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Objectives: To determine the potential of interleukin-13 (IL-13) to modify in vitro lipopolysaccharide-induced monocyte-macrophage (MO) activity in human cells from individuals who had sustained either major mechanical or burn injury and to investigate whether the effect of IL-13 is different on MOs that have been preactivated under traumatic stress than on monocytic cells from healthy volunteers., Design: Peripheral MOs from 20 controls and 16 patients after major burn or mechanical trauma were separated on days 1, 3, 5, and 7 after injury and incubated with lipopolysaccharide (1 microgram/mL) in the presence or absence of IL-13 (10 ng/mL) for 4 hours and for 20 hours. Thereafter, the following measures were determined from the culture supernatants: neopterin, nitric oxide, tumor necrosis factor alpha, IL-1 beta, IL-6, and IL-8., Results: Ex vivo lipopolysaccharide-activated MOs, compared with control cells, displayed considerably enhanced inflammatory activity during the immediate posttraumatic course, with a substantial and consistent elevation of levels of tumor necrosis factor alpha and IL-6. The addition of human recombinant IL-13 to the MO cultures resulted in an effective down-regulation of the synthesis of tumor necrosis factor alpha, IL-1 beta, and IL-6 as well as IL-8, showing an average reduction of mediator production to two thirds of the value found in corresponding sole lipopolysaccharide-stimulated cultures. The impact of human recombinant IL-13 on control MOs was almost identical for IL-6 and IL-1 beta, slightly lower for IL-8, and nonexistent for tumor necrosis factor alpha., Conclusion: From this study and preexisting findings, we conclude that, based on its biologic properties, IL-13 should be tested as a biologic response modifier for acute states of trauma-induced host defense deficiency.

Background: The proteolytic enzyme elastase released by granulocytes (polymorphonuclear leukocytes [PMN]) in high concentrations during sepsis causes degradation of essential plasma proteins, endothelial damage, and tissue edema. This may result in organ dysfunction and organ failure during sepsis, since increased elastase plasma levels correlate with the mortality rate of patients with sepsis. In vitro studies demonstrated a regulatory role of inflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin 1 beta [IL-1 beta], IL-8]) upregulating protease release by PMN. In this light, the interactions between cytokine release by macrophages and altered elastase secretion during sepsis remain to be determined., Methods: An ex vivo model consisting of lipopolysaccharide stimulation of human whole blood as a relevant physiological milieu was used. Heparinized blood was obtained from 20 patients with sepsis syndrome (APACHE II [Acute Physiology and Chronic Health Evaluation II] score 28.5 +/- 1.2 points [mean +/- SD]) on days 0 through 3, 5, 7, and 10 after sepsis diagnosis and from 20 control patients without infection. Blood was incubated with lipopolysaccharide (1 mg/L) for 8 hours. Plasma levels of elastase, TNF-alpha, IL-1 beta, and IL-8 were determined using enzyme-linked immunosorbent assay or bioassay (TNF-alpha), respectively., Results: Elastase plasma levels in whole blood from patients with sepsis were increased up to 188% (P < .01) above normal, while the release of TNF-alpha (-87%), IL-1 beta (-91%), and IL-8 (-51%) was markedly (P < .01) decreased compared with control patients. Neutralization of TNF-alpha or IL-1 beta did not attenuate the increased release of elastase., Conclusions: These data indicate an increased release of elastase by PMN despite a reduced secretion of PMN-activating cytokines. Although priming effects of TNF-alpha, IL-1 beta, and IL-8 on protease secretion in vivo cannot be excluded completely, other mediators or mechanisms may be involved in the upregulation of detrimental protease release during sepsis.

