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

Abstract

BackgroundAmbient 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 (59Fe2O3) particles of 0.5 and 1.5 μm geometric mean diameter. Fe2O3 particles were examined for the induction of the release of interleukin 6 (IL-6) as pro-inflammatory and prostaglandin E2 (PGE2) 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.ResultsParticles 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 59Fe2O3 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 PGE2 synthesis (1.9-fold; p < 0.01). By contrast, 0.5 μm particles did not enhance IL-6 release but strongly increased PGE2 synthesis (2.5-fold, p < 0.005). Inhibition of PGE2 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.ConclusionsFe2O3 particle-induced neutrophilic inflammatory response in vivo and pro-inflammatory cytokine release in vitro might be modulated by intracellular soluble iron via PGE2 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.

Intracellular fate of carbon nanotubes inside murine macrophages: pH-dependent detachment of iron catalyst nanoparticles

“…Such event could have severe consequences in case of interaction with DNA [32], as suggested by the activation of p53 and H2AX pathways in our experimental settings, and could therefore explain the genotoxic effects often associated with CNT exposure [33-37]. Interestingly, iron oxide particles have been shown to dissolve inside murine alveolar macrophages [38], suggesting a potential additional mechanism of toxicity related to the interaction of soluble iron with proteins. However, since the intracellular levels of the iron storage protein H-Ferritin were not increased in SWCNT-exposed macrophages, the generation of ionic iron from the detached iron nanoparticles seems unlikely, at least within the timeframe of exposure used here.…”

Ultrafine particles affect the balance of endogenous pro- and anti-inflammatory lipid mediators in the lung: in-vitro and in-vivo studies

“…The cell homogenates were centrifuged at 10,000 x g for 15 min at 4°C. The supernatants were taken for measurements of protein and lipid mediators [25,26]. Analysis of the cell lysates is a reliable tool to quantify the parameters in each sample [25].…”

Human inhalation exposure to iron oxide particles

“…The observed oxidative stress and inflammation could be due to free iron released from the particles. Although iron oxides are relatively insoluble in aqueous conditions, Beck-Speier et al reported that Fe 2 O 3 particles can dissolve in the acidic lysosomal environment after phagocytosis by alveolar macrophages [27]. However, they also report that the intracellular free iron may suppress particle induced inflammation since the level of inflammatory marker IL-6 was not significantly elevated.…”

“…A characterization of welding fumes conducted by Jenkins determined the presence of magnetite (Fe 3 O 4 ) in the GMAW process and MnFe 2 O 4 in the SMAW process [25]. A more recent welding fume characterization study assessed the components of arc welding fume and found three crystalline phases of iron: Fe 0 , FeO and Fe 3 O 4 [27]. It is important to note that characterization of welding fumes has confirmed the presence of nanosized iron oxide particles, providing likely evidence for occupational exposure to inhaled particles of this size [25,28].…”