Abstract
Silicosis is an occupational disease triggered by the inhalation of fine particles of crystalline silica and characterized by inflammation and scarring in the form of nodular lesions in the lungs. In spite of the therapeutic arsenal currently available, there is no specific treatment for the disease. Flunisolide is a potent corticosteroid shown to be effective for controlling chronic lung inflammatory diseases. In this study, the effect of flunisolide on silica-induced lung pathological changes in mice was investigated. Swiss-Webster mice were injected intranasally with silica particles and further treated with flunisolide from day 21 to 27 post-silica challenge. Lung function was assessed by whole body invasive plethysmography. Granuloma formation was evaluated morphometrically, collagen deposition by Picrus sirius staining and quantitated by Sircol. Chemokines and cytokines were evaluated using enzyme-linked immunosorbent assay. The sensitivity of lung fibroblasts was also examined in in vitro assays. Silica challenge led to increased leukocyte numbers (mononuclear cells and neutrophils) as well as production of the chemokine KC/CXCL-1 and the cytokines TNF-α and TGF-β in the bronchoalveolar lavage. These alterations paralleled to progressive granuloma formation, collagen deposition and impairment of lung function. Therapeutic administration of intranasal flunisolide inhibited granuloma and fibrotic responses, noted 28 days after silica challenge. The upregulation of MIP-1α/CCL-3 and MIP-2/CXCL-2 and the cytokines TNF-α and TGF-β, as well as deposition of collagen and airway hyper-reactivity to methacholine were shown to be clearly sensitive to flunisolide, as compared to silica-challenge untreated mice. Additionally, flunisolide effectively suppressed the responses of proliferation and MCP-1/CCL-2 production from IL-13 stimulated lung fibroblasts from silica- or saline-challenged mice. In conclusion, we report that intranasal treatment with the corticosteroid flunisolide showed protective properties on pathological features triggered by silica particles in mice, suggesting that the compound may constitute a promising strategy for the treatment of silicosis.
Highlights
Silicosis is a work-related and occupational disease caused by long-term exposure to inhaled dust containing crystalline silica particles which can progress to severe lung inflammation and fibrosis [1]
Flunisolide inhibited granuloma formation and collagen deposition induced by silica in the mouse lungs
This effect appeared related to the decrease in the content of F4/80 and α-smooth muscle actin (α-SMA) positive cells in the lungs, which paralleled with reduction of pro-inflammatory and pro-fibrotic cytokines and chemokines
Summary
Silicosis is a work-related and occupational disease caused by long-term exposure to inhaled dust containing crystalline silica particles which can progress to severe lung inflammation and fibrosis [1]. There are three forms of silicosis (acute, accelerated, and chronic) dependent on the amount and time of silica particle exposure [2], which can be complicated by increased risk of infections [3] and/or chronic obstructive pulmonary disease [4]. It became a greater public health problem worldwide after the Industrial Revolution, which increased dust levels and the number of workers exposed around the world [5]. Since no effective treatment exists for silicosis currently, new therapies are badly needed in this field [1]
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