Effects of in vivo 'priming' on endotoxin-induced hypotension and tissue injury: The role of PAF and tumor necrosis factor

Exogenously administered tumor necrosis factor-α (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-Guerin (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, zymosan-primed 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 TNP 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.