Intratracheal administration of endotoxin and cytokines. IV. The soluble tumor necrosis factor receptor type I inhibits acute inflammation.
Endotoxin lipopolysaccharide (LPS) administered intratracheally to rats causes pulmonary tumor necrosis factor alpha (TNF) and interleukin-1 (IL-1) production and results in acute broncho-alveolar neutrophilic inflammation. In the present study, the recombinant human TNF soluble receptor type I (sTNFrI) co-injected intratracheally with LPS is shown to inhibit significantly (P < 0.0001) the number of neutrophils in bronchoalveolar lavage specimens at 6 hours as compared to intratracheal injection of LPS alone. The sTNFrI was at least as effective as the recombinant human IL-1 receptor antagonist (IL-1ra) as an inhibitor of acute inflammation. Inhibition of LPS-induced acute inflammation by the combination of sTNFrI and IL-1ra was not significantly more than the inhibition afforded by sTNFrI alone. Intratracheal co-injection of sTNFrI with LPS unexpectedly increased TNF levels in BAL specimens, perhaps by changing the normal catabolism of TNF. On the other hand, co-injection of sTNFrI and LPS decreased IL-6 levels in BAL fluid, most likely by interfering with the induction of IL-6 by TNF. The sTNFrI may prove to be an important pharmacological down-regulator of acute inflammation.
Department of Pathology, UC San Diego School of Medicine 921030.
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Ulich
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Yin
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Remick
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Russell
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Eisenberg
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D000208:Acute Disease; D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D004731:Endotoxins / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control*; D007267:Injections; D007700:Kinetics; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000502:physiology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D018124:Receptors, Tumor Necrosis Factor; D012485:Salmonella typhi; D012995:Solubility; D014132:Trachea
D016207:Cytokines; D004731:Endotoxins; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor