Citation:

BECK-SPEIER, I., U. P. KODAVANTI, M. SCHLADWEILER, M. SEMMLER, AND W. KREYLING. FE2O3 PARTICLE-INDUCED PROSTAGLANDIN E2 (PGE2) SYNTHESIS IN ALVEOLAR MACROPHAGES (AM) DETERMINES PARTICULATE INFLAMMATORY POTENTIAL. Presented at European Respiratory Society Annual Congress 2005, Copenhagen, DENMARK, September 17 - 21, 2005.

Description:

As shown by epidemiologic studies, acute exposure to ambient particles is associated with exacerbation of pulmonary and cardiovascular diseases. Metals associated with particles are able to mediate lung injury via oxidant-catalyzed reactions. However, the underlying mechanism is not well characterized. To study the inflammatory potential of metal-containing particles, we exposed WKY and hypertensive SH rats with Fe2O3 particles of 1.5 �m and of 0.5 �m geometric mean diameter by intratracheal instillation. In addition, alveolar macrophages (AMs) as key regulatory cells of the pulmonary immune system were exposed in-vitro to the same particles and studied for activation and mediator release. In the lungs of WKY rats 1.5 �m particles (4 mg/kg) induced an inflammatory response indicated by influx of neutrophils, increased vascular permeability, cell injury and slight increase of glutathione, whereas 0.5 �m particles were less effective. SH rats responded similarly after particle exposure. AMs of both rat strains were not affected in-vitro by the particles in activation parameters including production of reactive oxygen species, phagocytic uptake of zymosan and cytokine release such as interleukin 6 (IL-6). To study the underlying mechanism, WKY AMs (106cells/ml) were exposed in-vitro to the particles (10 �g/ml) for 24 h at 37�C, and analyzed for IL-6 release and prostaglandin E2 synthesis by specific ELISAs. 1.5 �m Particles elicited an increased release of IL-6 (1.8 fold) with a concomitant increase in intracellular PGE2 formation (1.9-fold). 0.5 �m Particles did not significantly enhance IL-6 release (1.4-fold) but increased strongly intracellular PGE2 synthesis (2.5-fold). Co-stimulation of cells with interferon � resulted in a similar reaction pattern. Inhibition of COX pathway and PGE2 synthesis by indomethacin elevated significantly IL-6 release from particle-treated cells (up to 3-fold). In conclusion, 1.5 �m particles with a small surface area of 7.1 m2/g induced more cytokine release and less PGE2 formation than 0.5 �m particles with a larger surface area of 16.7 m2/g, which did not alter IL-6 release but stimulated PGE2 synthesis in AMs. This inverse relationship between pro-inflammatory cytokine release and immune-modulating PGE2 is dependent on the surface area of the particles and determines their biologic effect including an inflammatory potential. (Does not reflect US EPA policy).

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