Abstract
15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) has been described as an anti-inflammatory lipid mediator in several in vitro and in vivo studies, but its effect on allergic pulmonary inflammation remains elusive. The aim of this study was to investigate the therapeutic potential of 15d-PGJ2 based on distinct murine models of allergic asthma triggered by either ovalbumin (OVA) or house dust mite extract (HDM). Characteristics of lung inflammation, airway hyper-reactivity (AHR), mucus exacerbation, and lung remodeling in sensitized A/J mice treated or not with 15d-PGJ2 were assessed. 15d-PGJ2 treatments were carried out systemically or topically given via subcutaneous injection or intranasal instillation, respectively. Analyses were carried out 24 h after the last allergen provocation. Irrespective of the route of administration, 15d-PGJ2 significantly inhibited the peribronchial accumulation of eosinophils and neutrophils, subepithelial fibrosis and also mucus exacerbation caused by either OVA or HDM challenge. The protective effect of 15d-PGJ2 occurred in parallel with inhibition of allergen-induced AHR and lung tissue production of pro-inflammatory cytokines, such as interleukin (IL)-5, IL-13, IL-17, and TNF-α. Finally, 15d-PGJ2 was found effective in inhibiting NF-κB phosphorylation upon HDM challenge as measured by Western blotting. In conclusion, our findings suggest that 15d-PGJ2 can reduce crucial features of asthma, including AHR, lung inflammation, and remodeling in distinct murine models of the disease. These effects are associated with a decrease in lung tissue generation of pro-inflammatory cytokines by a mechanism related to downregulation of NF-κB phosphorylation.
Highlights
Atopic asthma is a chronic inflammatory disease of the lung airways, triggered by a combination of genetic predisposition and environmental allergens, such as pollen, air pollution, and the fecal matter from dust mites and cockroaches [1,2,3]
To access the putative effect of subcutaneous treatment of 15d-PGJ2 on lung remodeling triggered by OVA provocation, we have assessed distinct lung sections stained with PAS and Gömöri trichrome
We have done investigations into the putative capacity of the PPAR-γ ligand 15d-PGJ2 to reverse ongoing lung pathological changes triggered by allergen in two distinct mouse models of asthma
Summary
Atopic asthma is a chronic inflammatory disease of the lung airways, triggered by a combination of genetic predisposition and environmental allergens, such as pollen, air pollution, and the fecal matter from dust mites and cockroaches [1,2,3]. Asthma pathogenesis is driven by T cells and T-helper 2 (Th2) cytokines, resulting in eosinophil infiltration into lung tissue, peribronchiolar fibrosis, thickening of airway wall layers, epithelial. 15d-PGJ2 Improves Allergen-Induced Asthma in Mice goblet cell metaplasia, and AHR [5, 6]. The asthma therapy is based on inhaled antiinflammatory steroids and β2 adrenergic agonists, which control the symptoms of the disease quite effectively [7,8,9]. Some asthmatics are insensitive to glucocorticoids and present adverse effects, indicating the need to develop new therapy alternatives safe and effective in controlling the disease [10,11,12]
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