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Time-Dependent Airway Epithelial and Inflammatory Cell Responses Induced by Influenza Virus A/PR/8/34 in C57BL/6 Mice

¹ Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824, USA
² Center for Integrative Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824, USA
³ Department of Pathobiology and Diagnostic Investigation, National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824, USA

Correspondence: Address correspondence to: Norbert E. Kaminski, 315 National Food Safety and Toxicology Center, Michigan State University, Michigan State University, East Lansing, MI 48824, USA; e-mail:kamins11{at}msu.edu

The present study examines the kinetics of airway epithelial remodeling and inflammation in the airways of C57BL/6J mice infected with influenza virus A/PR/8/34 (PR8). Mice were intranasally instilled with 50 plaque forming units (pfu) of virus or its respective vehicle, saline, and then were sacrificed at 3, 7, 10, 15, or 21 days postinfection (dpi). PR8 treatment resulted in airway epithelial cell regeneration as suggested by proliferating cell nuclear antigen (PCNA) positive staining at 7 and 10 dpi and mucous cell metaplasia (MCM) evident at 10, 15, and 21 dpi. PR8 treatment resulted in a classic pattern of inflammation observed in bronchoalveolar lavage fluid (BALF), in which neutrophils peaked at 3 and 7 dpi and monocytes, lymphocytes, and eosinophils peaked at 10 dpi before returning to background levels of detection. Chemokine (MCP-1) and cytokine (IL-6, TNF-, IFN-, IL-5, IL-4, and IL-9) levels peaked at 7 dpi in BALF. IL-13 levels were unaffected by PR8 treatment. Concurrent with inflammation, MUC5AC gene expression was markedly increased by PR8 treatment at 7 dpi. Collectively, the results of this study indicate that the onset of MCM in airway epithelium occurs during the remodeling process and persists after the inflammatory response has diminished.

Key Words: Mouse • lung • airway epithelial cells • mucous cell metaplasia • influenza virus • immunohistochemistry • cytokines

Abbreviations: AB, alcian blue • ANOVA, analysis of variance • BALF, bronchoalveolar lavage fluid • C_T, cycle threshold • dpi, days postinfection • G5, axial airway generation 5 • H&E, hematoxylin and eosin • MCM, mucous cell metaplasia • PAS, periodic acid-Schiff • PCNA, proliferating cell nuclear antigen • pfu, plaque forming units • PR8, Influenza A/PR/8/34 • RSV, respiratory syncytial virus • SAL, saline • SEM, standard error of the mean • T_H1, T-helper cell type-1 • T_H2, T-helper cell type-2 • Vs, volume density

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