Tsuguhiko Tashiro

Influences of soybean oil emulsion on stress response and cell-mediated immune function in moderately or severely stressed patients

OBJECTIVES We previously reported that omega-6 fat emulsion increases cytokine production in burned rats. Effects of soybean oil emulsion on surgical stress responses and lymphocyte function according to the surgical severity have not been studied in detail. We investigated the effects of soybean oil emulsion, which contains 50% omega-6 fatty acid, on postoperative stress responses and cell-mediated immune function according to the severity of surgical stress. METHODS Eight patients who underwent gastric or colorectal surgery and nine who underwent esophagectomy were fed fat-free total parenteral nutrition. Ten patients who underwent gastric or colorectal surgery and seven who underwent esophagectomy were fed total parenteral nutrition with soybean oil emulsion. Total parenteral nutrition provided 1.5 g of protein and 40 kcal per kilogram every day from 7 d before surgery to postoperative day 14. Soybean oil emulsion (Intralipid) accounted for 20% of the total calories. Serum interleukin-6, C-reactive protein, glucagon, and concanavalin A- or phytohemagglutinin-stimulated lymphocyte proliferation were determined. RESULTS In the group of moderately stressed patients, soybean oil emulsion did not amplify the measured levels. In the group of severely stressed patients, soybean oil emulsion amplified the level of serum interleukin-6 and decreased concanavalin A- or phytohemagglutinin-stimulated lymphocyte proliferation. CONCLUSIONS Soybean oil emulsion amplifies the stress responses and possibly suppresses cell-mediated immune function induced by surgical stress in severely stressed patients, but not in moderately stressed patients.

n-3 Versus n-6 Polyunsaturated Fatty Acids in Critical Illness

The effects of n-6 and n-3 polyunsaturated fatty acids (PUFA) on protein metabolism, cell-mediated immunity, and production of cytokines and prostanoids were studied in experimental animals and patients with esophageal cancer. In the experimental study using a rat burn model, n-6 PUFA increased serum interleukin-6 (IL-6) and tumor necrosis factor (TNF), alpha (P < 0.05), and decreased nitrogen balance (NB) (P < 0.05), when compared with a fat-free control. But addition of n-3 PUFA reduced TNF-alpha and IL-10 (P < 0.05) and improved NB (P < 0.05). Suppressed delayed type hypersensitivity (DTH) induced by burn injury, which was not influenced by n-6 PUFA, was significantly improved by the administration of n-3 PUFA. n-6 PUFA tended to increase, and n-3 PUFA significantly decreased the endotoxin translocation. DTH, granulocyte-macrophage colony-stimulating factor, and eicosapentaenoic acid (EPA) content increased proportionately with the intravenous dose of fish oil emulsion. The effects of n-6 and n-3 PUFA were studied in the patients who underwent surgery for esophageal cancer. In the group of patients fed by total parenteral nutrition with soybean oil emulsion, the serum IL-6 significantly increased at 2 and 6 h after operation (P < 0.05). Oral/enteral supplementation of EPA ethyl ester (1.8 g/d) significantly reduced the postoperative IL-6 production (P < 0.05 at 1, 2, and 6 h after operation), and improved cell-mediated immune function 3 wk after operation (P = 0.05). During the chemoradiation therapy, cell-mediated immune function was improved significantly in the patients fed enterally with EPA ethyl ester (n = 5), when compared with the patients without EPA (n = 14).

Modulating Effects of the Feeding Route on Stress Response and Endotoxin Translocation in Severely Stressed Patients Receiving Thoracic Esophagectomy