The macrophage exerts its stimulatory and regulatory functions within the specific immune response via the interleukin 1 (IL-1) and prostaglandin E2 (PGE2), respectively. In a screening study of macrophage-related variables following injury, a total of 58 patients (mean age, 32 years; mean injury Severity Score, 38), macrophagic phenotyping with the monoclonal antibody Leu M3 and serial measuring of the antagonistic monokines IL-1 and PGE2 and of the macrophage-activating lymphokine interferon gamma were carried out on posttrauma days 0, 1, 3, 5, 7, 10, 14, and 21. The posttraumatic course was characterized by significant monocytosis, showing a peak value of 32% of Leu M3-positive cells compared with 15% of these cells in normal control subjects. During the posttrauma course, the macrophagic PGE2 output was significantly elevated up to eightfold on days 5 and 7 compared with that of control subjects (0.441 +/- 0.14 ng/mL vs 0.052 +/- 0.01 ng/mL). Conversely, macrophagic IL-1 synthesis was significantly suppressed until day 10. Levels of interferon gamma were suppressed to a significant degree during the two-day observation period, with a trend to slow recovery at the end of week 3. These data suggest that a negative regulatory macrophagic function may be the event initiating posttraumatic immunosuppression. To restore impaired macrophagic T-helper cell interaction, cyclo-oxygenase inhibition and substitution of interferon gamma may be useful to potentiate facilitatory macrophagic function and to block inhibitory macrophagic activity.

The effects of perioperative administration of thymopentin (TP-5) on in vivo and in vitro measurements of cell-mediated immunity in elderly patients undergoing major surgery were investigated. A placebo-controlled study was conducted in 25 patients (mean age, 67 years) with congenital or acquired heart disease undergoing surgery with cardiopulmonary bypass. Patients were divided into three groups: Group 1 patients were given 50 mg of TP-5 subcutaneously two hours preoperatively. Group 2 patients were given 50 mg of TP-5 subcutaneously two hours preoperatively and 48 hours postoperatively. Group 3 patients were given placebo at corresponding times. Cell-mediated immunity measurements were the in vivo delayed-type hypersensitivity (DTH) response on day 0 and on day 7 to an antigen skin test battery. The in vitro studies included antigen cocktail-induced lymphocyte proliferation of peripheral blood mononuclear cells. The DTH response on day 7 after surgery was significantly suppressed in group 3 patients compared with the preoperative baseline value, while it remained unaltered in group 1 and 2 patients. There was a considerable difference of DTH measurements (number of positive antigen responses and sum of their mean diameters) between group 2 and 3 patients. Antigen cocktail-induced lymphocyte proliferation, following initial suppression in the majority of patients, was significantly different between the placebo group and patients in group 2 on day 7 after surgery. The data indicate that perioperative administration of TP-5 might be of considerable clinical utility in preventing a defective cellular immune response.

This study examined a group of surgical patients with respect to the ability of their peripheral blood mononuclear cells to respond to phytohemagglutinin (PHA). Depression of the PHA response of more than 30% below baseline five to seven days after injury was found in 11 of 19 patients, and eight of them developed infectious complications. The addition of indomethacin to in vitro cultures resulted in an average enhancement of the PHA response of 37% baseline. Improvement at five to seven days with in vitro indomethacin was from 34% to 74% in infected patients. These data suggest that major injury can lead to depression of the PHA response, which correlates with the subsequent development of infectious complications. Indomethacin in vitro seems to be able to reverse or decrease this immunologic defect and deserves further study.

Major mechanical trauma causes a severe suppression of B-cell differentiation and IgM synthesis in mononuclear leukocyte cultures. In this study the effect of recombinant lymphokines and physiologic T-cell supernatants on B-cell differentiation was investigated. The influence of potentially suppressing monocytes and positive regulatory T-lymphocytes was eliminated using purified B-cell cultures. Antigen-induced IgM synthesis was reduced on all days following trauma. Addition of recombinant interleukin 2 or T-cell supernatant enhanced but did not restore IgM synthesis. Although recombinant interleukin 4 and recombinant interferon gamma had a suppressive effect on IgM synthesis in controls, both lymphokines were ineffective in the patients' IgM synthesis. Spontaneous IgG production in patients was dramatically elevated, and the addition of lymphokines did not show any enhancing effect in patients. These results demonstrate that the IgM/IgG shift observed in peripheral blood mononuclear cell cultures also exists in purified B-cell cultures. Interleukin 2 partially restored suppressed IgM synthesis, while interleukin 4 and interferon gamma were ineffective in patients' B-cell differentiation. Interleukin 2 was the most effective lymphokine for the induction of Ig synthesis. These results lead us to conclude that the altered B-cell metabolism might also be responsible for the suppression of humoral immunity following trauma.