Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma

Narala, Venkata Ramireddy; Ranga, Rajesh; Smith, Monica R.; Berlin, Aaron A.; Standiford, Theodore J.; Lukacs, Nicholas W.; Reddy, Raju C.

doi:10.1186/1465-9921-8-90

Cited by 47 publications

(37 citation statements)

References 66 publications

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“…37 Previous research has shown that DEX is an effective treatment for mouse models of inflammatory pulmonary disease. 36,38,39 Narala et al 38 compared pioglitazone to dexamethasone treatment in a CRA induced model of asthma and showed that these agents were equally effective at reducing airways resistance and lung mucus production. Therefore we expected that DEX would have a large effect on the inflammatory profile in our model of allergic pulmonary inflammation.…”

Section: Vaickus Et Almentioning

confidence: 99%

Assessing Pulmonary Pathology by Detailed Examination of Respiratory Function

Vaickus

Bouchard

Kim

et al. 2010

The American Journal of Pathology

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Pulmonary inflammation causes multiple alterations within the lung , including mucus production , recruitment of inflammatory cells , and airway hyperreactivity (AHR). Measurement of AHR by direct , invasive means (eg , mechanical ventilation)or noninvasive techniques , like whole body plethysmography (WBP) , assesses the severity of pulmonary inflammation in animal models of inflammatory lung disease. Direct measurement of AHR is acknowledged as the most accurate method for assessing airway mechanics , but analysis of all data obtained from WBP may offer insights into which inflammatory aspects of the lung are altered along with AHR. Using WBP , we compared the respiratory parameters of two groups of mice sensitized with cockroach allergen. One group was treated with dexamethasone (Dex) before final challenge (DexAsthma) , while the other group received vehicle treatment (Asthma). Respiratory parameters from plethysmography revealed that Dex-Asthma mice compensated to maintain high minute ventilation , whereas Asthma mice showed significant impairment in minute ventilation despite increased peak expiratory flow (103 ؎ 5 ml/min vs. 69 ؎ 70 ml/ min). The WBP data suggest that enhanced air exchange in the Dex-Asthma mice results from significant decreases in airway mucus production. Additional studies with quantitative morphometry of histological sections confirmed that Dex reduced airway mucus. In conclusion , a detailed examination of WBP parameters can accurately assess the respiratory health of mice and will help direct additional studies. Numerous relevant animal models of disease have advanced the understanding of biology and provided important insights into the pathogenesis of human disease. The vast majority of these studies have been carried out in mice, due to their small size and the extensive characterization of the murine inflammatory system. Several robust murine models of allergic asthma have been developed in recent years, 1 including many experimental systems which induce allergic sensitization to ovalbumin (Ova). Although this system allows close control over the nature of the sensitizing agent, Ova is a relatively poor allergen and requires adjuvant co-administration or relatively high and frequent doses to achieve satisfactory immunization.2-5 Our model, conversely, uses an allergen composed of the defatted, total body extract of German cockroaches (cockroach allergen, CRA) containing appreciable lipopolysaccharide. CRA is a highly potent allergen (robust immunization is achieved with a dose thousands of times less than that required for Ova) and does not require an adjuvant for sensitization.6,7 Campbell et al 7 established the first CRA induced model of asthma in mice and demonstrated robust pulmonary inflammation with many asthma-like features. The complex nature of this allergen and its close correspondence with its urban environmental counterpart makes this model highly applicable to the study of human disease.In most models of allergic airways inflammation, disease severity and or therape...

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Section: Vaickus Et Almentioning

confidence: 99%

Assessing Pulmonary Pathology by Detailed Examination of Respiratory Function

Vaickus

Bouchard

Kim

et al. 2010

The American Journal of Pathology

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“…Mouse models have shown that PPAR-c deletion from alveolar macrophages causes airway inflammation [8,9]. Furthermore, rosiglitazone inhibits the development of lipopolysaccharide (LPS)-induced airway neutrophilia [10], and pioglitazone inhibits allergic pulmonary inflammation in mice to a similar degree to corticosteroids [11]. In addition to its role in the inflammatory response, PPAR-c is also involved in the regulation of macrophage efferocytosis; PPAR-c deletion reduces macrophage clearance of apoptotic cells [12].…”

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 vitro, these drugs inhibit the release of various cytokines from activated lymphocytes (12), monocytes (13), endothelial cells (14), microglia, and Phorbol 12-myristate 13-acetate-differentiated THP-1 cells (a human monocytic cell line) (15). 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).…”

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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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Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma

Abstract: Background: While glucocorticoids are currently the most effective therapy for asthma, associated side effects limit enthusiasm for their use. Peroxisome proliferator-activated receptor-γ (PPAR-γ) activators include the synthetic thiazolidinediones (TZDs) which exhibit anti-

Cited by 47 publications

References 66 publications

Assessing Pulmonary Pathology by Detailed Examination of Respiratory Function

Assessing Pulmonary Pathology by Detailed Examination of Respiratory Function

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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