Quercetin Accelerates Resolution of Lung Pathological Changes Caused by Silica Particles in Mice

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RATIONALE: Silicosis is a chronic lung disease caused by inhalation of silica particles, which is characterized by fibrosis and granuloma formation. There is no treatment for silicosis. Quercetin is a flavonoid widely found in nature that is known by its antioxidant and anti-inflammatory activities. We evaluated the therapeutic activity of quercetin in the experimental model of silicosis in mice. METHODS: Male Swiss-Webster mice were instilled with intranasal silica (10 mg/50 L) and quercetin was administered orally (2.5 -10 mg/kg) for 7 consecutive days, starting 21 days post-silica. The analyses were performed 24 h after the last dose and included: leukocyte infiltration, collagen deposition and granuloma formation evaluated in the lung tissue by classical histology (H&E and Picrus sirius). Cytokines were measured by ELISA. Pulmonary mechanics and airways hyperreactivity to methacholine were measured by invasive plethismography (DSI Finepoint). RESULTS: Silicotic mice exhibited an increased lung resistance and elastance, as well as airways hyper-reactivity. The presence of inflammatory cell infiltration, fibrosis and extensive collagen deposition and granuloma formation in silicotic lungs were also noted. Levels of cytokines (IL-1, TNF- and IL-6) and chemokines (KC, MIP-1a, MIP-2 and MCP-1) as well as reactive oxygen species and altered activity of oxidative stress enzymes. Oral therapeutic administration of quercetin to silicotic mice reversed lung inflammation and fibrosis as well as cytokine and chemokine generation. Quercetin showed antioxidant properties as attested by reduction ROS, isoprostane and MDA levels as well as SOD and GPx and NOX4 enzymes. Treatment with the classical antioxidant compound N-acetylcysteine (NAC) showed similar anti-inflammatory suppressive effects including inhibition of mediators and enzymes associated with oxidative stress, but not NOX-4. By means of in vitro assays, we noted that quercetin inhibited IL-13-induced lung fibroblast activation, a response also noted after NOX-4 knockdown in these cells. CONCLUSION: Our findings show that oral administration of quercetin is effective in inhibiting decreased lung function and hyperreactivity in silicotic mice, in correlation with the blockade of inflammation and fibrosis, by a mechanism that seems dependent on the blockade of NOX-4 enzyme. This is an indication that quercetin is a potential pharmacological tool to be used therapeutically in the treatment of fibrotic lung diseases such as silicosis.

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