You are here:
ALTERATIONS OF FE HOMEOSTASIS IN RAT CARDIOVASCULAR DISEASE MODELS AND ITS CONTRIBUTION TO CARDIOPULMONARY TOXICITY
Citation:
Shannahan, J., A. J. GHIO, S. H. GAVETT, AND U. P. KODAVANTI. ALTERATIONS OF FE HOMEOSTASIS IN RAT CARDIOVASCULAR DISEASE MODELS AND ITS CONTRIBUTION TO CARDIOPULMONARY TOXICITY. Presented at International Conference on Chelation, Grand Rapids, MI, October 22 - 25, 2010.
Impact/Purpose:
This abstract addresses the role of impaired iron homeostastis and its influence on susceptibility to injury caused by asbestos exposure. The data show that rat models of cardiovascular disease with associated dysregulated iron homeostasis have persistent inflammation and enhanced oxidative stress following exposure to Libby amphibole.
Description:
Introduction: Fe homeostasis can be disrupted in human cardiovascular diseases (CVD). We addressed how dysregulation of Fe homeostasis affected the pulmonary inflammation/oxidative stress response and disease progression after exposure to Libby amphibole (LA), an asbestifonn mineral fiber. Methods: Healthy Wistar Kyoto (WKY), Spontaneously Hypertensive (SH), and the Spontaneously Hypertensive Heart Failure (SHHF) rats were evaluated for CVD, and baseline pulmonary differences in biomarkers of inflammation, oxidative stress and Fe homeostasis at 14-15 wks age. We also examined the same parameters following exposure to LA. Animals were intratracheally instilled with 0, 0.25, or 1.0 mg of LA and biomarkers were analyzed I-d, l-wk, l-mo, and 3-mo. post-exposure. Results: Consistent with human CVD, SH and SHHF had alterations at baseline of selected biomarkers compared to WKY. Increased pulmonary inflammation accompanied transcriptional activation of MIP-2, IL-1α TNF-α, and HO-l mRNA in SH and SHHF relative to WKY. Non-heme Fe, transferrin, ferritin and Fe-binding capacity were increased in alveolar lining of SHHF compared to WKY. SHHF had baseline upregulation of ferritin mRNA. LA exposure caused a concentration-and time-dependent progression of inflammation and pathology in all strains. WKY mounted an inflammatory response by transcriptionally activating MIP-2 but not HO-l or ferritin. This response was rapidly reversible only in WKY but was progressive in SH and SHHF without induction of MIP-2. SH and SHHF but not WKY showed elevations in alveolar lining ferritin, and mRNA in the lung following LA exposure. SH and SHHF did not induce ascorbate, an antioxidant, that was seen in WKY following LA exposure. Gene expression profiling depicted changes in biomarkers of heme metabolism at baseline and following LA exposure more readily in SHHF than WKY or SH. Only SHHF rats showed lung epithelial proliferation and transcriptional changes in biomarkers of cancer following LA exposure. Discussion and Conclusion: We demonstrated that rat models of CVD exist with cardiopulmonary inflammation and oxidative stress that accompanies major increases in ferritin and Fe-binding capacity in the lung. SHHF were unable to maintain antioxidant homeostasis, induce HO-l expression or increase inflammatory cytokine production. Gene expression profiling provides insights into the likely role of dysregulated Fe metabolism in disease progression and susceptibility to a proliferative lung phenotype in response to LA. Abstract does not reflect U.S. EPA policy.