INHIBITION OF SEPHADEX-INDUCED LUNG INJURY IN THE RAT BY RO-45-2081, A TUMOR-NECROSIS-FACTOR RECEPTOR FUSION PROTEIN

Tumor necrosis factor (TNF) is an inflammatory cytokine produced by ma ny cell types which may contribute to the pathophysiology of a variety of lung diseases. In this study we have used Ro 45-2081 (a soluble re ceptor composed of the human p55 TNF receptor and human heavy-chain im munoglobulin G) to explore the role of TNF in the acute inflammatory r esponse in the rat lung to intravenous injection of Sephadex beads. Th e effects of Ro 45-2081 have also been compared with those of dexameth asone. At 24 and 72 h after Sephadex, there was a significant increase in the total number of leukocytes in bronchoalveolar lavage fluid (BA LE). At 24 h, the number of neutrophils comprised around 50% of the to tal leukocyte number, decreasing to around 10% of total by 72 h. The e osinophil count was maintained at around 10% of the total leukocyte nu mber. Pretreatment with either Ro 45-2081 [1 and 3 mg kg(-1), intraper itoneally (i.p.)] or dexamethasone (0.1 and 0.3 mg kg(-1), i.p.) inhib ited the neutrophilia at 24 h after Sephadex, although Ro 45-2081 had no significant effect on total cell number. At 72 h after Sephadex, Ro 45-2081 (1 and 3 mg kg(-1), i.p., daily) significantly reduced the ne utrophil influx into BALE but had no inhibitory effect on eosinophil n umber. In contrast, dexamethasone (0.1 and 0.3 mg kg(-1), i.p., daily) virtually abolished the infiltration of neutrophils and eosinophils i nto BALE The lack of effect of Ro 45-2081 on eosinophil infiltration i nto the rat lung and the inhibition caused by dexamethasone suggest th at factors other than TNF are involved in this part of the inflammator y response induced by Sephadex. However, the inhibitory effects of Ro 45-2081 show that TNF may play an important role in the recruitment of neutrophils into the lungs of Sephadex-treated rats.