Proinflammatory mediator activity, endogenous antagonists and the systemic inflammatory response in intra-abdominal sepsis. Scottish Sepsis Intervention Group.

BACKGROUND: Severe intra-abdominal sepsis continues to carry a high mortality rate. The physiological response to sepsis in this condition and its relationship with proinflammatory mediators and their endogenous antagonists require further clarification. METHODS: Fifty-seven patients were stratified by Acute Physiology And Chronic Health Evaluation (APACHE) II score at the time of admission to an intensive care unit (group 1, score of less than 20; group 2, score of 20 or more). Serial measurements of clinical and immunological variables were made. RESULTS: Non-survivors from group 2 had a raised acute physiology score (P = 0.01), a higher peak serum interleukin (IL) 6 concentration (P = 0.03) and a depressed level of endogenous immunoglobulin (Ig) G class antiendotoxin core antibody (P = 0.005). In group 1, although organ failure score increased progressively in non-survivors, physiology score and peak IL-6 level were similar to those in survivors, and endogenous IgG class antiendotoxin core antibody titre rose (P = 0.02). In both groups IL-1 and tumour necrosis factor alpha were detected infrequently, but their natural antagonists were present in much higher concentrations in both survivors and non-survivors. Levels of C-reactive protein were raised in both but were not significantly different between survivors and non-survivors. CONCLUSION: During the development of organ failure and death, the pattern of proinflammatory mediators and their endogenous antagonists can vary markedly and may in part be determined by the extent of the initial physiological disturbance.

Neutrophil activation, vascular leak toxicity, and cytolysis during interleukin-2 infusion in human cancer.

BACKGROUND: Recombinant interleukin-2 (rIL-2) therapy for advanced malignancy is usually associated with a vascular leak syndrome (VLS) similar to that seen in severe sepsis. We investigated the possibility that the IL-2-induced VLS may be associated with the presence of circulating activated polymorphonuclear (PMN) leukocytes as occurs in sepsis syndrome. METHODS: Estimation of phenotypic (CD11B/CD18) and functional (H2O2, HOCl) up-regulation of circulating neutrophil activity was made by fluorescence-activated cell sorter analysis and ultraviolet spectrophotometry. Associated systemic cytokine enhancement tumor necrosis factor-alpha by enzyme-linked immunosorbent assay for bioactivity and parallel estimation of clinical evidence of vascular leak syndrome were also studied in human subjects with advanced cancer receiving therapeutic doses of rIL-2. RESULTS: The present studies confirm previous reports that tumor necrosis factor-alpha is released into the circulation during infusional therapy with rIL-2. In addition, we have found that this is accompanied by both phenotypic (up-regulation of CD11b/CD18 adhesion receptor expression) and functional (hydrogen peroxide and hypochlorous acid production) evidence of potent PMN activation. Furthermore, patients showing disease response to treatment have significantly greater production of PMN oxidants. CONCLUSIONS: These data suggest that the VLS seen during rIL-2 infusion in human beings may be attributable to PMN mechanisms similar to those invoked during severe sepsis. Consequently, this study may provide further insights into the mechanism of rIL-2's therapeutic action in advanced malignant disease.

Surgery and the release of a neutrophil Fc gamma receptor.

BACKGROUND: The fact that the incidence and mortality from postsurgical sepsis have remained unchanged over the past 15 years raises the possibility that some patients possess an idiosyncratic predisposition to the development of a postoperative sepsis response. Genetic polymorphisms of the neutrophil receptor for immunoglobulin G, CD16, are known, and their inheritance is associated with functional differences in neutrophil phagocytosis. The present studies were designed to provide preliminary data on the effects of surgery on the level of expression of CD16 and its metabolism preparatory to detailed examination of the relationship of these polymorphisms to sepsis responses. PATIENTS AND METHODS: Neutrophil CD16 expression was measured by flow cytometry before and after operation in patients undergoing major resectional surgery of the digestive tract. Assays were performed on whole blood preparations as well as on isolated and activated neutrophil preparations from these patients. RESULTS: Neutrophil CD16 expression was constitutively higher both before and after surgery in patients who developed a postoperative sepsis response than in those who did not. Surgery had no effect on the level of surface neutrophil CD16 expression in either group. Surgery depleted intracellular CD16 stores despite the maintenance of a constant level of CD16 on the neutrophil surface, membrane-bound CD16 being more readily cleaved by physiological neutrophil activators after surgery than before surgery. CONCLUSIONS: The intrinsic level of expression and postsurgical metabolism of neutrophil CD16 may be an important component of the predisposition of some patients to develop infection or sepsis after injury. Further studies of the distribution of CD16 allotypes and neutrophil function among surgical patients are warranted.

