INCREASED TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA) GENE-EXPRESSION IN PARAINFLUENZA TYPE-1 (SENDAI) VIRUS-INDUCED BRONCHIOLAR FIBROSIS

Increased airway resistance and airway hyperresponsiveness induced in rats by infection with parainfluenza type I (Sendai) virus is associat ed with bronchiolar fibrosis, To determine whether increased tumor nec rosis factor (TNF)-alpha gene expression is an important regulatory ev ent in virus-induced bronchiolar fibrosis, pulmonary TNF-alpha mRNA an d protein expression was assessed in rat strains that are susceptible (Brown Norway; BN) and resistant (Fischer 344; F344) to virus-induced bronchiolar fibrosis. Virus-inoculated BN rats had increased TNF-alpha pulmonary mRNA levels (P < 0.05) and increased numbers of bronchiolar macrophages and fibroblasts expressing TNF-alpha protein compared wit h virus-inoculated F344 rats (P < 0.05). Virus inoculation also induce d elevated TNF-alpha mRNA and protein levels (P < 0.05) in cultured ra t alveolar macrophages (NR8383 cells). A 55-kd soluble TNF receptor-im munoglobulin G fusion protein (sTNFR-IgG) was used to inhibit TNF-alph a bioactivity in virus-inoculated BN rats. Treated rats had fewer prol iferating bronchiolar fibroblasts, as detected by bromodeoxyuridine in corporation, compared with virus-inoculated control rats (P < 0.05). T here was also increased mortality in p55sTNFR-IgG-treated virus-inocul ated rats associated with increased viral replication and decreased nu mbers of macrophages and lymphocytes in bronchoalveolar lavage fluid ( P < 0.05). The results of this study indicate that 1) Sendai virus can directly up-regulate TNF-alpha mRNA and protein expression in macroph ages, 2) TNF-alpha is an important mediator of virus-induced bronchiol ar fibrosis, and 3) TNF-alpha has a critical role in the termination o f Sendai viral replication in the lung.