The role of iron in Libby amphibole-induced acute lung injury and inflammation

Our plain-English summary of The role of iron in Libby amphibole-induced acute lung injury and inflammation, by J.H. Shannahan, A.J. Ghio, M.C. Schladweiler, et al (Inhalation Toxicology, 2011).

The study

• Authors: J.H. Shannahan, A.J. Ghio, M.C. Schladweiler, J.K. McGee, J.H. Richards, S.H. Gavett, U.P. Kodavanti
• Journal: Inhalation Toxicology
• Published: 2011;23(6):313-23
• Cited by: 17 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Complexation of host iron (Fe) on the surface of inhaled asbestos fibers has been postulated to cause oxidative stress contributing to in vivo pulmonary injury and inflammation. We examined the role of Fe in Libby amphibole (LA; mean length 4.99 µm ± 4.53 and width 0.28 µm ± 0.19) asbestos-induced inflammogenic effects in vitro and in vivo. LA contained acid-leachable Fe and silicon. In a cell-free media containing FeCl(3), LA bound #17 µg of Fe/mg of fiber and increased reactive oxygen species generation #3.5 fold, which was reduced by deferoxamine (DEF) treatment. In BEAS-2B cells exposure to LA, LA loaded with Fe (FeLA), or LA with DEF did not increase HO-1 or ferritin mRNA expression. LA increased IL-8 expression, which was reduced by Fe loading but increased by DEF. To determine the role of Fe in LA-induced lung injury in vivo, spontaneously hypertensive rats were exposed intratracheally to either saline (300 µL), DEF (1 mg), FeCl(3) (21 µg), LA (0.5 mg), FeLA (0.5 mg), or LA + DEF (0.5 mg). LA caused BALF neutrophils to increase 24 h post-exposure. Loading of Fe on LA but not chelation slightly decreased neutrophilic influx (LA + DEF > LA > FeLA). At 4 h post-exposure, LA-induced lung expression of MIP-2 was reduced in rats exposed to FeLA but increased by LA + DEF (LA + DEF > LA > FeLA). Ferritin mRNA was elevated in rats exposed to FeLA compared to LA. In conclusion, the acute inflammatory response to respirable fibers and particles may be inhibited in the presence of surface-complexed or cellular bioavailable Fe. Cell and tissue Fe-overload conditions may influence the pulmonary injury and inflammation caused by fibers.

In plain English

This laboratory study tested whether iron (Fe) bound to Libby amphibole (LA) asbestos increases its ability to cause oxidative stress and inflammation. The authors measured leachable metals on LA, its binding of exogenous ferric chloride and oxidant generation in cell-free systems, then exposed human bronchial epithelial (BEAS-2B) cells and male spontaneously hypertensive rats (intratracheal instillation, n = 8 per group, sampled 4 h and 24 h later) to LA, Fe-loaded LA (FeLA), or LA with the chelator deferoxamine (DEF). LA carried small amounts of water- and acid-leachable Fe and silicon and bound about 16.6 µg Fe per mg of fiber; Fe loading raised cell-free reactive oxygen species 3.5-fold, and DEF lowered it. In cells, LA raised IL-8 mRNA; Fe loading of the fiber or of the cells lowered this induction, while DEF raised it. In rats, LA increased lavage neutrophils and lung MIP-2, with the ordering LA + DEF greater than LA greater than FeLA, and FeLA raised ferritin heavy chain mRNA.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Experimental laboratory study combining cell-free (acellular) chemistry, in vitro human cell exposures, and an in vivo rat instillation experiment
• Who was studied: BEAS-2B human bronchial epithelial cells (n = 9 per treatment group) and male, 11- to 12-week-old spontaneously hypertensive (SH) rats (n = 8 per group), studied at a U.S. EPA laboratory
• Exposure: Libby amphibole (LA) asbestos, water-elutriated respirable fraction from the 2007 Rainy Creek Complex sample (mean length 4.99 µm ± 4.53, width 0.28 µm ± 0.19), given alone, loaded with iron (FeLA), or with the iron chelator deferoxamine; comparison exposures were saline, FeCl3 and DEF alone
• Main results:
  • Only a very small amount of iron was leachable from the LA surface with saline (6.04 ± 2.96 ng Fe/mg LA), rising roughly 100-fold with 1 M HCl
  • Incubation with FeCl3 bound about 16.6 µg Fe per mg of LA fiber, not removed by three water washes
  • In the cell-free system, deferoxamine cut LA-generated reactive oxygen species by about half, while iron loading of LA increased generation 3.5-fold
  • In BEAS-2B cells, LA caused no change in cytotoxicity at any concentration tested (50, 100, 200 µg/mL) at 4 h
  • In BEAS-2B cells, LA significantly induced IL-8 mRNA, and loading iron onto the fiber reduced that induction
  • In BEAS-2B cells, adding deferoxamine to LA increased IL-8 expression above LA alone, whereas preloading cells with iron decreased LA-induced IL-8
  • In rats at 24 h, neutrophils in lavage fluid were raised by all LA exposures versus saline, but were lower with FeLA than with LA alone
  • In rat lung at 4 h, MIP-2 mRNA induction was smaller with FeLA and larger with LA + DEF than with LA alone
  • In rat lung, ferritin heavy chain mRNA rose only in the Fe-loaded LA group, while HO-1 mRNA rose only after FeCl3; ferritin light chain was unchanged in all groups
  • In lavage fluid at 24 h, ferritin was raised by all LA treatments and transferrin was unchanged; heme rose with DEF and non-heme iron only with FeCl3
• The authors' conclusion: The authors concluded that LA binds iron and that this binding increases oxidant generation in a cell-free system, but that iron loading decreased LA's inflammatory effect in cells and in rats while chelation increased it, suggesting iron at moderate concentrations inhibits the fiber-induced inflammatory response
• Limitations the authors state:
  • The authors stated that the short exposure duration prevented them from examining whether endogenous iron keeps binding to LA fibers over time
  • The authors noted that intratracheal instillation produces an acute bolus response
  • The authors noted the LA fibers used were relatively short, so iron-binding processes might differ with longer fibers
  • The authors stated that real-time measurement of reactive oxygen species was technically challenging, so surrogate markers were used

Mines named here

Asbestos mines this study is about. Each mine's page says who ran it, when it worked, and what it produced.

• Libby vermiculite mine, Montana

All asbestos mines

Topics

Medical terms in this study, explained in our Lexicon: Libby amphiboles, Inflammation, Oxidative Stress, Reactive Oxygen Species (ROS), Ferritin, Respirable Fiber.

Related studies

• Acute phase response, inflammation and metabolic syndrome biomarkers of Libby asbestos exposure — J.H. Shannahan, O. Alzate, et al. (2012)
• Transcriptional activation of inflammasome components by Libby amphibole and the role of iron — J.H. Shannahan, A.J. Ghio, et al. (2012)
• Synthetic secoisolariciresinol diglucoside (LGM2605) inhibits Libby amphibole fiber-induced acute inflammation in mice — M. Christofidou-Solomidou, R.A. Pietrofesa, et al. (2019)
• Vascular and thrombogenic effects of pulmonary exposure to Libby amphibole — J.H. Shannahan, M.C. Schladweiler, et al. (2012)
• Long-term response of rats to single intratracheal exposure of Libby amphibole or amosite — J.M. Cyphert, D.J. Padilla-Carlin, et al. (2012)
• Disruption of iron homeostasis in mesothelial cells after talc pleurodesis — A.J. Ghio, J.M. Soukup, et al. (2012)

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