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An Argument for Vitamin E Supplementation in the Management of Systemic Inflammatory Response Syndrome

Bulger, Eileen M.; Maier, Ronald V.

Review Article

The systemic inflammatory response syndrome results from an uncontrolled, overexpression of the normal host inflammatory response, leading to destruction of host tissue and subsequent organ failure. Oxidant stress has been implicated in this process both as a mechanism for direct cellular injury, as well as activation of intracellular signaling cascades within inflammatory cells resulting in progression of the inflammatory response. Vitamin E is an inexpensive, nontoxic, chain-breaking antioxidant that has therapeutic potential in regulating this process. This review seeks to evaluate the current literature regarding the use of Vitamin E in controlling the excessive inflammation seen in systemic inflammatory response syndrome and argues for further study of its therapeutic potential for these critically ill patients.

Department of Surgery, Harborview Medical Center, University of Washington, Seattle, Washington 98104

Received 18 Jun 2002;

first review completed 27 Jun 2002; accepted in final form 15 Jul 2002

Address reprint requests to Eileen M. Bulger, MD, Box 359796 Harborview Medical Center, 325 Ninth Ave. Seattle, WA 98104.

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The systemic inflammatory response syndrome (SIRS) has evolved as a unifying etiology for the late morbidity and mortality among the critically ill after trauma, burns, and sepsis (1). This syndrome is the clinical expression of an uncontrolled, overexpression of the normal host inflammatory response that can lead to end-organ injury and potential multiple organ failure (2,3). Despite recent advances in critical care, the management of these patients has remained primarily supportive. Therapeutic strategies to combat the excessive inflammatory response have been largely unsuccessful either because of the infectious complications of global immune suppression, as seen with corticosteroids, or because of redundancy in the system-making agents that target only one inflammatory mediator ineffectively. A more logical, intermediate therapeutic approach focuses on the global control of the cells of the innate immune system, particularly the macrophage, a central coordinator of the overall inflammatory response. Control of excessive inflammation may be better achieved by controlling the initial cellular activation rather than trying to block the multitude of mediators produced once activation has occurred. In fact, even at the cellular level, control may not be possible once the cell is fully activated. Thus, there is a need to test therapeutic approaches that modulate the activation of inflammatory cells, even at very proximal stages of activation, such as during inflammatory stimulus signal transduction.

The role of oxidative stress in the development and manifestation of SIRS has been of interest for many years. Oxidative stress occurs when the level of reactive oxygen intermediates (ROIs) exceed the control of or are sequestered away from the numerous endogenous antioxidants of the host. ROIs are produced in great quantities as a result of the respiratory burst of neutrophils, other phagocytes, including macrophages, and endothelial cells during the inflammatory process. In addition, in the setting of ischemia/reperfusion injury, ROIs are produced after the activation of the xanthine oxidase system during reperfusion of hypoxic tissue in multiple cell lineages (4). During ischemia, the consumption of ATP leads to the increased formation of the purine metabolites, hypoxanthine and xanthine. In addition, xanthine dehydrogenase is converted to xanthine oxidase and thus when oxygen is reintroduced during reperfusion, a large amount of superoxide is produced, which can trigger free radical chain reactions (Fig. 1). In these settings, endogenous antioxidants, particularly those that are intracellular, are quickly consumed and the excessive unchecked free radical activity can lead to tissue destruction via the peroxidation of membrane lipids, cellular proteins, and nucleic acids.

Fig. 1

Fig. 1

Of significant interest is recent evidence that ROIs, in addition to causing direct cytotoxicity, also play a role as second messengers in the intracellular signaling pathways of inflammatory cells. The mitogen-activated protein kinases represent a family of signaling cascades implicated in the regulation of inflammatory gene transcription. Many studies have reported the phosphorylation and activation of the various mitogen-activated protein kinases by exogenous hydrogen peroxide (reviewed in Ref. 5). In addition, the activation of the critical nuclear transcription factor, nuclear factor (NF)-κB, has been induced by hydrogen peroxide and blocked by several antioxidants including Vitamin E (6–8). NF-κB has been demonstrated to be a central transcription factor involved in the regulation of numerous inflammatory genes including many cytokines (tumor necrosis factor [TNF], interleukin [IL]-1, IL-6, IL-8, IL-2), hematopoietic growth factors (granulocyte macrophage-colony stimulating factor [GM-CSF], M-CSF, G-CSF), cell adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], ELAM-1, VCAM-1), and inducible nitric oxide synthase (iNOS) (9). NF-κB has been demonstrated to be an important mediator in the signal transduction for both LPS and inflammatory cytokine-induced activation (9). A second major transcription factor, AP-1, also appears to be regulated by changes in the redox state of the cell and can be activated by both oxidants and antioxidants depending upon the cell type and intracellular conditions (10–12). AP-1 consists of homo- or heterodimers of the c-fos/c-jun family. The basic region of DNA-binding domains of c-Fos and c-Jun contain a single conserved cysteine residue that must be reduced for DNA binding activity (13). Several inflammatory genes have promotor sites for AP-1, although its obligatory role in inflammatory signaling remains to be defined (10).

