The role of cardiovascular disease-associated iron overload in Libby amphibole-induced acute pulmonary injury and inflammation

Abstract

Pulmonary toxicity induced by asbestos is thought to be mediated through redox-cycling of fiber-bound and bioavailable iron (Fe). We hypothesized that Libby amphibole (LA)-induced cute lung injury will be exacerbated in rat models of cardiovascular disease (CVD)-associated Fe-overload and oxidative stress. Healthy male Wistar Kyoto (WKY), spontaneously hypertensive (SH) and SH heart failure (SHHF) rats were intratracheally instilled with 0.0, 0.25 or 1.0 mg/rat LA and examined at 1 day, 1 week or 1 month. Although histologically it was not possible to distinguish severity differences between strains in LA-induced initial inflammation and later fibrosis, quantitative assessment of biomarkers showed strain-related differences. LA-induced neutrophilic inflammation was reversible in WKY but persisted more in SH and SHHF. Lung MIP-2 mRNA increased only in WKY at 1 day in response to LA but not in SH and SHHF. Bronchoalveolar lavage fluid (BALF) protein increased in SH but not WKY at 1 week and 1 month, while γ-glutamyltransferase and N-acetyl-β-D-glucosaminidase activities increased in all strains (WKY>SH=SHHF). BALF ferritin levels were high at baseline and increased following LA exposure only in SH and SHHF. Ferritin heavy chain mRNA increased only in SHHF at 1 day. At 1 month ferritin light chain mRNA declined from already high baseline levels in SHHF but increased in WKY and SH suggesting its differential involvement in LA-induced injury in Fe-overload. Unlike WKY, both SHHF and SH failed to increase the lung lining antioxidant, ascorbate, in response to LA. We conclude that underlying CVD-associated Fe-overload is likely linked to persistent lung injury, inflammation and antioxidant decompensation following LA exposure in rats.

Keywords::

• Libby Amphibole
• Iron
• Inflammation

Acknowledgements

We thank Dr. Stephen Wilson and Dr. Gregory Meeker of the US Geological Survey, Denver, CO, for collection, preparation, and provision of the raw LA 2007 sample used in these studies. We also thank Dr. Denise MacMillan, Mr. Scott Rhoney and Mr. Jermaine Ford of the US EPA for analysis of ascorbic acid in lung tissue and lavage fluid samples. Finally, we thank Drs. Aimen Farraj and Maureen Gwinn of the US EPA, and the members of the Libby Action Team for their review of the manuscript.

Declaration of interest

This work was supported by EPA/UNC Toxicology Research Program, Training Agreement CR833237, with the Curriculum in Toxicology, University of North Carolina at Chapel Hill.