Whole blood tumor necrosis factor-alpha production and its relation to systemic concentrations of interleukin 4, interleukin 10, and transforming growth factor-beta(1) in multiply injured blunt trauma victims

Objective: To study the relation of whole blood endotoxin responsiveness to inhibitory mediators systemically released after severe blunt trauma. Design: Prospective, observational study. Setting: University trauma center. Patients: Thirty-two patients with blunt trauma (mean injury severity score , 33 points). Interventions: Standard emergency department, surgical care, and postoperat ive intensive care unit treatment. Measurements and Main Results: Whole blood and serum were obtained immediat ely after admission to the emergency department (<8 hrs after trauma, denot ed day 0) and on days 1, 2, 4, 6, 8, and 14 after trauma, Whole blood speci mens were assayed for endotoxin-induced tumor necrosis factor (TNF)-alpha s ynthesis ex vivo and serum specimen were assayed for interleukin (IL)-4, IL -10, and transforming growth factor (TGF)-beta(1) concentrations. Moreover, the TNF-alpha inhibitory capacity of recombinant human (rh) IL-4, rhIL-10, and TGF-beta(1) as well as the inhibitory capacity of patients' serum from days 0, 1, 2, 4, 6, 8, and 14 were tested on uninjured donors' whole blood . Cytokines were determined by ELISA. Whole blood endotoxin responsiveness in multiply injured patients was signi ficantly reduced during the observation period and was found to be signific antly related to the total inhibitory activity detected in the correspondin g sera. Exchange of patients' serum for uninjured donors' or recovered pati ents' serum restored TNF-alpha production of peripheral blood mononuclear c ells from multiply injured patients. Serum levels of IL-4 and IL-10 were no t related to trauma patients' whale blood TNF-alpha production upon endotox in stimulation, whereas TGF-beta(1) concentrations were positively related. Compared with the apparent half-maximal inhibition concentrations determin ed, serum revels of TGF-beta(1), IL-10, and IL-4 were 20- to 20,000-fold be low the quantities required to explain the inhibitory serum activity in mul tiply injured patients on day 0. Conclusions: Whole blood hyporesponsiveness to endotoxin in multiply injure d patients is caused by soluble serum factors systemically released after t rauma, whereas;the intrinsic leukocyte function appears unaffected. inhibit ory mediators other than IL-4, IL-10, or TGF-beta(1) are supposed to be of major biological relevance for the posttraumatic regulation of leukocyte fu nction. Characterization of the causative suppressive mediators is supposed as a prerequisite for the development of immunologically based therapeutic approaches in critically ill patients.