Inflammation and fibrosis in the present study. Given a previous report

Inflammation and fibrosis in the ASP-015K site present study. Given a previous report showing that doxycycline suppressed fibrosis in a beomycininduced lung injury/fibrosis model through the inhibition of MMP production [21], we used UBC-GFP transgenic mice to study theeffect of doxycycline on silica-induced lung fibrosis. The lungs of the silica-exposed doxycycline-treated mice showed similar levels of inflammation, granuloma formation, and collagen deposition compared with the distilled water-treated mice in both the D15 and D30 groups (Figure S3). These data suggest that the doxycycline that was used for the overexpression of hApoA1 did not contribute to the inhibition of lung inflammation and fibrosis in our silica-induced lung fibrosis model. Silica deposits in the lung cause a persistent, toxic, and inflammatory response, including the alveolar accumulation of macrophages and neutrophils [26]. We found that in the ApoA1_D7 and D15 groups, lung mRNA levels of the proinflammatory mediators KC, MIP-2 and MCP-1, which are known to recruit neutrophils and macrophages to inflamed sites, were significantly decreased compared to those of the silica group (Fig. 7). We also observed abundant silica particles without inflammatory cell accumulation in the airspaces of the ApoA1_D7 and D15 mice, indicating that ApoA1 overexpression in the airspace reduced silica-induced inflammatory cell accumulation and silica nodule formation, despite the presence of silica particles in the lung. We speculate that ApoA1 inhibited the accumulation and migration of alveolar inflammatory cells, particularly macrophages and neutrophils. A decrease in the number or activity of inflammatory cells could account for the observed reduction in the level of TGF-b1, which can induce mesenchymal cell proliferation and extracellular collagen deposition in fibrosis [30]. There areApoA1 Attenuated Silica Induced Lung Fibrosisother possible mechanisms for the protective and therapeutic effect of ApoA1 including, an anti-oxidative effect [4] against silicainduced oxidant stress, a direct anti-inflammatory effect of ApoA1 on silica particles since ApoA1 is known to bind to silica particles leading to repression of the inflammatory cytokine and chemokine responses [31]. However, these findings should be validated in further studies. Lipid mediators participate in the resolution of inflammation and the return to homeostasis in inflamed tissues [32]. LXA4 is a potent anti-inflammatory lipid mediator [33]. In the present study, LXA4 levels were increased in the lung and BAL fluid of ApoA1_D15 mice, suggesting that ApoA1 regulates inflammationrelated lipid mediators. The reduction in established silicosis in the lungs of the ApoA1_D7 and D15 mice may be explained in part by the increase in LXA4 activity. Lipoxins are biologically active Eliglustat web eicosanoids with anti-inflammatory properties that are produced by lipoxygenases at sites of inflammation [33,34]. LXA4 has been reported to inhibit leukocyte trafficking by attenuating the release of pro-inflammatory cytokines and chemokines such as TNF-a, IL-8, and macrophage inflammatory protein-2 by inflammatory cells [35,36,37]. In addition to its anti-inflammatory activity, LXA4 stimulates neutrophils to phagocytize apoptotic cells without the release of pro-inflammatory cytokines [38,39], thereby leading to the resolution of inflammation. Exogenous resolvin E1 was recently shown 1407003 to regulate LXA4 in resolving established airway inflammation in an ovalbumin-.Inflammation and fibrosis in the present study. Given a previous report showing that doxycycline suppressed fibrosis in a beomycininduced lung injury/fibrosis model through the inhibition of MMP production [21], we used UBC-GFP transgenic mice to study theeffect of doxycycline on silica-induced lung fibrosis. The lungs of the silica-exposed doxycycline-treated mice showed similar levels of inflammation, granuloma formation, and collagen deposition compared with the distilled water-treated mice in both the D15 and D30 groups (Figure S3). These data suggest that the doxycycline that was used for the overexpression of hApoA1 did not contribute to the inhibition of lung inflammation and fibrosis in our silica-induced lung fibrosis model. Silica deposits in the lung cause a persistent, toxic, and inflammatory response, including the alveolar accumulation of macrophages and neutrophils [26]. We found that in the ApoA1_D7 and D15 groups, lung mRNA levels of the proinflammatory mediators KC, MIP-2 and MCP-1, which are known to recruit neutrophils and macrophages to inflamed sites, were significantly decreased compared to those of the silica group (Fig. 7). We also observed abundant silica particles without inflammatory cell accumulation in the airspaces of the ApoA1_D7 and D15 mice, indicating that ApoA1 overexpression in the airspace reduced silica-induced inflammatory cell accumulation and silica nodule formation, despite the presence of silica particles in the lung. We speculate that ApoA1 inhibited the accumulation and migration of alveolar inflammatory cells, particularly macrophages and neutrophils. A decrease in the number or activity of inflammatory cells could account for the observed reduction in the level of TGF-b1, which can induce mesenchymal cell proliferation and extracellular collagen deposition in fibrosis [30]. There areApoA1 Attenuated Silica Induced Lung Fibrosisother possible mechanisms for the protective and therapeutic effect of ApoA1 including, an anti-oxidative effect [4] against silicainduced oxidant stress, a direct anti-inflammatory effect of ApoA1 on silica particles since ApoA1 is known to bind to silica particles leading to repression of the inflammatory cytokine and chemokine responses [31]. However, these findings should be validated in further studies. Lipid mediators participate in the resolution of inflammation and the return to homeostasis in inflamed tissues [32]. LXA4 is a potent anti-inflammatory lipid mediator [33]. In the present study, LXA4 levels were increased in the lung and BAL fluid of ApoA1_D15 mice, suggesting that ApoA1 regulates inflammationrelated lipid mediators. The reduction in established silicosis in the lungs of the ApoA1_D7 and D15 mice may be explained in part by the increase in LXA4 activity. Lipoxins are biologically active eicosanoids with anti-inflammatory properties that are produced by lipoxygenases at sites of inflammation [33,34]. LXA4 has been reported to inhibit leukocyte trafficking by attenuating the release of pro-inflammatory cytokines and chemokines such as TNF-a, IL-8, and macrophage inflammatory protein-2 by inflammatory cells [35,36,37]. In addition to its anti-inflammatory activity, LXA4 stimulates neutrophils to phagocytize apoptotic cells without the release of pro-inflammatory cytokines [38,39], thereby leading to the resolution of inflammation. Exogenous resolvin E1 was recently shown 1407003 to regulate LXA4 in resolving established airway inflammation in an ovalbumin-.