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Pulmonary Gene Expression Profiles of Spontaneously Hypertensive Rats Exposed to Environmental Tobacco Smoke*

Srikanth S. Nadadur, PhD; Kent E. Pinkerton, PhD; Urmila P. Kodavanti, PhD
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*From the Pulmonary Toxicology Branch (Drs. Nadadur and Kodavanti), Environmental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, NC; and Department of Anatomy (Dr. Pinkerton), Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA.

Correspondence to: Srikanth S. Nadadur, PhD, Pulmonary Toxicology Branch, Mail Drop 82, National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC 27711; e-mail: nadadur.srikanth@epa.gov.



Chest. 2002;121(3_suppl):83S-84S. doi:10.1378/chest.121.3_suppl.83S
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Global gene expression profile analysis can be utilized to derive molecular footprints to understand biochemical pathways implicated in the origin and progression of disease. Functional genomics efforts with tissue-specific focused gene array appears to be the most reasonable approach to derive relevant and meaningful information. In our efforts to understand the molecular basis for the toxicity and exacerbations in susceptible populations to environmental exposures, we are developing a gene expression database for a rat cardiopulmonary disease model exposed to air pollutants. The spontaneously hypertensive (SH) rat with underlying cardiovascular and pulmonary disease risk is being utilized toward these efforts. SH rats with polygenic traits toward hypertension exhibit similar heritable risk factors that are found in patients with COPD. We have shown that SH rats are more susceptible to lung injury/inflammation, and oxidative stress from exposure to combustion source particles, and from experimental induction of pulmonary disease compared to healthy normotensive Wistar rats. SH rats also elicited an inflammatory response to ETS exposure, which is less remarkable in other conventional rat strains used in laboratory studies. To understand the molecular basis for the inflammatory response, we screened for a pulmonary gene expression profile in SH rats exposed to ETS. Male SH rats (12 weeks old) were exposed either to filtered air or ETS at 90 mg/m3 for 6 h/d for 2 consecutive days; on the third day, total RNA was isolated from right lung lobes. Pulmonary gene expression was assayed by hybridizing 32P-labeled complementary DNA generated from total RNA to Atlas Rat complementary DNA expression array filter containing 588 genes (Clontech; Palo Alto, CA). Gene expression profile data indicated strong hybridization signals for 40 genes, including N-myc, p53, transforming growth factor-β, p21, bax-α and cytokine macrophage inflammatory protein-2. Pairwise comparison indicated ETS exposure-associated differential expression in 16 genes: increased expression of CYPIA1, calcium pump, RhoGAP, p122, and decreased expression of bile salt-activated lipase precursor, a fatty acid binding protein and fatty acid amide hydrolase. ETS induced a twofold to threefold increase in macrophage inflammatory protein-2 expression, suggesting lung injury and inflammation. Overexpression of matrix metalloproteinase-7 suggests a possible release of proteases from ETS-induced infiltration of neutrophils into the airways, consistent with our earlier observations. Increased expression of p27(Kip1), caspase-1, and Stat3 observed in the present study further supports apoptosis of infiltrating neutrophils in the lungs following exposure to ETS. Efforts are underway to explore whether long-term ETS exposure of SH rats will lead to a chronic disease state. A comprehensive expression database indicating ETS-induced changes in susceptible animal models will provide identification and the role of risk factors in understanding health effects of ETS and other environmental pollutant-induced cardiopulmonary disease.

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