Microarray analysis of gene expression in lung tissues of indium-exposed rats: possible roles of S100 proteins in...

Indium compounds are used in manufacturing displays of mobile phones and televisions. These compounds cause interstitial pneumonia in workers and lung cancer in animals, but their precise mechanisms are unclear. In this study, we performed microarray analysis of gene expression in lung tissues of indium-exposed rats. Male Wistar rats (8-week-old) were exposed to indium oxide (In₂O₃, mean particle diameter 0.14 μm) and indium-tin oxide (ITO, mean particle diameter 0.95 μm) by intratracheal instillation (10 mg indium/kg body weight/instillation) twice a week and five times in total. These rats were sacrificed immediately, 3 weeks and 12 weeks after the last instillation. Hematoxylin and eosin and Masson's trichrome staining showed that indium compounds induced infiltration of neutrophils and macrophages into alveolar space, and fibrosis around bronchial epithelium and in alveolar wall. Microarray analysis revealed that In₂O₃ and ITO significantly upregulated 233 and 676 genes at 12 weeks, respectively (> twofold, p < 0.05 by ANOVA + Tukey's test). In₂O₃ and ITO largely upregulated Lcn2 (lipocalin-2) (49.4- and 91.8-fold), S100a9 (30.2- and 46.5-fold) and S100a8 (11.5- and 22.0-fold), respectively. Metascape database predicted that these genes participate in immunomodulatory and inflammatory responses. Real-time PCR confirmed that these genes were upregulated by indium compounds throughout the experiments. In Western blotting, S100A9 expression was significantly increased by indium exposure, whereas LCN2 expression was only slightly increased. Fluorescent immunohistochemistry revealed that S100A9 and S100A8 were expressed in alveolar epithelial cells and neutrophils in indium-exposed rats. These results suggest that S100 proteins contribute to indium-induced lung diseases via neutrophil-mediated inflammatory responses.