Effects of recombinant human superoxide dismutase on tumor necrosis factor-induced lung injury in awake sheep.
Tumor necrosis factor alpha (TNF) is a mediator of acute lung injury after endotoxemia, but the precise mechanism of TNF-induced lung injury remains unclear. To clarify the role of oxygen radicals, especially superoxide anion, in TNF-induced lung injury, we examined the effects of recombinant human superoxide dismutase (rhSOD; 4,200 U/mg) on lung physiological and biochemical changes after TNF infusion in awake sheep (n = 17). We prepared chronically instrumented sheep for lung lymph collection and hemodynamic monitoring. Recombinant human TNF (3.5 micrograms/kg iv) induced a biphasic response in awake sheep. Pulmonary hypertension peaked within 15 min of initiation of TNF and remained elevated for 3 h, followed by increased lung vascular permeability. rhSOD attenuated the pulmonary hypertension in both early and late phases but caused no change in the timing or magnitude of lung fluid balance changes during the late phase. Thromboxane A2 (thromboxane B2) and prostacyclin (6-ketoprostaglandin F1 alpha) metabolite levels in plasma and lymph increased after the TNF infusion, and rhSOD attenuated these changes. The intravenous infusion of rhSOD resulted in the appearance of significant levels of SOD activity in both plasma and lung lymph before and after TNF infusion. These findings suggest that superoxide anion may be implicated in the pathogenesis of the pulmonary hypertension induced by TNF in sheep.
First Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
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T
Amari
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Kubo
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Kobayashi
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Sekiguchi
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D055370:Lung Injury; D011652:Pulmonary Circulation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D012756:Sheep; D013482:Superoxide Dismutase / Q000494:pharmacology*; D013481:Superoxides / Q000097:blood / Q000378:metabolism; D013929:Thromboxane B2 / Q000097:blood; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D013482:Superoxide Dismutase