Parainfluenza virus-induced persistence of airway inflammation, fibrosis, and dysfunction associated with TGF-beta(1), expression in brown Norway rats

Parainfluenza type 1 (Sendai) virus infection in young rats induces airway grow 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 bonchiolar 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 al 10, 1 a, and 30 d after inoculation. We conclude that recruitment-and persistance of airway inflammatory cells and airway wall fibrosis may be important alterations induced by viral sower respiratory disease during early life that can lead to longterm 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.