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

¹ Comparative Medicine and Integrative Biology, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
² Pacific Northwest National Laboratory, Richland, Washington 99352, USA
³ Department of Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
⁴ CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA
⁵ Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294, USA
⁶ Department of Anatomy, Physiology and Cell Biology, California National Primate Center, School of Veterinary Medicine, University of California, Davis, CA 95616, USA

Correspondence: Address correspondence to: Jack R. Harkema, Department of Pathobiology and Diagnostic Investigation, 212 National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824-1224, USA; e-mail: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

Abbreviations: 2D, two-dimensional • 3D, three-dimensional • AB, Alcian blue • ANOVA, analysis of variance • BALT, bronchus-associated lymphoid tissue • CAD, computer-aided design • CFD, computational fluid dynamics • DDV, Digital Data Viewer • DOE, United States Department of Energy • ET, ethmoturbinate • FA, filtered air • GALT, gut-associated lymphoid tissue • GMA, glycol methacrylate • GMV, General Mesh Viewer • H&E, hematoxylin and eosin • HP, hard palate • HPLC, high performance liquid chromatography • ID, interior diameter • m³, cubic meter • MCM, mucous cell metaplasia • MRI, magnetic resonance imaging • MS, maxillary sinus • MT, maxilloturbinate • N, nostril • NALT, nasal-associated lymphoid tissue • NP, nasopharynx • NTE, nonciliated transitional epithelium • NV, nasal vestibule • PAS, periodic acid Schiff • PCNA, proliferating cell nuclear antigen • ppm, parts per million • RE, ciliated respiratory epithelium • RNA, ribonucleic acid • S, nasal septum • STL, stereolithography • TIFF, tagged-image file format

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