Soluble iron modulates iron oxide particle-induced inflammatory responses via prostaglandin E 2 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 ( 59 Fe 2 O 3 ) particles of 0.5 and 1.5 μm geometric mean diameter. Fe 2 O 3 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 Fe 2 O 3 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 μm and 0.0016 ± 0.0012 d -1 for 1.5 μm 59 Fe 2 O 3 particles. AM exposed in vitro to 1.5 μm particles (10 μg/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 μm 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 μm particles (up to 3-fold; p < 0.005). In the rat lungs, 1.5 but not 0.5 μm particles (4.0 mg/kg) induced neutrophil influx and increased vascular permeability. Conclusions Fe 2 O 3 particle-induced neutrophilic inflammatory response in vivo and pro-inflammatory 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.