Priming of human neutrophil functions by tumor necrosis factor: Enhancement of superoxide anion generation, degranulation, and chemotaxis to chemoattractants C5a and f-Met-Leu-Phe

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.

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Red Cell Regulation of Tumor Necrosis Factor-Induced Human Neutrophil Cytostatic Activity

Cancer Communications ◽

10.3727/095535491820873065 ◽

1991 ◽

Vol 3 (9) ◽

pp. 283-286 ◽

Cited By ~ 1

Author(s):

Shau Hungyi

Keyword(s):

Tumor Necrosis Factor ◽

Human Neutrophil ◽

Tumor Necrosis ◽

Cytostatic Activity ◽

Red Cell ◽

Cell Regulation ◽

Necrosis Factor

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Tumor necrosis factor-alpha stimulates superoxide anion generation by perfused rat liver and Kupffer cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1991.261.6.g891 ◽

1991 ◽

Vol 261 (6) ◽

pp. G891-G895 ◽

Cited By ~ 5

Author(s):

A. P. Bautista ◽

A. Schuler ◽

Z. Spolarics ◽

J. J. Spitzer

Keyword(s):

Tumor Necrosis Factor ◽

Organ Failure ◽

Rat Liver ◽

Kupffer Cells ◽

Superoxide Anion ◽

Tumor Necrosis ◽

Perfused Rat Liver ◽

Experimental Conditions ◽

Necrosis Factor

Tumor necrosis factor (TNF) has been implicated as one of the mediators of the immunologic and metabolic changes in endotoxemia. Under adverse conditions, TNF can also be cytotoxic, and its effects can ultimately contribute to organ failure. This study shows that a 30-min infusion of a nonlethal dose of TNF induced the release of superoxide anion (0.9 nmol.min-1.g-1) by the in situ perfused rat liver. TNF also primed the liver to generate more superoxide anion (2.0 nmol.min-1.g-1) in response to an in vitro challenge with phorbol 12-myristate 13-acetate (PMA). Kupffer cells are most likely responsible for the superoxide anion production under these conditions, because the isolated Kupffer cells from TNF-infused rats produced increased quantities of superoxide anion (4-8 nmol/10(6) cells) when subsequently treated in vitro with either PMA or opsonized zymosan (control less than 1 nmol/10(6) cells). Thus, under these experimental conditions, TNF in vivo primed the Kupffer cells, but not the hepatocytes, endothelial cells, and the blood or hepatic neutrophils, to release more superoxide anion. These studies indicate that during a short-term nonlethal TNF infusion, Kupffer cells are a major target of TNF action, leading to the release of toxic-oxygen metabolites that may contribute to organ failure.

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