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Pulmonary Toxicity and Modifications in Iron Homeostasis Following Libby Amphibole Asbestos Exposure in Rat Models of Cardiovascular Disease
Shannahan, J., M. SCHLADWEILER, D. Carlin, J. E. RICHARDS, S. H. GAVETT, AND U. P. KODAVANTI. Pulmonary Toxicity and Modifications in Iron Homeostasis Following Libby Amphibole Asbestos Exposure in Rat Models of Cardiovascular Disease. Presented at American Thoracic Society Conference, New Orleans, LA, May 14 - 19, 2010.
This Abstract compared susceptibility of 3 rat models of cardiovascular diseases to Libby amphibole asbestos and showed that baseline differences in gene expression pattern and underlying pathology influence asbestos-indcued lung toxicity.
Rationale: Individuals suffering from cardiovascular disease (CVD) develop iron dysregulation which may influence pulmonary toxicity and injury upon exposure to asbestos. We hypothesized spontaneously hypertensive (SH) and spontaneously hypertensive heart failure (SHHF) rats would exhibit increased pulmonary injury and alterations in iron-homeostasis upon exposure to Libby amphibole (LA) asbestos compared to normotensive Wistar Kyoto (WKY) rats. Methods: WKY (n=12/group), SH (n=6/group), and SHHF (n=6/group) were exposed at 12wks of age to either saline (300]J.I), or a rat-respirable fraction of LA (0.25 or 1 mg/rat) by intratracheal instillation and analyzed at day-l , day-7, or l-month post-exposure. Bronchoalveolar lavage fluid (BALF) and lung mRNA expression for markers of iron homeostasis, oxidative stress and inflammation were analyzed. Results: Totallavageable cells were higher in unexposed SH and SHHF relative to WKY (SHHF>SH). Total cell counts did not change in WKY but did increase in SH and HF at day-I, and 7. BALF protein increased in WKY and SH at day-l and day-7 but decreased in SHHF at day-I, and remained elevated at l-month in SH and SHHF exposed to 1 mg LA. All strains responded to LA with increased yglutamyl transpeptidase, lactate dehydrogenase, and N-acetyl glucosaminidase in BALF at day-l through l-month, BALF ferritin was high at base line, and progressively increased at all times in SH and SHHF but not in WKY. Baseline BALF transferrin concentrations were high in SH and SHHF relative to WKY and further increased at day7, in WKY and SH. Transferrin remained elevated in SH exposed to 1 mg at l-month, mRNA expressions for oxidative stress and inflammatory proteins were higher at baseline in SH and SHHF compared to WKY. LA induced an increase in macrophage inflammatory protein-2 (MIP-2) at day-l in WKY, but not in other strains. Gene expressionofheme-oxygenase-l (HO-l),anoxidativestressmarker,wasinducedin WKY day-l and SH at day-7 with no effect on SHHF. Growth factors PDGFA and B mRNA levels were similar in all strains at baseline and reduced in WKY and SHHF following exposure. Conclusion: The underlying disease state of the SHHF might impair its ability to mount a pulmonary inflammatory response to LA exposure that is comparable to the WKY and SH. Underlying pulmonary complications secondary to CVD and the ability to sequester iron by ferritin might playa role in modulating LA injury. Funding: EPA/UNC CR833237. This abstract does not reflect USEPA
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL PUBLIC HEALTH DIVISION
CARDIOPULMONARY AND IMMUNOTOXICOLOGY BRANCH