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 receptor fusion protein, Ro 45-2081, our study investigated the involvement of TNF in allergic inflammatory responses in the airways of sensitized guinea pigs and Brown-Norway rats. Sensitized guinea pigs exhibited an enhanced airway reactivity to substance P (1-10 micrograms/kg, i.v.) at 6 hr after antigen challenge which was inhibited (P < .05) by Ro 45-2081 (3 mg/kg, i.p.). Treatment with Ro 45-2081 (1-3 mg/kg, i.p.) dose-dependently inhibited (P < .05) the accumulation of neutrophils and total cells in bronchoalveolar lavage fluid in sensitized guinea pigs examined at 6 and 24 hr postchallenge. Ro 45-2081 (3 mg/kg, i.p.) also significantly (P < .05) reduced the number of eosinophils in bronchoalveolar lavage at both time points whereas a lower dose (1 mg/kg, i.p.) had no effect. Ro 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 Brown-Norway rat, Ro 45-2081 (1-3 mg/kg, i.p.) caused a dose-dependent inhibition of neutrophil and eosinophil infiltration into bronchoalveolar lavage fluid at 24 hr after antigen challenge. In both guinea pig and 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 ability of Ro 45-2081 to inhibit antigen-induced responses in sensitized animals suggests that TNF is a mediator of allergic inflammation in the lung.
Renzetti
L M
LM
Inflammation/Autoimmune Diseases, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
Paciorek
P M
PM
Tannu
S A
SA
Rinaldi
N C
NC
Tocker
J E
JE
Wasserman
M A
MA
Gater
P R
PR
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D018836:Inflammation Mediators / Q000494:pharmacology*; D008297:Male; D051381:Rats; D012137:Respiratory System / Q000187:drug effects*; D013373:Substance P / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D013373:Substance P; D003907:Dexamethasone