EPA Science Inventory

SUBCHRONIC PULMONARY PATHOLOGY, IRON-OVERLOAD AND TRANSCRIPTIONAL ACTIVITY AFTER LIBBY AMPHIBOLE EXPOSURE IN RAT MODELS OF CARDIOVASCULAR DISEASE

Citation:

Shannahan, J., A. Nyska, M. Cesta, M. SCHLADWEILER, A. J. GHIO, B. Vallanat, W. Ward, S. H. GAVETT, AND U. P. KODAVANTI. SUBCHRONIC PULMONARY PATHOLOGY, IRON-OVERLOAD AND TRANSCRIPTIONAL ACTIVITY AFTER LIBBY AMPHIBOLE EXPOSURE IN RAT MODELS OF CARDIOVASCULAR DISEASE. ENVIRONMENTAL HEALTH PERSPECTIVES. National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, NC, 120(1):85-91, (2012).

Description:

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.Conclusion: 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.

Purpose/Objective:

This manuscript shows that pulmonary Libby amphibole exposure in cardiovascular compromised rats with preexisting iron overload causes iron accumulation in fiber laden macrophages increases the incidence of hyperplastic lesion development and associated decreases in inflammatory gene induction

URLs/Downloads:

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Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Start Date: 01/01/2012
Completion Date: 01/01/2012
Record Last Revised: 10/29/2012
Record Created: 06/01/2011
Record Released: 06/01/2011
OMB Category: Other
Record ID: 235700

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

ENVIRONMENTAL PUBLIC HEALTH DIVISION

CARDIOPULMONARY AND IMMUNOTOXICOLOGY BRANCH