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 ai rway grow abnormalities associated with persistent pulmonary dysfuncti on and hyperresponsiveness. The objectives of this study were to compa re virus-susceptible brown Norway (BN) rats and virus-resistant F344 r ats and to determine which of several virus-induced structural abnorma lities, including bonchiolar hypoplasia, alveolar dysplasia, bronchiol ar mural fibrosis, and increases in bronchiolar mast cells, were assoc iated with virus-induced increases in pulmonary resistance and hyperre sponsiveness to methacholine. We also determined whether bronchiolar m ural thickening and fibrosis may be caused by increased bronchiolar ex pression of cytokines such as TGF-beta 1 into airways. BN rats infecte d with virus developed increases in respiratory resistance and hyperre sponsiveness that persisted for 28 to 65 d after inoculation. Function al abnormalities were most strongly associated with bronchiolar mural thickening and fibrosis as well as with recruitment of inflammatory ce lls, including macrophages, mast cells, lymphocytes, and eosinophils, into the bronchiolar wall. F344 rats were resistant to significant vir us-induced alterations in bronchiolar airway wall thickness and mast c ell 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 tha t were localized in bronchiolar walls al 10, 1 a, and 30 d after inocu lation. We conclude that recruitment-and persistance of airway inflamm atory cells and airway wall fibrosis may be important alterations indu ced 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 indi viduals.