Role of HMGB1 in silica-induced inflammation and fibrogenesis in mouse lungs.
Joseph-LB; Cervelli-JA; Elzind-DA; Bremer-NM; Kim-Y; Castranova-V; Laskin-JD; Laskin-DL
Toxicologist 2010 Mar; 114(1):354-355
Occupational exposure to silica is known to cause small airway disease and fibrosis. Silica-induced oxidative stress at the particle surface is thought to contribute to these pathologies. Oxidative stress activates the beta-catenin signaling pathway which is important in mediating cellular proliferation, a key step in fibrogenesis. When activated, beta-catenin translocates into the nucleus where it binds to high mobility group box-1 (HMGB1), a chromosomal protein regulating expression of genes controlling cellular proliferation. Evidence suggests that HMGB1 is also passively released from necrotic cells where it binds to receptor for advanced glycation end products (RAGE) on macrophages and stimulates inflammatory mediator production. In the present studies, we analyzed the potential role of HMGB1 in silica induced inflammation and fibrogenesis. C57BL/6J mice were treated with silica (1 mg/kg Min-U-Sil 5) by aspiration. After 7 d, we found that silica administration resulted in increased expression of cycloxygenase-2 and inducible nitric oxide synthase in the lung, enzymes mediating the production of proinflammatory/cytotoxic prostaglandins and reactive nitrogen species. This was associated with increased expression of HMGB1 in macrophages and the appearance of soluble RAGE in bronchoalveolar lavage. We also found that Wnt1 and nuclear beta-catenin protein expression were upregulated in the lung of silica-treated animals, while glycogen synthase kinase-beta3 (GSK-beta3), which functions to negatively regulate beta-catenin signaling, was down regulated. This was correlated with increased proliferating cell nuclear antigen staining in the lung and the development of fibrotic lesions. These data suggest that HMGB1 and downstream signaling pathways may be important in both silica-induced inflammation and fibrosis.
Airborne-particles; Biological-effects; Cell-biology; Cellular-reactions; Chemical-hypersensitivity; Chemical-reactions; Cytotoxic-effects; Cytotoxicity; Exposure-assessment; Exposure-levels; Exposure-methods; Fibrogenesis; Fibrogenicity; Fibrous-bodies; Genes; Genetic-factors; Inhalation-studies; Laboratory-animals; Laboratory-testing; Lung-disorders; Lung-irritants; Occupational-diseases; Occupational-exposure; Particulates; Pulmonary-disorders; Pulmonary-system; Pulmonary-system-disorders; Respiratory-irritants; Respiratory-system-disorders; Toxins
The Toxicologist. Society of Toxicology 49th Annual Meeting and ToxExpo, March 7-11, 2010, Salt Lake City, Utah