INTRACHEAL ADMINISTRATION OF ENDOTOXIN AND CYTOKINES .4. THE SOLUBLE TUMOR-NECROSIS-FACTOR RECEPTOR TYPE-I INHIBITS ACUTE-INFLAMMATION

Endotoxin lipopolysaccharide (LPS) administered intratracheally to rat s causes pulmonary tumor necrosis factor a (TNF) and interleukin-1 (IL -1) production and results in acute bronchoalveolar neutrophilic infla mmation. In the present study, the recombinant human TNF soluble recep tor type I (sTNFrI) co-injected intratracheally with LPS is shown to i nhibit significantly (P < 0.0001) the number of neutrophils in broncho alveolar lavage specimens at 6 hours as compared to intratracheal inje ction of LPS alone. The sTNFrI was at least as effective as the recomb inant human IL-1 receptor antagonist (IL-1ra) as an inhibitor of acute inflammation. Inhibition of LPS-induced acute inflammation by the com bination of sTNFrI and IL-1ra was not significantly more than the inhi bition afforded by sTNFrI alone. Intratracheal co-injection of sTNFrI with LPS unexpectedly increased TNF levels in BAL specimens, perhaps b y changing the normal catabolism of TNF. On the other hand, co-injecti on of sTNFrI and LPS decreased IL-6 levels in BAL fluid, most likely b y interfering with the induction of IL-6 by TNF. The s2NFrI may prove to be an important pharmacological down-regulator of acute inflammatio n.