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.

• Authors: Jonathan Shannahan, Mette Schladweiler, Danielle Padilla-Carlin, Abraham Nyska, Judy Richards, Andrew Ghio, Stephen Gavett, Urmila Kodavanti
• Journal: Inhalation toxicology (Inhal Toxicol) Vol. 23 Issue 3 Pg. 129-41 (Feb 2011) ISSN: 1091-7691 [Electronic] England
• PMID: 21391781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Asbestos, Amphibole
• Biomarkers
• Chemokine CXCL2
• Cxcl2 protein, rat
• Particulate Matter
• RNA, Messenger
• Ferritins
• Ascorbic Acid

Topics

• Animals
• Asbestos, Amphibole (administration & dosage, toxicity)
• Asbestosis (metabolism, physiopathology)
• Ascorbic Acid (metabolism)
• Biomarkers (metabolism)
• Bronchoalveolar Lavage Fluid (chemistry, cytology)
• Cardiovascular Diseases (metabolism, physiopathology)
• Chemokine CXCL2 (genetics, metabolism)
• Dose-Response Relationship, Drug
• Ferritins (genetics, metabolism)
• Gene Expression Regulation (drug effects)
• Iron Overload (etiology, metabolism, physiopathology)
• Lung (drug effects, immunology, metabolism, pathology)
• Male
• Neutrophil Infiltration (drug effects)
• Neutrophils (drug effects)
• Oxidative Stress (drug effects)
• Particulate Matter (administration & dosage, toxicity)
• Pneumonia (chemically induced, metabolism, physiopathology)
• RNA, Messenger (metabolism)
• Rats
• Severity of Illness Index