title: Soluble iron modulates iron oxide particle-induced inflammatory responses via prostaglandin E(2 )synthesis: In vitro and in vivo studies.
abstract: 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 mum 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 mum and 0.0016 +/- 0.0012 d(-1 )for 1.5 mum (59)Fe(2)O(3 )particles. AM exposed in vitro to 1.5 mum particles (10 mug/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 mum 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 mum particles (up to 3-fold; p < 0.005). In the rat lungs, 1.5 but not 0.5 mum 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.
authors.affiliation: Comprehensive Pneumology Center, Institute of Lung Biology and Disease, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Beck-Speier
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Kreyling
authors.forename: Konrad L
authors.initials: KL
authors.lastname: Maier
authors.forename: Niru
authors.initials: N
authors.lastname: Dayal
authors.forename: Mette C
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: Paula
authors.initials: P
authors.lastname: Mayer
authors.forename: Manuela
authors.initials: M
authors.lastname: Semmler-Behnke
authors.forename: Urmila P
authors.initials: UP
authors.lastname: Kodavanti