Based on these studies, one could argue that antioxidants are potentially potent therapeutic agents in the regulation of an aberrant host inflammatory response such as SIRS. Antioxidants can protect both extracellularly by scavenging toxic ROIs and intracellularly by interrupting lipid peroxidation within the membrane and also by interfering early in the inflammatory responses by blocking or modifying the signal transduction of inflammatory cytokines and endotoxin, thereby modulating cellular activation (Fig. 2). To be optimally functional, however, the antioxidant selected must be rapidly internalized by inflammatory cells in vivo. We have previously shown that only those antioxidants that achieve cellular uptake are effective at modulating the macrophage response to endotoxin (14).

Fig. 2

Fig. 2

An ideal agent for potential therapeutic consideration is Vitamin E (Vit. E). Vit. E is a generic term encompassing a mixture of tocopherol and tocotrienol isomers derived from plant oils. α-Tocopherol is the most common form found in cellular membranes and the most biologically active as an antioxidant (15). Vit. E has been described as the major chain-breaking antioxidant in mammalian cellular membranes as a result of its extremely efficient antioxidant capacity interrupting the chain of membrane lipid peroxidations (16). The α-tocopherol molecule includes an aromatic chromanol head and a 16-carbon hydrocarbon tail (Fig. 3). The antioxidant function is localized to a phenolic hydroxy group on the chromanol head, whereas the hydrocarbon tail is important for rapid uptake and localization within the membrane. Because of its ability to localize in the bi-lipid cell membrane, Vit. E has been shown to have several additional biologically important effects. These include the inhibition of arachidonic acid oxidative metabolism and the inhibition of protein kinase C (PKC) activity, another important step in signal transduction (17,18). The inhibition of PKC by Vit. E does not appear to be dependent on its antioxidant activity (19).

Fig. 3

Fig. 3

The purpose of this review is to examine the current literature regarding the activity of Vit. E in inflammatory conditions both in vitro and in vivo. In addition, we will review the safety of Vit. E supplementation in humans. Taken together, these studies suggest a potential role for Vit. E supplementation in the management of patients with SIRS.

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In vivo, the tissue-fixed macrophage appears to play a key role in coordinating, upregulating, and maintaining the inflammatory response, which can then lead to the development of SIRS. These cells are optimally located in the end-organs, where damage occurs, and they produce multiple mediators that can act both locally and systemically to drive the inflammatory response. Furthermore, we have demonstrated that the tissue-fixed macrophage is sensitive to changes in the intracellular redox state, as evidenced by enhanced cytokine production in response to endotoxin when oxidant stress is increased by either depletion of intracellular antioxidants or exposure to an excess of ROI (20). We believe that modulation of the macrophage proinflammatory response can serve as a potential therapeutic approach to controlling the overall excessive inflammatory process in SIRS.

Studies of the effects of Vit. E on inflammatory cells in culture have been hampered by difficulties in delivering the highly lipid-soluble α-tocopherol molecule to cells in a form that could be incorporated and used effectively. Studies in our laboratory have demonstrated that free α-tocopherol and α-tocopherol acetate are not well incorporated into the membranes of alveolar macrophages when given in vitro and, thus, have minimal effect on cellular activation (21). We have found that α-tocopherol succinate, however, has an increased solubility and is rapidly taken up by these cells in vitro. Pretreatment with α-tocopherol succinate results in a significant inhibition of LPS-induced TNF procoagulant activity, and prostaglandin E2 production by tissue-derived macrophages (22). This differential incorporation has been observed in other cell lines and is believed to be due to micellar formation of the nonsuccinate derivatives of α-tocopherol, which prevents their incorporation into the cell membrane in an active configuration. (23,24) The mechanism of this effect by α-tocopherol succinate on macrophage activation remains to be fully elucidated; however, we have shown inhibition of transcription of the TNF gene along with inhibition of nuclear upregulation of NF-κB. (22) In addition, we have demonstrated that α-tocopherol succinate does not significantly affect membrane fluidity as measured by fluorescence recovery after photobleaching using confocal microscopy (unpublished data). However, α-tocopherol succinate does inhibit LPS-induced membrane lipid peroxidation as measured by F2-isoprostane production, a marker of nonenzymatic peroxidation of membrane lipids (25). These data suggest that the effect of α-tocopherol succinate is due to membrane localization of the antioxidant activity and thus the succinate moiety is presumably cleaved by cellular esterase activity to expose the active antioxidant site.

