PHARMACOLOGICAL EVIDENCE FOR TUMOR-NECROSIS-FACTOR AS A MEDIATOR OF ALLERGIC INFLAMMATION IN THE AIRWAYS

Tumor necrosis factor (TNF) has been implicated in the pathophysiology of a number of inflammatory diseases of the lung. Using the TNF recep tor fusion protein, Ro 45-2081, our study investigated the involvement of TNF in allergic inflammatory responses in the airways of sensitize d guinea pigs and Brown-Norway rats. Sensitized guinea pigs exhibited an enhanced airway reactivity to substance P (1-10 mu g/kg, i.v.) at 6 hr after antigen challenge which was inhibited (P < .05) by Po 45-208 1 (3 mg/kg, i.p.). Treatment with Ro 45-2081 (1-3 mg/kg, i.p.) dose-de pendently inhibited (P < .05) the accumulation of neutrophils and tota l cells in bronchoalveolar lavage fluid in sensitized guinea pigs exam ined at 6 and 24 hr postchallenge. Ro 45-2081 (3 mg/kg, i.p.) also sig nificantly (P < .05) reduced the number of eosinophils in bronchoalveo lar lavage at both time points whereas a lower dose (1 mg/kg, i.p.) ha d no effect. Po 45-2081 (1 or 3 mg/kg, i.p.) abolished antigen-induced microvascular leakage (quantified by tissue content of Evans blue dye ) in the trachea and main bronchi in sensitized guinea pigs. In the Br own-Norway rat, Po 45-2081 (1-3 mg/kg, i.p.) caused a dose-dependent i nhibition of neutrophil and eosinophil infiltration into bronchoalveol ar lavage fluid at 24 hr after antigen challenge. In both guinea pig a nd Brown-Norway rat models, treatment with dexamethasone (30 mg/kg, i. p., for guinea pig and 0.3 mg/kg, i.p., for Brown-Norway rat) produced virtually identical results to those obtained with Ro 45-2081. The ab ility of Ro 45-2081 to inhibit antigen-induced responses in sensitized animals suggests that TNF is a mediator of allergic inflammation in t he lung.