Comprehensive toxioological assessment of fibrous particles by differential gene expression.

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The present study was designed to study differences in biological responses of alveolar macrophages between phagocytosis of he spherical and fibrous particles. Although titanium dioxide is thought to be biologidlay inert, the cytotoxicity of fibrous titanium dioxide (FTiO2) was much higher than spherical TiO2 (STiO2). Differential display and the following Northern blot analysis indicated that transcription of krox2O/egr-2 gene was slightly and greatly upregulated in S and F-TiO2-exposed alveolar macrophages, repectively. The mRNA level of krox20/egr-2 ineased up to 8 hr, when alveolar macrophages were exposed to FTiO2. Quite interestingly the krox20/egr-2 mRNA level was transiently increased, when alveolar macrophages were plated into the culture dish. The analysis with 5' rapid amplification of cDNA ends (5'TACE) suggested that there is a heterogeneity in the upstream region of this gene (Krox20/egr-2 and krox20H1 ; acassion numbers AB032120 and AB032419, respectively). The PCR analysis with specific primers for krox-20/egr-2 and krox20H1 indicated that both genes were almost equally upregulated following either adhesion to the plastic dish or phagocytosis of FTiO2. Picetannol, a Syk kinase inhibitor, completely inhibited the krox20/egr-2 gene expression. These results suggest that tyrosine phosphorylation is implicated in adhesion and phagocytosis of alveolar macrophages, and the expression of krox20/egr-2 may reflect interaction of alveolar macrophages with foreign substances.