In addition to the macrophage, other inflammatory cells such as neutrophils and lymphocytes are also effected by Vit. E treatment. Neutrophils from Vit. E-deficient animals show evidence of increased membrane lipid peroxidation, produce more hydrogen peroxide, and have depressed chemotaxis and phagocytosis (26). This has also been seen in premature infants who have very low Vit. E levels and poor neutrophil function. After supplementation of Vit. E in these infants, the chemotaxis and phagocytosis of the neutrophil are markedly improved (27). Lymphocytes are also affected by Vit. E-deficient diets, including depressed mitogenic responses for both T and B lymphocytes, depressed mixed lymphocyte response, and decreased IL-2 production (28). Taken together, these data suggest that Vit. E may be necessary for the maintenance of an appropriate immune response to infection. Thus, repletion, or supplementation of Vit E in the SIRS patient may serve to both modulate the excessive inflammatory response, coordinated by the macrophage, while preserving and enhancing the leukocyte response to resist infection.

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Serum and tissue α-tocopherol levels fall steadily and dramatically in the first 24 h after endotoxin infusion or cecal-ligation and puncture (29,30). Several investigators have demonstrated improved survival after α-tocopherol treatment in these animal models of sepsis (31–34). In addition, α-tocopherol treatment in these animals has been shown to decrease hepatic lipid peroxidation, attenuate disseminated intravascular coagulation (DIC), and reduce plasma lactate levels (32,35,36). Additional models of excessive inflammation in which α-tocopherol has been shown to have beneficial effects include a murine hepatic ischemia-reperfusion model, a rat renal ischemia-reperfusion model, and in pulmonary inflammation after zymosan-induced peritonitis in rats (37–39). In the liver ischemia-reperfusion study, the α-tocopherol–treated group demonstrated decreased lipid peroxidation, enhanced ATP generation, increased survival, and attenuation of hepatic damage (38). In a model of renal warm ischemia, α-tocopherol pretreatment had protective effects on the kidney, as evidenced by enhanced ATP levels during reperfusion, and lower serum creatinine levels. Increased survival was also noted in the ischemic rats after treatment with α-tocopherol (39). In the case of zymosan-induced peritonitis, administration of α-tocopherol immediately after i.p. zymosan injection led to a decrease in production of pulmonary lipid peroxidation byproducts and attenuation of pulmonary tissue damage when compared with controls (37).

Several authors have also examined the effects on inflammatory cells harvested from Vit. E-treated animals. Peritoneal macrophages harvested from rats supplemented with Vit. E have been shown to have decreased superoxide production, decreased phosphatase activity, and inhibition of PGE2 production when stimulated in vitro (40–42). Studies in our laboratory using rats enterally supplemented with Vit. E have demonstrated suppression of TNF production by both whole blood and peritoneal macrophages in response to LPS challenge in vitro (43). Lymphocyte activity, however, appears to be enhanced in Vit. E-treated rats as shown by increased natural killer cell activity and enhanced splenic lymphocyte response to con A stimulation (44). These authors also observed enhanced phagocytic activity in alveolar macrophages from these rats. Others have confirmed this protection of Vit. E on cellular immunity (reviewed in Ref. 45).

Taken together, these studies demonstrate the protection of animals from the systemic inflammatory responses seen after sepsis and ischemia-reperfusion, which may, in large part, be mediated by effects on macrophage function. Encouraging from a therapeutic standpoint is the preservation or even enhancement of cellular immunity, which should prevent or reverse the susceptibility to infectious complications seen during these aberrant inflammatory conditions.

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Several studies of critically ill patients have confirmed evidence of ongoing systemic lipid peroxidation as measured by elevations in plasma thiobarbituric reactive substances and conjugated dienes as markers of lipid peroxidation byproducts (46–48). These include not only patients after major burn or traumatic injury but also those with septic shock. In addition, widespread consumption of multiple endogenous antioxidants has been observed following these insults, including a fall in serum α-tocopherol levels (46–49). Acute respiratory distress syndrome (ARDS) is the most common organ dysfunction noted following the disseminated inflammatory condition identified as SIRS. Studies of patients with ARDS reveal evidence of increased oxidant activity in bronchoalveolar lavage fluid (50–52). Richard et al. demonstrated a significant fall in Vit. E plasma levels during the course of ARDS but initial Vit. E plasma levels, although lower than control subjects, correlated with lower overall plasma lipid levels (53). Cross et al. were also unable to demonstrate a fall in α-tocopherol levels in ARDS patients when standardized for changes in plasma lipids; however, they did observe a fall in vitamin C levels (51). This may be predictive since vitamin C is believed to be a critical constituent for the recycling of oxidized Vit. E in vivo.