Experimental studies have demonstrated that the route of nutritional supply impacts the systemic metabolic responses after surgical injury. Intestinal mucosal atrophy, as induced by total parenteral nutrition (TPN) or prolonged bowel rest, has been reported to enhance bowel endotoxin translocation. The operative procedure for thoracic esophageal cancer, including thoracotomy, laparotomy, and three-field lymph-node dissection, is a particularly stressful surgery that requires long-term aggressive nutritional support and often results in the postoperative hypermetabolic state, leading to perturbation of postoperative immune function. Interleukin-6 (IL-6) plays an important role in host inflammatory responses, whereas IL-10 is linked to suppression of cellular immunity. The aim of this study was to investigate how the antecedent nutritional routes influence systemic IL-6 and IL-10 responses and endotoxin translocation after an operation for thoracic esophageal cancer. Twenty-nine patients who underwent esophagectomy with three-field lymphadenectomy were investigated. They were assigned to groups receiving either TPN (n = 18) or enteral nutrition (EN; n = 11) providing 35 kcal x kg(-1) x d(-1) of energy and approximately 1.2-1.5 g x kg(-1) x d(-1) of amino acids. These nutritional supports were conducted from 1 wk before the operation to 14 d after the operation. Serum IL-6, IL-10, and endotoxin concentration were measured before and during the operation and at 2 h and 1, 3, and 7 d after the operation. IL-6 in sera was significantly higher after the operation in both groups. In the EN group, however, significantly less IL-6 production was observed on the third and seventh postoperative days when compared with those patients in the TPN group. Similarly, serum IL-10 concentration in the TPN group showed a significantly higher level than that in the EN group. Serum IL-6 showed a significant positive correlation with IL-10 at 2 h and at 7 d after the operation, suggesting that the reduced inflammatory responses were related to the inhibition of the development of postoperative immunosuppression. Endotoxin concentration in sera was significantly lower in the EN group after the operation than in the TPN group. Perioperative EN provides better regulation of inflammatory cytokine responses and may contribute less to immunosuppression after major surgery than parenteral nutrition. The attenuated production of endotoxin induced by EN may play an important role in these phenomena.

Effects of Soybean Oil Emulsion and Eicosapentaenoic Acid on Stress Response and Immune Function After a Severely Stressful Operation

OBJECTIVE To investigate the effects of soybean oil emulsion and oral or enteral administration of eicosapentaenoic acid (EPA) on stress response, cytokine production, protein metabolism, and immune function after surgery for esophageal cancer. SUMMARY BACKGROUND DATA It has been reported that safflower oil, rich in n-6 polyunsaturated fatty acid (n-6 PUFA), affects the survival rate of septic animals and decreases the immune function. It has also been reported that the administration of fish oil, in contrast, reduces these stress responses and stress-induced immunosuppression. In humans, the effects of soybean oil emulsion and the administration of EPA on stress response and immune function after surgery have not been established. METHODS Patients who underwent esophagectomy with thoracotomy were divided into three groups. Seven patients were fed by total parenteral nutrition (TPN) with soybean oil emulsion, which accounted for 20% of total calories. Seven patients were given oral or enteral administration of 1.8 g/day EPA, in addition to TPN with soybean oil emulsion. Nine patients served as the control group; these patients received fat-free TPN. Serum interleukin-6 (IL-6), C-reactive protein, concanavalin A (con A)- or phytohemagglutinin (PHA)-stimulated lymphocyte proliferation, natural killer cell activity, and stress hormones were measured. RESULTS The postoperative level of serum IL-6 was significantly higher in the group receiving soybean oil emulsion than in the fat-free group. Oral or enteral supplementation of EPA with soybean oil emulsion significantly reduced the level of serum IL-6 compared with the patients receiving soybean oil emulsion. Con A- or PHA-stimulated lymphocyte proliferation decreased significantly on postoperative day 7 in all groups of patients. The supplementation of EPA with soybean oil emulsion significantly improved the lymphocyte proliferation and natural killer cell activity on postoperative day 21 compared with the group receiving soybean oil emulsion. CONCLUSIONS Soybean oil emulsion amplifies, and the supplementation of EPA reduces, the stress response and stress-induced immunosuppression.

Changes in immune function following surgery for esophageal carcinoma.

