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Soluble Iron in Alveolar Macrophages Modulates Iron Oxide Particle-Induced Inflammatory Response via Prostaglandin E2 Synthesis
Beck-Speier, I., W. Kreyling, K. L. Maier, N. Dayal, M. SCHLADWEILER, M. Semmler-Behne, AND U. P. KODAVANTI. Soluble Iron in Alveolar Macrophages Modulates Iron Oxide Particle-Induced Inflammatory Response via Prostaglandin E2 Synthesis. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 22(6):34, (2009).
Our study demonstrates that increased intracellular soluble iron modulates Fe2O3 particle-induced IL-6 release and inflammatory response via PGE2 production by alveolar macrophages. This is based on the evidence that greater solubility of 0.5 µm particles resulting in higher intracellular soluble iron was associated with higher PGE2 production and suppressed IL-6 release when compared to 1.5 µm particles. This conclusion is further supported by the fact that rats intratracheally instilled with 1.5 but not 0.5 µm Fe2O3 particles demonstrated lung neutrophilic inflammation. The suppressive effect of intracellularly released soluble iron on particle-induced inflammation has implication on how ambient PM-associated but soluble metals influence pulmonary toxicity of ambient PM. This work supports two health initiatives of PM. Identification of the mechanisms of PM health effects and causative components.
Ambient particulate matter (PM)-associated metals have been shown to play an important role in cardiopulmonary health outcomes. To study the modulation of inflammation by PM-associated soluble metal, we investigated intracellular solubility of radiolabelled iron oxide (59Fe2O3) particles of 0.5 and 1.5 µm geometric mean diameter. Further, Fe2O3 particles were examined for the release of interleukin 6 (IL-6) as pro-inflammatory and prostaglandin E2 (PGE2) as anti-inflammatory marker in cultured Wistar Kyoto (WKY) rat alveolar macrophages (AMs). We also exposed male WKY rats to monodispersed Fe2O3 particles by intratracheal instillation (0, 1.3 or 4.0 mg/kg body weight) to examine in vivo inflammation. Particles of both sizes are insoluble extracellularly but moderately soluble in AMs with an intracellular dissolution rate of 0.0037 ± 0.0014 d-1 for 0.5 and 0.0016 d-1 for 1.5 µm 59Fe2O3 particles. AMs 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 PGE2 synthesis (1.9-fold; p < 0.01). By contrast, 0.5 µm particles did not enhance IL-6 but strongly increased PGE2 synthesis (2.5-fold, p < 0.01). Inhibition of PGE2 synthesis by indomethacin caused a proinflammatory phenotype as noted by increased IL-6 release from AMs exposed to 0.5 µm particles (up to3-fold; p < 0.05). In the rat lungs, 1.5 but not 0.5 µm particles (4.0 mg/kg) induced an influx of neutrophils and increased vascular permeability. In conclusion, intracellular soluble iron modulates Fe2O3 particle-induced neutrophilic inflammatory response in vivo and proinflammatory cytokine release in vitro by modulating PGE2 synthesis.