A Hyperlipidemic Rabbit Model Provides New Insights into Pulmonary Zinc Exposure Effects on Cardiovascular Health Adriana J. LaGier Æ Nick D. Manzo Æ Alex P. Carll Æ Richard H. Jaskot Æ Ralph Slade Æ Judy H. Richards Æ Darrell W. Winsett Æ Aimen K. Farraj Æ Janice A. Dye Published online: 25 October 2008 Ó Humana Press 2008 Abstract This study ascertains the effects of zinc, a major component of particulate matter, on pulmonary and systemic endpoints using hyperlipidemic rabbits to model diet-induced human atherosclerosis. New Zealand White rabbits were fed a normal or cholesterol-enriched diet and then were intratracheally instilled 19/week for 4 weeks with saline or 16 lg/kg of zinc, equal parts sulfate and oxide. Physiologic responses, blood after each exposure, and ter- minal bronchoalveolar lavage (BAL) were assessed. Rabbits fed a cholesterol-rich diet developed hyperlipidemia and had consistently higher circulating leukocyte counts than rabbits fed normal chow. Within minutes after zinc instil- lation, saturation of peripheral oxygen was decreased in hyperlipidemic rabbits and heart rate was increased in hyperlipidemic rabbits with total serum cholesterol levels greater than 200 mg/dl. Total circulating leukocytes levels were increased 24 h after the first zinc instillation, but upon repeated exposures this effect was attenuated. After repeated zinc exposures, BAL fluid (BALF) N-acetylglucosaminidase activity was increased regardless of hyperlipidemic state. Hyperlipidemic rabbits had an increase in BALF-oxidized glutathione and a decrease in serum nitrite. The study elu- cidates mechanisms by which the zinc metal component of PM drives cardiovascular health effects, as well as the pos- sible susceptibility induced by hyperlipidemia. Furthermore, the study exemplifies the benefits of monitoring circulatory physiology during exposure as well as after exposure. Keywords Zinc Á Rabbit Á Cardiovascular Á Particulate matter Á Hyperlipidemia Introduction Increases in particulate air pollution are associated with elevated cardiovascular hospital admissions and mortality (reviewed in [33]). Patients with existing cardiovascular disease (CVD) are more strongly affected than other patients [41]. These data indicate that individuals with pre- existing cardiovascular disease are at increased risk from particulate matter (PM) exposure. In addition, the pul- monary inflammation initiated by repeated PM insults may sustain sub-clinical systemic inflammation, which has a pivotal role in the development of atherosclerosis. Hence, chronic PM exposure could contribute to the development of cardiovascular disease [26]. Animal models of atherosclerosis have been used to study pulmonary PM exposure effects on this disease [4, 6, This article was reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. A. P. Carll and N. D. Manzo supported by EPA-CT82947101 and EPA-CT826512010, respectively. A. J. LaGier (&) Á R. H. Jaskot Á R. Slade Á J. H. Richards Á D. W. Winsett Á A. K. Farraj Á J. A. Dye Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, 109 TW Alexander Drive, MD: B143-01, Research Triangle Park, NC 27711, USA e-mail: lagier.adriana@epa.gov N. D. Manzo Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27606, USA A. P. Carll School of Public Health, ENVR, University of North Carolina, Chapel Hill, NC 27599, USA Cardiovasc Toxicol (2008) 8:195–206 DOI 10.1007/s12012-008-9028-9