Exogenously administered
tumor necrosis factor-alpha (TNF) and bacterial
endotoxin (LPS) induce
shock and tissue injury. Here, the authors studied the effect of endogenous TNF on LPS-
induced hypotension and tissue injury and investigated the role of PAF in these responses. Rats were primed with
intraperitoneal injection of
zymosan 24 hours before, or Bacillus Calmette-Guérin (BCG) 12 to 15 days before
intravenous injection of low dose (0.5 mg/kg) LPS. It was found that nonprimed animals showed mild
hypotension and moderate
leukopenia in response to LPS. In contrast, zymosanprimed rats developed
shock and marked
leukopenia, and more severe bowel injury than nonprimed rats. The authors then showed that, following LPS injection,
zymosan-primed animals had higher TNF and
platelet-activating factor (PAF) levels than nonprimed rats. Pretreatment of the animal with PAF antagonist,
SRI 63-441, markedly ameliorated the
hypotension and tissue injury. Interestingly, BCG-primed rats did not show aggravation of LPS-
induced hypotension. Only TNF (but not PAF) level in these animals was increased. Thus, it appears that TNF release alone, without a sufficient increase in PAF, is incapable of causing severe
hypotension. However, most of the BCG-primed animals showed tissue injury, which could be prevented by pretreatment with PAF antagonist. The authors discuss the possible mechanisms of this discrepancy between systemic and local responses in BCG-primed animals.