Tumor necrosis factor-induced lung injury is not mediated by platelet-activating factor.
Both tumor necrosis factor (TNF) and platelet-activating factor (PAF) have been incriminated as mediators of endotoxic shock. Since TNF stimulates PAF synthesis in vitro, we tested the hypothesis that PAF mediates TNF-induced lung injury in vivo using specific PAF receptor antagonists. Intravenous infusion of purified human recombinant TNF resulted in peripheral neutrophilia, lymphocytopenia, and hemoconcentration, caused hemorrhagic injury to the cecum, and increased lung tissue levels of thromboxane B2 and 6-ketoprostaglandin F1 alpha. In addition, plasma glutathione disulfide (GSSG), an in vivo index of oxidative stress, was significantly increased. TNF (0.01-1 mg/kg) caused a dose-dependent increase in lung permeability-surface area product (PS) measured in isolated perfused lungs removed from rats 90 min after injection of TNF. [Lung PS in controls and after 0.01, 0.1, and 1.0 mg/kg of TNF were 0.022 +/- 0.001, 0.027 +/- 0.002, 0.033 +/- 0.001, and 0.036 +/- 0.005, respectively (P less than 0.05 from control for TNF 0.1 and 1 mg/kg).] Pretreatment of the rats with the PAF receptor antagonists WEB 2086 (10 mg/kg) and SRI 63-441 (10 mg/kg), at doses that previously protected against endotoxin-induced lung injury, did not significantly affect TNF-induced (0.1 mg/kg) changes in hematocrit, plasma GSSG, or lung PS. Moreover, WEB 2086 (10 mg/kg) did not inhibit TNF-induced (1 mg/kg) lymphocytopenia or the increases in lung tissue eicosanoid products. We conclude that TNF causes oxidative stress, eicosanoid activation, and acute lung injury in rats by a mechanism largely independent of PAF receptor activation.
Chang
S W
SW
Cardiovascular Pulmonary Research Laboratory, University of Colorado Health Sciences Center, Denver 80262.
Ohara
N
N
Kuo
G
G
Voelkel
N F
NF
D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D015777:Eicosanoids / Q000032:analysis; D005978:Glutathione / Q000097:blood; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D013499:Surface Properties; D014227:Triazines / Q000494:pharmacology*; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D001381:Azepines; D015777:Eicosanoids; D010972:Platelet Activating Factor; D014227:Triazines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C052518:WEB 2086; D005978:Glutathione