REDUCED TUMOR-NECROSIS-FACTOR PRODUCTION IN ENDOTOXIN-SPIKED WHOLE-BLOOD AFTER TRAUMA - EXPERIMENTAL RESULTS AND CLINICAL CORRELATION

Background. The overproduction of tumor necrosis factor-alpha (TNF) plays a key role in virtually every experimental model of septic shock, which has led to the development of several therapies that target TNF and other cytokines in clinical sepsis. However, our previous work showed that plasma TNF was reduced, rather than increased, when a septic challenge was administered 3 days after hemorrhagic shock. In this study we compared whole-blood TNF production ex vivo in human beings and animals after trauma. Methods. TNF was measured before and after a 4-hour incubation of whole blood with 0 or 5 mu g/ml Escherichia coli endotoxin (LPS) at 37 degrees C ex vivo. Samples were obtained from trauma patients with (n = 8) and without (n = 14) sepsis and compared with those obtained in healthy volunteers (n = 11). In parallel experiments in a pig model TNF was measured before and after fluid resuscitation from trauma after an ex vivo (0 or 5 mu g/ml LPS) or an in vivo (5 mu g/kg LPS, 30 minutes intravenously) challenge. Results. With either an immunoassay or a bioassay in either human beings or pigs before or after trauma, TNF was at or below the threshold of detection, unless the blood sample was spiked with LPS. After spiking, TNF was markedly elevated, but the increment was reduced after trauma. In pigs an LPS challenge in vivo delayed 3 days after trauma evoked an increment in plasma TNF that was blunted compared with that in an uninjured control. This trauma-induced reduction in blood TNF could not be attributed to a simple reduction in the number of monocytes nor to changes in cortisol, nor to increased numbers of neutrophils, whose proteolytic enzymes can impair production or increase the degradation of TNF. Although the plasma concentration of soluble TNF-binding proteins (60 kd) was elevated in nonsepsis (p = 0.0358) and sepsis trauma patients (p = 0.0148), the correlation with TNF production was relatively weak (R(2) = 0.260). Conclusions. There was no evidence of TNF overproduction in whole blood after trauma. If these results could be generalized to other tissues, it would be difficult to justify therapeutic targeting of TNF in exaggerated inflammatory response (or septic complications) after trauma.