Efeito do tratamento com a proteína quimérica IL-13PE sobre a inflamação pulmonar induzida por partículas de sílica em camundongos

Abstract

The interleukin 13 (IL-13) has been identified as a key mediator in process of activation of fibroblasts and induction of pulmonary fibrosis, and it is therefore, considered an important therapeutic target. The silicosis is a chronic inflammatory lung disease, occupational beginning, characterized by an intense fibrotic and granulomatous response. Based on these observations, we had the aim to investigate the potential effect of administration of immunotoxin IL-13-PE38QQR (IL-13PE) on the silicotic fibrotic component. In this regard, Swiss-Webster mice were anesthetized and intranasally instilled with silica particles (10 mg), some of them were treated with IL-13PE (200 ng / day) performed by intranasal via once daily on alternate days in the period between 21 to 28 days after challenge. We analyzed the inflammatory component, the deposition of collagen and the area of granuloma evaluated using classical histological techniques, including staining with HE and Picrus sirius or the system of colorimetric quantification of collagen content by Sircol. The components of extracellular matrix fibronectin and laminin were evaluated by immunohistochemistry. Cytokines and chemokines were quantified by ELISA system. Measures of pulmonary function and hyperreactivity response were performed through the invasive whole body plethysmography. We found that the curative treatment with IL-13PE dramatically inhibited the lung function in silicotic mice, including increased resistance and the elastance, and the response of airway hyperreactivity to methacholine broncoconstrictor agent. In agreement, when silicotic mice were treated with IL-13PE a marked reduction in the inflammatory component and the pulmonary fibrotic response were noted, attested by the decrease in the collagen production, as well as laminin and fibronectin and significant reduction in the area of granuloma. Similarly, cytokines (TNF-α and TGF-) and chemokines (MIP-1α, MIP-2, TARC, IP-10, MDC) found in increased levels in the lungs of silicotic mice were sensitive to the IL-13PE treatment. In conclusion, our results show that the curative administration of IL- 13PE was able to inhibit the inflammatory and fibrotic components of the chronic phase of the silicosis in mice, which is clearly reflected by the impairment of lung function. Thus, together our findings indicate that the use of IL-13PE appears to be a very promising therapeutic approach in cases of fibrotic diseases such as silicosis.