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ToxSci Advance Access published online on August 23, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl087
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Published by Oxford University Press 2006.
Received June 12, 2006
Accepted August 17, 2006

Respiratory Toxicology

The Spontaneously Hypertensive Rat: An Experimental Model of Sulfur Dioxide-Induced Airways Disease

Urmila P. Kodavanti 1 *, Mette C. Schladweiler 1, Allen D. Ledbetter 1, Roselia Villalobos Ortuno 2, Marie Suffia 2, Paul Evansky 1, Judy H. Richards 1, Richard H. Jaskot 1, Ronald Thomas 1, Edward Karoly 3, Yuh-Chin T. Huang 3, Daniel L. Costa 1, Peter S. Gilmour 4, and Kent E. Pinkerton 2

1 Pulmonary Toxicology Branch, Experimental Toxicology Division, NHEERL, ORD, US Environmental Protection Agency, Research Triangle Park, NC, USA
2 Center for Health and the Environment, University of California, Davis, CA, USA
3 Human Studies Division, NHEERL, ORD, US Environmental Protection Agency, Chapel Hill, NC, USA
4 Center for Environmental Medicine, Asthma and Lung Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

* To whom correspondence should be addressed.
Urmila P. Kodavanti, E-mail: Kodavanti.urmila{at}epa.gov


  Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction, inflammation and mucus hypersecretion; features that are common in bronchitis, emphysema and often asthma. However, current rodent models do not reflect this human disease. Because genetically predisposed spontaneously hypertensive (SH) rats display phenotypes such as systemic inflammation, hypercoagulation, oxidative stress, and suppressed immune function that are also apparent in COPD patients, we hypothesized that SH rat may offer a better model of experimental bronchitis. We therefore, exposed SH and commonly used Sprague Dawley (SD) rats (male, 13-15 wk old) to 0, 250, or 350 ppm sulfur dioxide (SO2), 5h/d for 4 consecutive days to induce airway injury. SO2 caused dose-dependent changes in breathing parameters in both strains with SH rats being slightly more affected than SD. Increases in bronchoalveolar lavage fluid (BALF) total cells and neutrophilic inflammation were dose-dependent and significantly greater in SH than in SD rats. The recovery was incomplete 4 days following SO2 exposure in SH rats. Pulmonary protein leakage was modest in either strain, but lactate dehydrogenase and n-acetyl glucosaminidase activity were increased in BALF of SH rats. Airway pathology and morphometric evaluation of mucin demonstrated significantly greater impact of SO2 in SH than in SD rats. Baseline differences in lung gene expression pattern suggested marked immune dysregulation, oxidative stress, impairment of cell signaling and fatty acid metabolism in SH rats. SO2 effects on these genes were more pronounced in SH than in SD rats. Thus, SO2 exposure in SH rats may yield a relevant experimental model of bronchitis.

Keywords: Chronic obstructive pulmonary disease; bronchitis; spontaneously hypertensive rats; sulfur dioxide exposure; mucus hypersecretion; inflammation.
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