Endotoxaemia sepsis and trauma

The importance of a hyperinflammatory response, characterized by overproduction of TNF-a, IL-1p, IL-6 and IL-8, in the progression of trauma patients towards sepsis is now recognized. Enhanced production of arachidonic acid-derived eicosanoids, such as PGE2, is also associated with trauma and burns. The inflammatory effects of infection can be mimicked by administration of endotoxin (bacterial lipopolysaccharide). Essential fatty acid deficiency in rats increased mortality after endotoxin challenge (Cook et al., 1981). Arachidonic acid administration increased mortality following endotoxin (Cook et al., 1981), while feeding a high linoleic acid diet increased mortality in guinea pigs recovering from burns injury (Alexander et al., 1986). Fish oil feeding or infusions enhanced the survival of guinea pigs following endotoxin challenge (Mascioli et al., 1988, 1989) and decreased the accompanying metabolic perturbations in guinea pigs and rats (for references, see Calder, 1997). Mice fed fish oil and then injected with endotoxin had lower plasma TNF-a, IL-p and IL-6 concentrations than mice fed safflower oil (Sadeghi et al., 1999), while fish oil-containing parenteral nutrition decreased serum TNF-a, IL-6 and IL-8 concentrations in burned rats (Hayashi et al., 1998; Tashiro et al., 1998). Total parenteral nutrition using fish oil as the lipid source was found to prevent the endotoxin-induced reduction in blood flow to the gut and to reduce the number of viable bacteria in mesenteric lymph nodes and liver following exposure to live bacteria (Pscheidl et al., 2000). Fish oil did not, however, decrease bacterial translocation across the gut and the authors concluded that fish oil must have improved bacterial killing. Fish oil administration prior to exposure to live pathogens decreased the mortality of rats compared with vegetable oil (Barton et al., 1991; Rayon et al., 1997). These studies did not measure inflammatory cytokine levels, but they showed that PGE2 levels were decreased by fish oil (Barton et al., 1991; Rayon et al., 1997). More recently, fish oil infusion after induction of sepsis by caecal ligation and puncture in rats was shown to decrease mortality (and PGE2 production) compared with vegetable oil (Lanza-Jacoby et al., 2001).

An understanding of the inflammatory changes occurring during sepsis and of the anti-inflammatory effects of fish oil, combined with the outcome of these animal experiments, has prompted clinical studies investigating the influence of fish oil administered either parenterally or enterally. Patients receiving par-enteral fish oil following major abdominal surgery had lower serum concentrations of TNF-a and IL-6 than those receiving a control mix (Wachtler et al., 1997). This study did not report clinical outcome. A large number of clinical trials (at least 20) have been performed in intensive care or surgical patients using enteral formulae containing n-3 PUFAs. The majority of these trials have used the commercially available product IMPACT®, which contains arginine, yeast RNA and n-3 PUFAs. Many of these trials report beneficial outcomes, including decreased numbers of infections and infectious or wound complications, decreased severity of infection, decreased need for mechanical ventilation, decreased progression to systemic inflammatory response syndrome and decreased length of intensive-care unit and/or total hospital stay. A comprehensive meta-analysis of 15 randomized, controlled studies using IMPACT® or Immun-Aid® (also rich in arginine, RNA and n-3 PUFAs) has been performed (Beale et al., 1999). This analysis confirmed significant reductions in infection rate, number of ventilator days and length of hospital stay, but not in overall mortality. Few of the studies reviewed measured immune outcomes. However, some other studies of IMPACT®, not included in the meta-analysis, did so, focusing especially on inflammatory cytokines. Several of these studies show decreased circulating TNF-a and/or IL-6 concentrations in patients given IMPACT® or similar formulae before (Braga et al., 1999; Gianotti et al., 1999; Tepaske et al., 2001) or after (Braga et al., 1996; Wu et al., 2001) major surgery. Although these observations fit with the predicted effects of n-3 PUFAs and could be used as evidence of their efficacy in the trauma and post-surgery settings, the complex nature of the formulae prevents such a clear interpretation. The effects could be due to any one of the specified nutrients (i.e. arginine, RNA, n-3 PUFAs) or to a combination of these nutrients. Indeed, the positive outcomes from the use of IMPACT® and similar formulae have often been used as evidence for the benefit of arginine in these settings (see Duff and Daly, Chapter 5, this volume).

Cancer

The immune system obviously plays an important role in anti-cancer defence. There is a progressive decrease in many immune surveillance defences in animal models of cancer (Shewchuk et al., 1996) and in humans with cancer (Keissling et al., 1999). A major focus of current research in immunology and oncology is the development of methods to augment host antitumour immune defences. Feeding fish oil to experimental animals protects against the development of carcinogen-induced mammary tumours, reduces the growth of mammary tumours and prevents the development of cachexia and metastatic diseases (see Cave, 1991). Although dietary fat can modulate anti-cancer defences, such as natural killer cell cytotoxicity and humoral and T-cell responses, the application of studies in healthy humans and animals to the cancer state may not be as straightforward. The influence of dietary n-3 PUFAs on the immune response may be different between healthy animals and those with suppressed immune systems (Robinson et al., 2001, 2002). Tumour-bearing rats fed long-chain n-3 PUFAs as part of a low-PUFA diet had significantly increased natural killer cell cytotoxicity, a higher proportion of CD8+ and CD28+ cells that were activated (i.e. expressing CD25) and increased nitric oxide and IL-2 production after mitogen stimulation, whereas these immune enhancements were not found when n-3 PUFAs were supplemented in a high-PUFA diet.

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