Changes in immune function due to surgical injury have been well-documented. Immunosuppression is one of the causes of infectious complications leading to organ dysfunction in critical illness. It is not known what kind of surgery in the daily clinical practice causes immunosuppression. Stress response and immune function following surgery for esophageal carcinoma, assuming a highly-stressed operation, were studied and then compared with the stress response and immune function following gastric surgery, a moderately-stressed procedure. Forty patients who underwent esophagectomy and 39 patients receiving gastric operation were studied. The concentrations of serum interleukin-6 (IL-6) were measured preoperatively, at 1, 2, and 6 h, and at 1, 3, and 10 d after operation. Total protein, serum albumin, rapid turnover protein, serum CRP, and cortisol were measured before operation and at 1, 3, 7, and 21 d after operation. ConA- and PHA-stimulated lymphocyte proliferation, IgA, IgG, and IgM were also measured preoperatively, and on 7 and 21 d following surgery. The patients were fed exclusively by total parenteral nutrition (TPN). A striking rise of IL-6 was observed, with a peak in both groups at 1 to 6 h following operation. The peak values were 419+/-30 pg/mL, which was approximately twice as high in the esophagectomy patients as in the gastrectomy patients (195+/-40 pg/mL). CRP and cortisol also increased after operation, and these increases were also significantly greater in the esophagectomy patients. ConA- and PHA-stimulated lymphocyte proliferation decreased significantly 7 d after esophagectomy (P<0.05), but was unchanged in the patients receiving gastrectomy. Suppression of cellular immunity correlated significantly with serum cortisol, and was preceded by a rise in serum IL-6. The IgA, IgG, and IgM levels, however, remained unchanged from their preoperative values throughout the study in both groups. Nutritional status in terms of serum protein, albumin, and rapid turnover protein, decreased postoperatively, but there was no difference between the two groups. It is, therefore, concluded that cell-mediated immunosuppression, preceded by a hyperinflammatory response, is an observable reaction in patients following esophageal surgery, but not in patients undergoing gastric surgery.

An essential role of macrophage inflammatory protein 1α/CCL3 on the expression of host’s innate immunities against infectious complications

Sepsis was induced by well‐controlled cecal ligation and puncture (CLP) in macrophage inflammatory protein 1α (MIP‐1α)/CCL3 knockout (CCL3−/−) and severe combined immunodeficiency (SCID) mice. CCL3−/− mice and their littermates (CCL3+/+ mice) treated with anti‐CCL3 monoclonal antibodies were susceptible (0–20% survival) to CLP‐induced sepsis, and CCL3−/− mice supplemented with recombinant (r)CCL3 (250 ng/mouse) and CCL3+/+ mice were resistant (70–80% survival). The resistance of SCID mice to CLP was markedly improved by the rCCL3 administration (88% survival), and SCID mice treated with saline were shown to be middling resistant to the same CLP (45% survival). However, the resistance of SCID‐M mice (SCID mice depleted of the macrophage function) to CLP was not improved by the rCCL3 administration (11% survival), and 41% of SCID‐M mice reconstituted with normal peritoneal macrophages and 79% of SCID‐M mice inoculated with CCL3‐treated peritoneal macrophages survived. In addition, the resistance of SCID‐MN mice (SCID mice depleted of functional macrophages and neutrophils) to CLP was improved by the inoculation of CCL3‐treated macrophages (78% survival), and all of SCID‐MN mice inoculated with CCL3‐treated neutrophils died. CCL3 is shown to be essential to the host resistance against bacterial sepsis. Macrophages but not neutrophils are highlighted as the major effector cells when protective innate immunities against sepsis are improved by CCL3.

Effect of severity of stress on whole-body protein kinetics in surgical patients receiving parenteral nutrition

A study was conducted to clarify the quantitative relationship between the alteration of protein metabolism and the severity of surgical stress to further understand the mechanisms of body nitrogen losses in surgical trauma. Twenty-one patients undergoing esophagectomy for esophageal cancer (group E), and 22 undergoing gastrectomy or colorectal operations for gastric or colorectal cancer (Group GC) were studied. All patients were fed exclusively by parenteral nutrition (PN) providing 1.5 g protein.kg-1.d-1 and 35 kcal.kg-1.d-1 before and after the operation. The measurements of whole-body protein turnover, synthesis, and breakdown were performed preoperatively and on postoperative days (PODs) .3 and 10. Urinary excretion of total nitrogen and total catecholamines was also measured. Urinary excretion of the total catecholamines of group E was twice as high as that of group GC on the POD 3 and well reflected the severity of surgical stress. Negative correlation of nitrogen retention to urinary excretion of the total catecholamines was also observed (r = 0.64; P < 0.01). The correlations between the urinary excretion of the total catecholamines and the whole-body protein flux, synthesis, and breakdown were statistically significant (r = 0.57, 0.27, and 0.57, respectively; P < 0.01 in all). Rate of elevation in breakdown according to the stress level was greater than that of synthesis. Consequently the progressive aggravation of nitrogen balance according to the severity of surgical stress was observed.

