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Transcriptional activation of inflammasome components by Libby amphibole and the role of iron
Citation:
Shannahan, J., A. J. GHIO, M. SCHLADWEILER, J. R. Richards, G. Knapp, D. Andrews, S. H. GAVETT, AND U. P. KODAVANTI. Transcriptional activation of inflammasome components by Libby amphibole and the role of iron. INHALATION TOXICOLOGY. Informa Healthcare USA, New York, NY, 24(1):60-9, (2012).
Impact/Purpose:
This manuscript shows that pulmonary inflammation induced by Libby amphibole in rats is mediated by activation of NALP3 inflammasome and IL-l beta activation. Presence of iron on fibers inhibits the inflammation and inflammasome activation likely via inhibiting ERK activation.
Description:
Recently it has been demonstrated that complexation of iron (Fe) on the surface of Libby amphibole (LA) fibers inhibits the acute pulmonary inflammation induced after exposure in epithelial cells and rats. The inflammatory effects of other asbestos fibers have been shown to involve activation ofthe inflammatory cascade through induction of the NALP3 inflammasome complex. We examined the ability of LA to induce the inflammasome cascade as well as the possible role of Fe in modulating LA-induced inflammasome activity. Spontaneously hypertensive rats were exposed intratracheally to either saline (300ul), DEF (1mg), FeCi3) (21ug), LA (O.5mg), FeLA (O.5mg), or LA+DEF (O.5mg). LA caused BALF neutrophils to increase at 24h after exposure, while loading of Fe on LA but not chelation inhibited this neutrophilic influx (LA+DEF>LA> FeLA). At 4h postexposure, LA increased lung expression o fmany genes related to the inflammasome including IL-lß, cathepsin B, NALP3, IL-6; and NFkBl, while Fe loading of LA inhibited the induction of these genes. Lung antioxidants at 4 h post-exposure at 24 h post-exposure were found to be unchanged. Phosphorylation of ERK but not MEK was increased at 4 h after LA exposure compared to controls, however Fe loading of LA slightly inhibited this activation of ERK. In conclusion, activation of the inflammasome contributes to the acute inflammatory response after LA exposure. Furthermore, activation of the inflammasome is inhibited in the presence of surface complexed Fe possibly through decreased ERK signaling.
