Soluble iron modulates iron oxide particle-induced inflammatory responses via prostaglandin E2 synthesis: In vitro and in vivo studies

Background: Ambient particulate matter (PM)-associated metals have been shown to play an important role in cardiopulmonary health outcomes. To study the modulation of PM-induced inflammation by leached off metals, we investigated intracellular solubility of radio-labeled iron oxide ((Fe2O3)-Fe-59) particles of 0.5 and 1.5 mu m geometric mean diameter. Fe2O3 particles were examined for the induction of the release of interleukin 6 (IL-6) as pro-inflammatory and prostaglandin E-2 (PGE(2)) as anti-inflammatory markers in cultured alveolar macrophages (AM) from Wistar Kyoto (WKY) rats. In addition, we exposed male WKY rats to monodispersed Fe2O3 particles by intratracheal instillation (1.3 or 4.0 mg/kg body weight) to examine in vivo inflammation. Results: Particles of both sizes are insoluble extracellularly in the media but moderately soluble in AM with an intracellular dissolution rate of 0.0037 +/- 0.0014 d(-1) for 0.5 mu m and 0.0016 +/- 0.0012 d(-1) for 1.5 mu m (Fe2O3)-Fe-59 particles. AM exposed in vitro to 1.5 mu m particles (10 mu g/mL) for 24 h increased IL-6 release (1.8-fold; p < 0.05) and also PGE(2) synthesis (1.9-fold; p < 0.01). By contrast, 0.5 mu m particles did not enhance IL-6 release but strongly increased PGE(2) synthesis (2.5-fold, p < 0.005). Inhibition of PGE(2) synthesis by indomethacin caused a pro-inflammatory phenotype as noted by increased IL-6 release from AM exposed to 0.5 mu m particles (up to 3-fold; p < 0.005). In the rat lungs, 1.5 but not 0.5 mu m particles (4.0 mg/kg) induced neutrophil influx and increased vascular permeability. Conclusions: Fe2O3 particle-induced neutrophilic inflammatory response in vivo and proinflammatory cytokine release in vitro might be modulated by intracellular soluble iron via PGE(2) synthesis. The suppressive effect of intracellular released soluble iron on particle-induced inflammation has implications on how ambient PM-associated but soluble metals influence pulmonary toxicity of ambient PM.