ARV initiation (38)(39)(40)(41). Abnormal immune restoration similar to that in the immune reconstitution inflammatory syndrome may result in response to occult infection or colonization in the respiratory tract and lead to airway obstruction (12,42,43).…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Function Abnormalities in HIV-Infected Patients during the Current Antiretroviral Therapy Era

Gingo¹,

George²,

Kessinger³

et al. 2010

Am J Respir Crit Care Med

190

237

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Rationale: Before the introduction of combination antiretroviral (ARV) therapy, patients infected with HIV had an increased prevalence of respiratory symptoms and lung function abnormalities. The prevalence and exact phenotype of pulmonary abnormalities in the current era are unknown. In addition, these abnormalities may be underdiagnosed. Objectives: Our objective was to determine the current burden of respiratory symptoms, pulmonary function abnormalities, and associated risk factors in individuals infected with HIV. Methods: Cross-sectional analysis of 167 participants infected with HIV who underwent pulmonary function testing. Measurements and Main Results: Respiratory symptoms were present in 47.3% of participants and associated with intravenous drug use (odds ratio [OR] 3.64; 95% confidence interval [CI], 1.32-10.046; P 5 0.01). Only 15% had previous pulmonary testing. Pulmonary function abnormalities were common with 64.1% of participants having diffusion impairment and 21% having irreversible airway obstruction. Diffusion impairment was independently associated with ever smoking (OR 2.46; 95% CI, 1.16-5.21; P 5 0.02) and Pneumocystis pneumonia prophylaxis (OR 2.94; 95% CI, 1.10-7.86; P 5 0.01), whereas irreversible airway obstruction was independently associated with pack-years smoked (OR 1.03 per pack-year; 95% CI, 1.01-1.05; P , 0.01), intravenous drug use (OR 2.87; 95% CI, 1.15-7.09; P 5 0.02), and the use of ARV therapy (OR 6.22; 95% CI, 1.19-32.43; P 5 0.03). Conclusions: Respiratory symptoms and pulmonary function abnormalities remain common in individuals infected with HIV. Smoking and intravenous drug use are still important risk factors for pulmonary abnormalities, but ARV may be a novel risk factor for irreversible airway obstruction. Obstructive lung disease is likely underdiagnosed in this population.Keywords: HIV; respiratory function tests; smoking; antiretroviral therapy, highly active; AIDS Pulmonary complications have been a major cause of morbidity and mortality in patients with HIV infection (1, 2). With the development of combination antiretroviral (ARV) therapy and improvements in prophylaxis for Pneumocystis pneumonia (PCP) and other opportunistic infections, the incidence of infectious pulmonary complications has decreased drastically in patients with HIV infection (1, 3, 4). Changes in noninfectious pulmonary complications, such as chronic obstructive pulmonary disease (COPD) and asthma, are less clear, and these diseases may actually be increasing. Studies before the introduction of combination ARV demonstrated that persons with HIV infection had a higher prevalence of impaired diffusing capacity for carbon monoxide (DL CO ), increased emphysema, accelerated airway obstruction and small airways disease, and more frequent respiratory symptoms than subjects not infected with HIV (2, 5-8).Limited data exist regarding the extent and types of pulmonary function abnormalities in the current era. In one recent study, veterans with HIV infection had an increased risk of COPD compared wi...

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Section: Discussionmentioning

confidence: 99%

Pulmonary Function Abnormalities in HIV-Infected Patients during the Current Antiretroviral Therapy Era

Gingo¹,

George²,

Kessinger³

et al. 2010

Am J Respir Crit Care Med

190

237

View full text Add to dashboard Cite

show abstract

“…There is an urgent need for more effective antiinflammatory therapies for COPD that target macrophage function. Certainly, there is evidence from asthma clinical trials that the PPAR-c agonist rosiglitazone has therapeutic benefits [21,22]. There is concern about the clinical use of rosiglitazone due to cardiac side-effects [23].…”

Section: Introductionmentioning

confidence: 99%

The effect of peroxisome proliferator-activated receptor-γ ligands onin vitroandin vivomodels of COPD

et al. 2013

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Peroxisome proliferator-activated receptor (PPAR)-c is expressed in alveolar macrophages. The anti-inflammatory potential of the PPAR-c ligands rosiglitazone and pioglitazone were investigated using in vitro alveolar macrophage models and in vivo animal models relevant to chronic obstructive pulmonary disease (COPD).PPAR-c protein and gene expression in COPD alveolar macrophages was compared with control smokers and never-smokers. COPD macrophages were used to investigate the effects of PPAR-c ligands and corticosteroids on lipopolysaccharide-induced cytokine production, alternative macrophage activation (M2) gene expression and efferocytosis. The effects of PPAR-c ligands in a subchronic tobacco smoke model in mice were investigated.PPAR-c protein expression was similar in COPD patients compared to controls, although increased gene expression levels were observed in COPD patients and control smokers compared to never-smokers. PPAR-c ligands reduced tumour necrosis factor-a and CC chemokine ligand-5, but not CXC chemokine ligand-8, in COPD alveolar macrophages; these effects were generally less than those of the corticosteroid dexamethasone. Rosiglitazone increased M2 gene expression and enhanced efferocytosis of apoptotic neutrophils. Rosiglitazone and pioglitazone attenuated airway neutrophilia in a corticosteroid-resistant mouse model of pulmonary inflammation.We show biological actions of PPAR-c agonists on corticosteroid-resistant disease, tobacco smokeinduced pulmonary inflammation, skewing of macrophage phenotype and clearance of apoptotic neutrophils.@ERSpublications Biological actions of a PPAR-c agonist shown in COPD-relevant models may affect progression and side-effects in patients

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“…In vivo, rosiglitazone and pioglitazone also effectively inhibit airway inflammation in various murine models of asthma (16,17). Most importantly, in a recent clinical trail, the inhalation of rosiglitazone improved lung function, and also reduced sputum IL-8 concentrations in steroid-resistant patients with asthma (18). In cultured HASM cells, troglitazone was shown to attenuate the TNF-a-induced production of eotaxin and MCP-1 expression (19), whereas ciglitazone prevented the IL-1b-induced production of granulocyte-macrophage colony-stimulating factor and granulocyte-colony stimulating factor (20).…”

mentioning

confidence: 99%

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

Zhu¹,

Flynt

Ghosh

et al. 2011

Am J Respir Cell Mol Biol

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Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dosedependently reduced the IL-1b-induced release of IL-6 and vascular endothelial growth factor, the TNF-a-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-a-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-g (PPARg), these anti-inflammatory effects were not affected by a specific PPARg inhibitor (GW 9662) or by the knockdown of PPARg using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the antiinflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARg or AMPK.

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Bronchodilatory Effect of the PPAR-γ Agonist Rosiglitazone in Smokers With Asthma

Cited by 89 publications

References 28 publications

Pulmonary Function Abnormalities in HIV-Infected Patients during the Current Antiretroviral Therapy Era

Pulmonary Function Abnormalities in HIV-Infected Patients during the Current Antiretroviral Therapy Era

The effect of peroxisome proliferator-activated receptor-γ ligands onin vitroandin vivomodels of COPD

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

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