Papel regulatório da proteína anexina-1 e de seu derivado Ac2-26 no modelo experimental de asma alérgica em camundongos

Abstract

Asthma is a chronic inflammatory disease characterized by airways hyperreactivity, eosinophil accumulation, mucus secretion as well as remodeling. During the establishment of the inflammatory process, endogenous mediators are released in order limit the progression of the pathological process (COHN, ELIAS e CHUPP, 2004). Glucocorticoid hormones are considered as critical based on their potent anti-inflammatory activity, which is at least partially dependent on the release of intermediate factors such as the protein annexin-1 (KAMAL, FLOWER e PERRETTI, 2005; PERRETTI, 2003). In this study, we investigated the role of annexin-1 (AnxA1) and its derived peptide Ac2-26 (50 200 µg/animal) on the experimental model of allergic asthma in mice. BALB/c (AnxA1+/+) and AnxA1 knockout mice (AnxA1-/-) were sensitized with subcutaneous injection of ovalbumin (OVA 50 µg) plus aluminum hydroxide (5 mg). On day 14, animals were boosted intraperitoneally with OVA (25 µg) and on days 19, 20 and 21 post-sensitization, mice were challenged intranasally with OVA (25 µg). Treatment was performed by intranasal administration of Ac2-26 peptide (50 - 200 µg), 1 h before each challenge. The analyses were made 24 h after the last provocation and included: i) lung function (resistance and elastance) and airways hyperreactivity to methacholine (3-27 mg/ml) by invasive plethysmography, ii) morphology by classical histological techniques; iii) collagen quantification and iv) cytokine generation evaluated by ELISA. It was noted that AnxA1-/- mice, when sensitized and challenged with OVA showed exacerbation of airways hyperreactivity, eosinophils present in the bronchoalveolar lavage and peribronchial tissue, collagen deposition and increased levels of IL-13 as compared to AnxA1+/+. In parallel, it was showed that treatment of AnxA1+/+ mice with the Ac2-26 peptide markedly inhibited airways hyperreactivity, peribronchial eosinophil accumulation, mucus production and the generation of IL-13 and eotaxin-1 and -2. Taken together our results show that AnxA1-/- mice were more responsive to antigen stimulation, which is an indicative that AnxA1 plays an important regulatory role in the murine allergic inflammatory response. In addition, the inhibitory effect of the Ac2-26 peptide on the allergic lung inflammation clearly indicated that it seems to be a promising anti-inflammatory and anti-allergic agent to be used in the asthma therapy.