title: Subchronic pulmonary pathology, iron overload, and transcriptional activity after Libby amphibole exposure in rat models of cardiovascular disease.
abstract: BACKGROUND
  Surface-available iron (Fe) is proposed to contribute to asbestos-induced toxicity through the production of reactive oxygen species.
  
  
  OBJECTIVE
  Our goal was to evaluate the hypothesis that rat models of cardiovascular disease with coexistent Fe overload would be increasingly sensitive to Libby amphibole (LA)-induced subchronic lung injury.
  
  
  METHODS
  Male healthy Wistar Kyoto (WKY), spontaneously hypertensive (SH), and SH heart failure (SHHF) rats were intratracheally instilled with 0.0, 0.25, or 1.0 mg LA (with saline as the vehicle). We examined bronchoalveolar lavage fluid (BALF) and histological lung sections after 1 week, 1 month, or 3 months for pulmonary biomarkers and pathology. SHHF rats were also assessed at 6 months for pathological changes.
  
  
  RESULTS
  All animals developed concentration- and time-dependent interstitial fibrosis. Time-dependent Fe accumulation occurred in LA-laden macrophages in all strains but was exacerbated in SHHF rats. LA-exposed SHHF rats developed atypical hyperplastic lesions of bronchiolar epithelial cell origin at 3 and 6 months. Strain-related baseline differences existed in gene expression at 3 months, with persistent LA effects in WKY but not SH or SHHF rats. LA exposure altered genes for a number of pathways, including inflammation, immune regulation, and cell-cycle control. Cell-cycle control genes were inhibited after LA exposure in SH and SHHF but not WKY rats, whereas tumor suppressor genes were induced only in WKY rats. The inflammatory gene expression also was apparent only in WKY rats.
  
  
  CONCLUSIONS
  These data show that in Fe-overload conditions, progressive Fe accumulation occurs in fiber-laden macrophages within LA-induced lesions. Fe overload does not appear to contribute to chronic inflammation, and its role in hyperplastic lesion development requires further examination.
authors: Curriculum in Toxicology, University of North Carolina School of Medicine, Chapel Hill, NC 27711, USA.
authors: Jonathan H
authors: JH
authors: Shannahan
authors: Abraham
authors: A
authors: Nyska
authors: Mark
authors: M
authors: Cesta
authors: Mette C J
authors: MC
authors: Schladweiler
authors: Beena D
authors: BD
authors: Vallant
authors: William O
authors: WO
authors: Ward
authors: Andrew J
authors: AJ
authors: Ghio
authors: Stephen H
authors: SH
authors: Gavett
authors: Urmila P
authors: UP
authors: Kodavanti
mesh_terms: D000818:Animals; D017636:Asbestos, Amphibole / Q000633:toxicity*; D001195:Asbestosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology*; D002318:Cardiovascular Diseases / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D019190:Iron Overload / Q000150:complications*; D008168:Lung / Q000473:pathology; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D017636:Asbestos, Amphibole; D017382:Reactive Oxygen Species