Development of partial tolerance to the gastrointestinal effects of high doses of recombinant tumor necrosis factor-alpha in rodents.

Abstract

Treatment of healthy rats and mice with a single intravenous injection of recombinant human tumor necrosis factor-alpha (rHuTNF-a) caused a dose-dependent gastrointestinal inflammation. Within 30 min gastric emptying was blocked and tissue edema occurred in the small and large intestine. In the cecum hemorrhage occurred after 4 h at doses 2 250 ag/kg. The cecum exhibited an acute inflammatory response following rHuTNF-a treatment similar to that seen in tumor necrosis at the same dose. The vascular endothelium became swollen, increased numbers of neutrophils and other leukocytes attached to and penetrated the endothelium, and finally hemorrhage occurred. Treatment of rats with daily injections of rHuTNF-a (250 tig/kg per d) for 3 wk failed to produce cachexia. Within 2448 h rats became resistant to the hemorrhagic effect of rHuTNF-a, however, the cytokine still caused a transitory block of gastric emptying after 10 d of treatment. Treatment at 5-or 10-d intervals produced results similar to the initial injection. These results suggest that maximum hemorrhagic response will occur when rHuTNF-a is administered at intervals of 5-10 d rather than daily.

In vivo targets of recombinant human tumour necrosis factor-α: blood flow, oxygen consumption and growth of isotransplanted rat tumours

“…Partial tolerance to the gastrointestinal effects of high rh-TNF-a doses developed when TNF application was repeated daily (Patton et al, 1987). In good agreement with these data haemorrhagic diarrhoea with weight loss developed only after the first TNF application.…”

Administration of Escherichia coli endotoxin to rat increases liver mass and hepatocyte volume in vivo

“…In the course of preliminary studies, we found that fed rats were not an appropriate control for the endotoxin-treated rats which, when fed ad libitum, manifested a profound decrease in spontaneous food intake and had distended stomachs with marked food stagnation. This is consistent with the published reports that endotoxin administration constricts the pyloric sphincter and thus inhibits gastric emptying [8,9]. In order to maintain the same post-absorptive state we therefore fasted both the endotoxin-and saline-treated group.…”

Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis.

“…Our laboratory (6,7) and others (8)(9)(10) have noted tolerance to the anorectic effects ofTNF with repetitive administration. In addition, we have noted that prior administration of recombinant (r) TNF-alpha also protects against a lethal injection of TNF or a lethal injection of endotoxin (6).…”