Uhl E W, Castleman W L, Sorkness R L, Busse W W, Lemanske R F, McAllister P K
Department of Pathobiology, College of Veterinary Medicine, University of Florida, Gainesville 32610-0145, USA.
Am J Respir Crit Care Med. 1996 Dec;154(6 Pt 1):1834-42. doi: 10.1164/ajrccm.154.6.8970378.
Parainfluenza type 1 (Sendai) virus infection in young rats induces airway growth abnormalities associated with persistent pulmonary dysfunction and hyperresponsiveness. The objectives of this study were to compare virus-susceptible brown Norway (BN) rats and virus-resistant F344 rats and to determine which of several virus-induced structural abnormalities, including bronchiolar hypoplasia, alveolar dysplasia, bronchiolar mural fibrosis, and increases in bronchiolar mast cells, were associated with virus-induced increases in pulmonary resistance and hyperresponsiveness to methacholine. We also determined whether bronchiolar mural thickening and fibrosis may be caused by increased bronchiolar expression of cytokines such as TGF-beta 1 into airways. BN rats infected with virus developed increases in respiratory resistance and hyperresponsiveness that persisted for 28 to 65 d after inoculation. Functional abnormalities were most strongly associated with bronchiolar mural thickening and fibrosis as well as with recruitment of inflammatory cells, including macrophages, mast cells, lymphocytes, and eosinophils, into the bronchiolar wall. F344 rats were resistant to significant virus-induced alterations in bronchiolar airway wall thickness and mast cell increases as well as to pulmonary function abnormalities. BN rats had increase pulmonary mRNA levels of TGF-beta 1 at 10 and 14 d after viral inoculation as compared with F344 rats. BN rats also had greater numbers of bronchiolar macrophages expressing TGF-beta 1 protein that were localized in bronchiolar walls at 10, 14, and 30 d after inoculation. We conclude that recruitment and persistence of airway inflammatory cells and airway wall fibrosis may be important alterations induced by viral lower respiratory disease during early life that can lead to long-term airway dysfunction and hyperresponsiveness. Virus-induced airway fibrosis may be mediated in part by increased TGF-beta 1 gene expression by bronchiolar macrophages in genetically susceptible individuals.
1型副流感（仙台）病毒感染幼鼠会引发气道生长异常，伴有持续性肺功能障碍和高反应性。本研究的目的是比较病毒易感的棕色挪威（BN）大鼠和病毒抗性的F344大鼠，并确定几种病毒诱导的结构异常中，包括细支气管发育不全、肺泡发育异常、细支气管壁纤维化以及细支气管肥大细胞增多，哪些与病毒诱导的肺阻力增加和对乙酰甲胆碱的高反应性有关。我们还确定细支气管壁增厚和纤维化是否可能由气道中细胞因子如转化生长因子-β1（TGF-β1）的细支气管表达增加所致。感染病毒的BN大鼠在接种后28至65天出现呼吸阻力增加和高反应性。功能异常与细支气管壁增厚和纤维化以及炎症细胞（包括巨噬细胞、肥大细胞、淋巴细胞和嗜酸性粒细胞）募集到细支气管壁最为密切相关。F344大鼠对病毒诱导的细支气管气道壁厚度显著改变、肥大细胞增多以及肺功能异常具有抗性。与F344大鼠相比，BN大鼠在病毒接种后10天和14天肺中TGF-β1的mRNA水平升高。BN大鼠在接种后10天、14天和30天也有更多表达TGF-β1蛋白的细支气管巨噬细胞，这些细胞定位于细支气管壁。我们得出结论，气道炎症细胞的募集和持续存在以及气道壁纤维化可能是生命早期病毒性下呼吸道疾病诱导的重要改变，可导致长期气道功能障碍和高反应性。病毒诱导的气道纤维化可能部分由遗传易感个体中细支气管巨噬细胞TGF-β1基因表达增加介导。
