Science Inventory

Early Onset of Atypical Proliferative Lesions in the Lungs of a Libby Amphibole (LA) Exposed Rat Model of Cardiovascular Disease-Associated Iron Overlo


Shannahan, J., M. SCHLADWEILER, B. D. Vallanat, A. Nyska, S. H. GAVETT, AND U. P. KODAVANTI. Early Onset of Atypical Proliferative Lesions in the Lungs of a Libby Amphibole (LA) Exposed Rat Model of Cardiovascular Disease-Associated Iron Overlo. Presented at American Thoracic Society (ATS) Meeting, Denver, CO, May 13 - 18, 2011.


This abstract examined effects of Libby amphibole asbestos induced pulmonary injury in healthy and cardiovascular compromised rat models. The data show that heart failure rat model develops atypical hyperplastic lesions in the lung following 3 month exposure.


Rationale: Miners and residents of Libby, Montana have increased incidences of asbestos-related diseases associated with exposure to amphibole contaminated vermiculite. Amphiboles have been shown to bind endogenous iron and modulate fiber induced inflammatory response. We hypothesized rat models of genetic cardiovascular disease (CVD) with iron-overload would have increased susceptibility to developing asbestos-related disease. Methods: We exposed male healthy Wistar Kyoto (WKY) and genetically predisposed rats with CVD having pulmonary iron-overload (spontaneously hypertensive, SH; and spontaneously hypertensive heart failure, SHHF) to either saline (300 ul), or a rat-respirable fraction of Libby Amphibole (LA) (0.25 or 1 mg/rat) by intratracheal instillation. Three months post-exposure lung sections were evaluated for histological abnormalities and immunohistochemical staining of cytokeratins (CK) 7, 10, 14, and 19 in order to characterize the cellular origin of lesions. Lung mRNA samples from saline and 1 mg LA exposed animals were analyzed using Affrymetrix rat genome 2.0 microarrays. Results: Histologically concentration-related presence of inflammatory foci (macrophages) and interstitial fibrosis were apparent in all three strains. Surprisingly, only SHHF exhibited atypical hyperplastic lesions (4/6 at 1 mg and 2/6 at 0.25 mg doselevel), located in centriacinar regions, associated with the terminal bronchioles. Positive stain for CK19 but negative for CK7 and CKI0 were indicative of bronchiolar origin of these lesions. While only one rat stained somewhat positive for CKI4, the presence of squamous metaplasia could not be ruled out. Modifications in gene expression pattern indicated changes reflective of inflammation, tissue remodeling and lung disease in all strains. Interestingly, pathway analysis showed that genes related to the progression of cancer were altered to a greater extent in SHHF compared to WKY and SH after LA exposure. A total of 1,316 genes were altered in SHHF, of which 272 were related to cancer. Of these cancer-related genes, 65% were uniquely changed in SHHF and unchanged in WKY or SH. These SHHF uniquely expressed cancer genes were related to many pathways including p53, KRAS, NF-KB, JUN signaling and a variety ofothers. Conclusion: These results suggest that the underlying CVD and iron-overload might increase the susceptibility of SHHF to early onset of atypical hyperplastic lesions following LA exposure. Funding: EPAIUNC CR833237. This abstract does not reflect USEPA policy.

Record Details:

Product Published Date: 05/18/2011
Record Last Revised: 11/29/2012
OMB Category: Other
Record ID: 231950