Avaliação do efeito anti-inflamatório e antiasmático da 15-deoxy-delta-12,14-prostaglandina J2 em modelos murinos de asma

Abstract

Asthma is a chronic pulmonary disorder characterized by inflammation, obstruction and airway remodeling, leading to symptoms such as wheezing, coughing and breathlessness. Asthma therapy is based on inhaled corticosteroids and short or long term-β2 agonists. The treatment is limited by side effects and some refractory patients, justifying the study for new therapies. Studies have demonstrated that 15-deoxy-delta-12 ,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPAR-γ) can reduce pro-inflammatory cytokines expression, providing a protective effect in diseases with this profile. The aim of this study was to evaluate the anti-inflammatory and antiasthmatic properties of 15d-PGJ2 in murine models of experimental asthma. A/J mice rats were sensitized on days 0 and 7 by subcutaneous (s.c.) injection , containing ovalbumin (OVA) and Al(OH)3, and challenged with 4 intranasal OVA instillations at weekly intervals. 15d-PGJ2 treatment (30 and 100 μg/Kg) was performed 30 min before the challenges from the third antigen challenge. In another model, A/J mice were intranasally (i.n.) challenged with mite extract 3 times per week for 3 weeks. The administration of 15d-PGJ2 (30, 70 and 100 μg /Kg, s.c. and 0.65, 1.5 and 2.3 μg / animal, i.n.) were performed from the 3rd week, 30 min before the challenges. The analyzes were 24 h after the last challenge. Our results showed that in previously OVA-sensitized and challenged mice, administration of 15d-PGJ2 limited significantly (p <0.05), eosinophilic and neutrophilic inflammation and mucus production by goblet cells and sub-epithelial fibrosis, as well as airways hyperreactivity and IL-5 production. The reduction of bronchial epithelium and IL-13 and TNF-α were observed only at the highest dose administered. In HDM model, inflammatory and remodeling parameters were attenuated in all administered doses of compound, whereas bronchial hyperresponsiveness was inhibited only at doses of 70 and 100 μg/kg (s.c.) and 1.5 μg/animal (i.n.). Serum cytokine levels were attenuated by subcutaneous treatment, but only IL-17, Eotaxin-1 and TNF-α was inhibited by intranasal dose of 0.65 μg/ animal. The increased expression of NF-kB induced by HDM challenge was also significantly reduced by the administration of 15d-PGJ2. Together, our data indicate that treatment with 15d-PGJ2 inhibits critical changes associated with the pathogenesis of asthma in different experimental models of the disease, demonstrating great potential to control and reverse pulmonary inflammation, hyperresponsiveness and remodeling triggered by allergen challenge.