Buchweitz John P, Harkema Jack R, Kaminski Norbert E
Department of Pharmacology and Toxicology, National Food Safety and Toxicology Center, Michigan State University, East Lansing, MI 48824, USA.
Toxicol Pathol. 2007 Apr;35(3):424-35. doi: 10.1080/01926230701302558.
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-alpha, IFN-gamma, 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.
本研究检测了感染甲型流感病毒A/PR/8/34（PR8）的C57BL/6J小鼠气道上皮重塑和炎症的动力学变化。将50个空斑形成单位（pfu）的病毒或其相应载体生理盐水经鼻内滴注到小鼠体内，然后在感染后3、7、10、15或21天处死小鼠。PR8处理导致气道上皮细胞再生，表现为在感染后7天和10天增殖细胞核抗原（PCNA）染色呈阳性，在感染后10天、15天和21天出现明显的黏液细胞化生（MCM）。PR8处理导致支气管肺泡灌洗液（BALF）中出现典型的炎症模式，其中中性粒细胞在感染后3天和7天达到峰值，单核细胞、淋巴细胞和嗜酸性粒细胞在感染后10天达到峰值，然后恢复到检测背景水平。趋化因子（MCP-1）和细胞因子（IL-6、TNF-α、IFN-γ、IL-5、IL-4和IL-9）水平在BALF中于感染后7天达到峰值。IL-13水平不受PR8处理的影响。与炎症同时发生的是，PR8处理在感染后7天显著增加了MUC5AC基因的表达。总体而言，本研究结果表明，气道上皮中MCM的发生始于重塑过程，并在炎症反应减弱后持续存在。
