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Three-Dimensional Mapping of Ozone-Induced Injury in the Nasal Airways of Monkeys Using Magnetic Resonance Imaging and Morphometric Techniques

Comparative Medicine and Integrative Biology, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA

Kevin R. Minard

Pacific Northwest National Laboratory, Richland, Washington 99352, USA

Lynn L. Trease

Pacific Northwest National Laboratory, Richland, Washington 99352, USA

James G. Wagner

Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA

Guilherme J.M. Garcia

CT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA

Carol A. Ballinger

Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Julia S. Kimbell

CT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA

Charles G. Plopper

Department of Anatomy, Physiology and Cell Biology, California National Primate Center, School of Veterinary Medicine, University of California, Davis, CA 95616, USA

Richard A. Corley

Pacific Northwest National Laboratory, Richland, Washington 99352, USA

Edward M. Postlethwait

Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Jack R. Harkema

Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA, harkemaj{at}msu.edu

Age-related changes in gross and microscopic structure of the nasal cavity may alter local tissue susceptibility as well as the dose of inhaled toxicant delivered to susceptible sites. This article describes a novel method for the use of magnetic resonance imaging, 3-dimensional airway modeling, and morphometric techniques to characterize the distribution and magnitude of ozone-induced nasal injury in infant monkeys. Using this method, we generated age-specific, 3-dimensional, epithelial maps of the nasal airways of infant Rhesus macaques. The principal nasal lesions observed in this primate model of ozone-induced nasal toxicology were neutrophilic rhinitis, along with necrosis and exfoliation of the epithelium lining the anterior maxilloturbinate. These lesions, induced by acute or cyclic (episodic) exposures, were examined by light microscopy, quantified by morphometric techniques, and mapped on 3-dimensional models of the nasal airways. Here, we describe the histopathologic, imaging, and computational biology methods developed to precisely characterize, localize, quantify, and map these nasal lesions. By combining these techniques, the location and severity of the nasal epithelial injury were correlated with epithelial type, nasal airway geometry, and local biochemical and molecular changes on an individual animal basis. These correlations are critical for accurate predictive modeling of exposure-dose-response relationships in the nasal airways, and subsequent extrapolation of nasal findings in animals to humans for determining risk.

Key Words: Magnetic resonance imaging • nasal toxicology • ozone • computational fluid dynamics • morphometry.

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