MODEL FOR WHOLE-BODY PRODUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA IN EXPERIMENTAL ENDOTOXEMIA IN HEALTHY-SUBJECTS

1. Tumour necrosis factor-alpha is considered an important mediator in the pathophysiology of several diseases. Although much information is available about the serum concentrations of this cytokine in these illnesses, little is known about the production of tumour necrosis factor-alpha in disease in vivo. 2. Tn the present study we aimed to estimate the extent and the kinetics of whole body tumour necrosis factor-alpha synthesis in experimental endotoxaemia in six healthy humans. For this purpose we first examined the pharmacokinetic behaviour of an intravenously injected bolus of recombinant human tumour necrosis factor-alpha (50 mu g/m(2)) in another group of six normal subjects. We then calculated the total amount of tumour necrosis factor-alpha produced after intravenous injection of endotoxin (2 ng/kg) as the product of the systemic clearance of recombinant human tumour necrosis factor-alpha (9.5+/-5.0 ml min(-1) kg(-1)) and the area under the tumour necrosis factor-alpha concentration-time curves in the endotoxaemic subjects. 3. Recombinant human tumour necrosis factor-alpha showed evident two-compartment kinetics with an initial rapid disappearance (t(1/2) 5.1+/-2.2 min) and a terminal slower elimination (t(1/2) 49+/-5 min). Tumour necrosis factor-alpha synthesis after endotoxin varied markedly between individuals, ranging from 11.8 to 114.1 mu(g (52.7+/-34.7 mu g). The changes in time of the serum concentrations of tumour necrosis factor-alpha after administration of endotoxin could be accurately described with an adapted two-compartment open model that incorporated both rapid tumour necrosis factor-alpha production (74% of the total amount) and slow tumour necrosis factor-alpha production (26%). 4. Our results suggest that, in endotoxaemia, circulating tumour necrosis factor-alpha originates from two different sources, one in rapid and one in slow equilibrium with the circulation. We propose that the pharmacokinetic characteristics of intravenous recombinant human tumour necrosis factor-alpha may be used to estimate the production of tumour necrosis factor-and in clinical disease.