A recent study has examined the effect of oral Vit. E supplementation on human monocyte function (54). In this study, healthy volunteers were given 1200 IU/day of α-tocopherol for 8 weeks. Their monocytes were then harvested and found to have significantly suppressed responses to LPS, including decreased ROI production during the respiratory burst, decreased IL-1β production, and inhibition of monocyte-endothelial adhesion. Using the PKC inhibitor, calphostin C, these authors were able to reproduce the inhibition of ROI production, suggesting that the mechanism of action of Vit. E in this instance may be due to PKC inhibition. However, calphostin C had no effect on IL-1β production or monocyte/endothelial adhesion and thus Vit E's role as an antioxidant may affect additional crucial central pathways for these processes, rather than acting through PKC alone.

One study involved Vit. E supplementation of patients with ARDS (55). This study compared serum α-tocopherol levels after 1 g/day supplementation in controls and ARDS patients. They were unable to raise serum levels in the ARDS patients to the same degree as controls but could not determine whether this was due to excessive consumption of the Vit. E in these patients or malabsorption due to severity of illness. We have recently completed a randomized, prospective clinical trial of high-dose Vit. E and vitamin C supplementation for critically ill surgical patients who were at risk for the development of inflammatory organ injury (56). Upon admission to the ICU, patients were randomized to receive either antioxidant supplementation, which included α-tocopherol 1000 IU q8h per naso/orogastric tube and 1000 mg ascorbic acid i.v. q8h, or standard care with no antioxidant supplementation. Antioxidants were continued for the duration of the ICU admission or until 28 days. We demonstrated adequate vitamin absorption in these patients by elevated vitamin E and C plasma levels. Patients in the antioxidant group were found to have a decreased risk of pulmonary morbidity (ARDS and pneumonia, relative risk: 0.81, 95% CI 0.6–1.1), a decreased risk of developing multiple organ failure (relative risk 0.43, 95% CI 0.19–0.96), and a shorter duration of mechanical ventilation and length of ICU stay. This study suggests that supplementation with these higher doses of Vit. E, comparable to the animal studies, appears necessary to document a protective effect.

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Of concern whenever one recommends human studies, particularly with a high-dose supplementation of even natural substances, is the safety of the suggested therapy. Vit. E supplementation in humans involves primarily the enteral route. An i.v. preparation was trialed in the 1980s in premature infants (<1500 g) but was discontinued secondary to associated hepatic toxicity. It was unclear whether this toxicity was due to the α-tocopherol itself or to the polysorbate carrier (57,58). However, since that time, most studies have focused on enteral supplementation, and high-dose parenteral formulations are extremely limited. Vit. E is absorbed in the gastrointestinal tract similar to other lipids and thus is dependent on bile for absorption in normal subjects. Twenty-five percent of the ingested dose is absorbed and can be detected in the lymph (59). One international unit (IU) corresponds to one milligram of α-tocopherol acetate. The US recommended daily allowance for adults is 12–15 IU/day. A review of the literature by Bendich et al. revealed that several animal species can tolerate up to 200 mg/kg of Vit E without apparent toxicity and that deleterious effects were not observed until daily doses exceeded 1 g/kg (60). In humans, few side effects were reported in double-blind studies of Vit. E supplementation at doses up to 3200 mg/day (60,61). In a recent review by Meyers et al., the primary side effects reported with enteral supplementation of Vit. E included thrombophlebitis, gastrointestinal disturbances, breast soreness, and depression of vitamin K dependent coagulation factors when used in combination with other anticoagulation agents (62). Thrombophlebitis was reported in 80 patients from one physician's practice with no cases reported in larger prospective studies. (63) Gastrointestinal disturbances, including mild cramping and diarrhea, were seen in 4 of 18 patients taking 3200 IU/day (61). Breast soreness was reported in a case series of seven women with no other cases reported (64). Several other miscellaneous disorders have been attributed to Vit. E but these depend on individual case reports and have not been seen in large controlled studies (reviewed in Ref. 62).

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Taken together, these studies reveal Vit. E to be a potent immunomodulator, in vitro and in vivo with encouraging results in animal models of inflammatory syndromes. Its relative safety, even at high doses, make it an attractive agent for additional human studies. We believe that by identifying agents that interrupt the activation of inflammatory cells at the level of signal transduction, we can begin to develop strategies for the ultimate control of SIRS.

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α-Tocopherol; antioxidant; vitamin C; acute respiratory distress syndrome (ARDS); multiple organ failure syndrome (MOFS)

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