The role of the complement system in shock and tissue injury induced by tumour necrosis factor and endotoxin

It has previously been shown that tumour necrosis factor-alpha (TNF), together with bacterial lipopolysaccharide (LPS), induces shock and bowel necrosis in the rat. Since the complement system plays an important role in inflammation and tissue injury, its role has been studied in a similar model in mice. In most of the present experiments, a low dose (0.2 micrograms/g) of TNF was used for priming, followed 30 min later by LPS (3 micrograms/g), and the experiment was terminated in 150 min. It is shown that: (i) TNF exerts no systemic effects by itself; LPS elicits only mild hypotension but causes no lethality; (ii) TNF-primed mice show exaggerated effects of shock, hypothermia, haemoconcentration and bowel injury after LPS; the majority of these mice died within 150 min; (iii) administration of LPS alone mildly activates the complement system in vivo, while TNF alone has no effect; (iv) the effects of TNF and LPS on complement activation are synergistic; (v) the acute development of shock and bowel injury in response to TNF-LPS is dependent on an intact complement system, more specifically C5, since C5-deficient mice were protected from TNF-LPS-induced shock and tissue injury; C5-deficient mice also showed less hypotension, hypothermia, haemoconcentration and better intestinal perfusion compared with C5-sufficient animals; (vi) however, when the priming dose of TNF was raised to 0.5 micrograms/g, most of the C5-deficient mice developed marked hypothermia, hypotension, haemoconcentration, bowel injury and died. Thus, it is concluded that TNF and LPS act synergistically in activating the complement system, which plays an important role in mediating the tissue injury and lethality induced by these agents.