Effect of intravenous ω-6 and ω-3 fat emulsions on nitrogen retention and protein kinetics in burned rats

Abstract The effect of ω-3 fat emulsion on nitrogen retention and kinetics in relation to fatty acid profile were investigated in burned rats receiving total parenteral nutrition (TPN). A fat emulsion of a structured symmetrical triacylglycerol containing only eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (2:1) was prepared. Sprague-Dawley rats were fed by fat-free chow for 2 wk. Then rats were fed exclusively with one of three types of TPN for 7 d. Animals in group C received fat-free TPN ( n = 11). Group ω6 received safflower oil fat emulsion, which accounted for 20% of total caloric intake ( n = 11). Group ω3 received fat emulsion containing only EPA and DHA (1% of total calories, n = 11), in addition to safflower oil emulsion (19% of total calories). On day 5, each rat was subjected to 20% full-thickness scald burns. Rats were sacrificed under ether anesthesia 48 h after burning. The rats in group C became deficient in ω-6 essential fatty acids. Cumulative nitrogen balance was decreased significantly in group ω6. The rates of whole-body protein synthesis were increased significantly in both groups ω6 and ω3. In ω6, however, the rates of whole-body protein breakdown were increased significantly. In conclusion, the rates of whole-body protein breakdown increased and nitrogen retention was aggravated significantly in animals administered the safflower oil emulsion. Significant increases of urinary excretion of total catecholamine were also observed. Prostaglandin E 2 and thromboxane B 2 concentrations were not significantly different among three groups. Supplementation with the new ω-3 fat emulsion, however, improved protein metabolism in burned rats receiving TPN.

Preoperative immunosuppression: its relationship with high morbidity and mortality in patients receiving thoracic esophagectomy

The operative procedure for thoracic esophageal cancer, including thoracotomy, laparotomy, and three-field lymph node dissection, is a particularly stressful surgery that is characterized by high morbidity and mortality. The aim of this study was to evaluate the immunologic and nutritional states of patients to determine possible predictive factors of morbidity and mortality in patients receiving thoracic esophagectomy. Patients receiving thoracic esophagectomy were retrospectively divided into two groups. One group had postoperative infectious complications (group C+, n = 27), and the other had no complications (group C-, n = 76). They were treated with total parenteral nutrition or enteral nutrition providing 35-40 kcal. kg(-1). d(-1) of energy and 1.3-1.5 kcal. kg(-1). d(-1) of amino acids throughout the study period. The phytohemagglutinin (PHA)- and concanavalin A (Con A)-induced proliferation of peripheral blood mononuclear cells (PBMC) from the patients were measured before and at days 7 and 21 after the operation. Serum albumin, prealbumin, transferrin, the retinol binding protein, and the C-reactive protein were also evaluated. Three patients out of 27 in group C+ died because of severe infectious complications, whereas none of patients was fatal in group C-. PHA- and Con A-induced proliferation of PBMC was significantly low before the operation and remained suppressed on the 21st postoperative day in group C+. No significant difference was observed in nutritional status during the perioperative days between the two groups. Our results indicate that esophageal cancer patients with preoperative suppression of the cell-mediated immunity can be identified as a higher risk population in the postoperative period. When adequate nutrition is received, however, the correlation between nutritional status and mortality disappears.

The effect of fat emulsion (Intralipid) on essential fatty acid deficiency in infants receiving intravenous alimentation.

Thirteen infants who received IVA in four different ways were studied. The serum fatty acid composition of the infants who received fat-free IVA showed EFA deficiency within 1 wk. This deficiency was cured by administering fat emulsion which accounted for 4% of the total caloric content of the infusate. Fat emulsion which accounted for 2% of the total calories neither improved nor prevented EFA deficiency. This means that intravenous fat emulsion, Intralipid, which accounted for 2% of the total calories as linoleic acid, still satisfies the essential fatty acid requirement.