Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice

Abstract

Intratracheal instillation of bleomycin (0.08 U) or silica (2 mg) to mice leads, after 15 days, to a patchy pulmonary fibrosis associated with a significant increase of the lung hydroxyproline. Since tumour necrosis factor (TNF) seems to be an important mediator in pulmonary fibrosis, we wondered whether this fibrosis might be prevented by a new TNF-α antagonist. Infusion of a 55 kD human recombinant soluble TNF receptor rsTNFR-β, at a rate of 20 μg · day-1, prevented the bleomycin/silica induced increase of lung hydroxy-proline content, as measured 15 days after instillation. Infusion of rsTNFR-β was also effective in the treatment of an established fibrosis, i.e. administered 25 or more days after instillation of bleomycin or silica, since it reduced lung collagen content. Recombinant soluble TNFR-β had no significant influence on the number of cells, mostly macrophages, recovered by bronchoalveolar lavage. The examination of histological sections indicated that the rsTNFR-β reduced the proportion of areas of damaged lung and, in silicosis, the formation of nodules with a rich collagen content. This study suggests that rsTNFR-β might be useful in the therapy of pulmonary fibrosis.