Effects of minimally invasive surgery on hypochlorous acid production by neutrophils.

The production of chlorinated oxidants such as hypochlorous acid is a central antimicrobial and immunoregulatory function of neutrophils. Neutrophil hypochlorous acid production was compared in patients undergoing uncomplicated laparoscopic surgery (group 1) and those submitted to conventional open surgery (group 2). Preoperative peak hypochlorous acid production was similar in the two groups (mean(s.e.m.) 0.60(0.05) versus 0.69(0.06) nmol/min respectively). In group 2, mean(s.e.m.) neutrophil hypochlorous acid production fell significantly on day 1 after surgery (0.36(0.05) nmol/min; P < 0.01) but this did not occur in group 1 (0.63(0.07) nmol/min). By day 6 hypochlorous acid kinetics had returned to preoperative levels in both groups. Minimally invasive surgery is less disruptive of neutrophil function than conventional open procedures.

Expression of a suppressive p15E-related epitope in colorectal and gastric cancer.

mRNA for the suppressive epitope of p15E was found to be present in 24 of 30 samples of human colorectal cancer and in all four specimens of gastric cancer. mRNA for p15E was seldom seen in nonmalignant colonic or gastric mucosa but, when present, was associated with inflammatory or pre-malignant conditions of the digestive tract. Synthetic peptides derived from the conserved p15E sequence were found to suppress some aspects of the immune response implicated in anti-tumour activity. These data suggest that a p15E-related material with immunomodulatory properties is elaborated within human tumours, either by the tumour itself or as a normal component of the endogenous anti-tumour reaction.

Polymorphonuclear leukocyte activation. An early marker of the postsurgical sepsis response.

It has been suggested that major surgery induces polymorphonuclear leukocyte (PMNL) dysfunction, which exposes patients to the development of sepsis. Conversely, the sepsis response and multisystem organ failure in patients after surgery is thought to be mediated by activated PMNLs. In a preliminary attempt to investigate this paradox, we studied functional (hydrogen peroxide production) and phenotypic (the adhesion/complement receptor CD11b) markers of PMNL activation in 28 patients undergoing elective major resectional surgery; 11 (39%) of these patients developed postoperative sepsis (the septic group). The mean (SEM) preoperative level of neutrophil CD11b expression (97.8 [6.2] mean channel fluorescence [MCF] and 101.42 [7.9] MCF; P = .74) and hydrogen peroxide production (109.51 [4.91] MCF and 104.53 [6.3] MCF; P = .5) were similar for the uncomplicated and septic groups, respectively. However, on the first postoperative day, both mean CD11b expression and hydrogen peroxide production were greater in those patients who subsequently developed postoperative sepsis (192.5 [38] MCF vs 128.6 [8.1] MCF for the septic group vs the uncomplicated group, respectively [P < .05], and 120.43 [2.56] MCF vs 109.61 [3.05] MCF for the septic group vs the uncomplicated group, respectively [P < .0001]). We suggest that an exaggerated PMNL activation response to surgery is an early event in those patients destined to develop postsurgical sepsis.

Changes in major histocompatibility complex class II expression in monocytes and T cells of patients developing infection after surgery.

Expression of class II major histocompatibility complex (MHC) on monocytes is a prerequisite for effective antigen presentation and processing, an important component of the immune response to infection. It has been reported that the level of monocyte class II expression may identify patients who go on to develop infective complications following trauma. In the present study, flow cytometry was used to measure MHC class II (human leucocyte antigen (HLA)-DR) expression on circulating monocytes and T cells in 36 patients undergoing elective major resectional surgery, of whom 12 developed septic complications. The percentage of HLA-DR positive monocytes fell significantly on the first day after operation in both groups (P < 0.001) but was significantly higher in those without than in those with sepsis on days 1, 3 and 5 (P < 0.05). In contrast, the level of T cell HLA-DR expression rose significantly on the first day after operation (P < 0.05) in patients without sepsis to a level higher than in those who developed infection (P < 0.05). These findings have important implications, as predictive biological elements and for biological response modification, in patients at risk of developing sepsis after surgery.