Effects of parenteral lipid emulsions on immune system response
Monika Jędrzejczak-Czechowicz, *Marek L. Kowalski
Department of Clinical Immunology, Rheumatology and Allergies, Medical University of Łódź
Lipid solutions used in parenteral nutrition (PN) are generally well tolerated. Recent studies reporting their effects on the immune system indicate that various compositions can modulate the immune response, thus affecting the response to pathogens and autoaggressive diseases. In this review, we discuss the compositions of various commercially available lipid solutions and their effects on the immune response to various pathologies.
We conclude that: 1. Soybean oil-based emulsions are immunosuppressive and should be used with caution in inflammatory conditions, and are contraindicated in sepsis. 2. Mixtures of medium-chain triglycerides and soybean oil are better tolerated. 3. Olive oil-based mixtures are neutral and are especially recommended for burned patients, premature infants and for long term PN. 4. Fish oil-based emulsions are beneficial in inflammatory conditions and in patients after major abdominal surgery.
The position of lipid emulsions (LEs) in parenteral nutrition of patients, in whom oral or enteral feeding cannot be used, i.e. critically ill, undernourished or at risk of malnutrition, is well established. Lipids contained in parenteral emulsions are an excellent source of energy while phospholipids are an integral part of cell membranes. Moreover, lipids are the carries of some vitamins and provide essential fatty acids (EFAs), required for proper functioning yet not synthesized in the body. Metabolites of lipid metabolism are involved in the processes of intercellular transduction and have significant effects on the inflammatory processes and activity of the immune system [1, 2, 3].
The term of immunomodulation is frequently used in analyses of the effects of ELs on the human body. The term is defined as changes in activity of the immune system caused by factors activating or inhibiting its functions. In the majority of cases, immunoregulators have marked immunosuppressive or immunostimulating effects and have been widely used in medicine. However, immunomodulation is often extended for the purposes of therapeutic interventions, which are not well documented and whose effects on the immune system are difficult to be explicitly defined. According to some literature reports, immunomodulation is a therapeutic process involving interventions in autoregulation of the immune system; such a definition of immunomodulation is often misused. Almost all biologically active substances may have some impact on the immune system (the immunomodulatory effect), which does not mean that their effects will be autoregulatory (repairing), thus beneficial for health. In fact, in order to assess whether the effects lead to desirable changes in the body, considered as a whole (and not in the isolated cell), the essence of the immunological disorder should be defined. If the repair is necessary, its relation to the pathomechanism of a given disease has to be determined and the beneficial changes as well as expected clinical effects that ‘immune intervention’ is going to induce should be demonstrated. Such conditions are not easy to fulfil as in the majority of clinical situations, the types of immunological disorders cannot be defined due to insufficient knowledge of immunological mechanisms of many systemic diseases or limited availability of immunological tests. Due to the limitations mentioned, practicing physicians, who have no access to elaborate immunological devices and techniques should use the term of ‘immunomodulation’ or ‘immune intervention’ with caution.
The use of lipid emulsions is an example of the situation described. Lipid emulsions, which are mainly nutrients, are increasingly considered in the context of their effects on the immune system and inflammatory processes associated with it, i.e. as agents with therapeutic effects on the diseases not precisely defined in terms of immunology. Although it has been demonstrated that lipids can influence (stimulate or inhibit) the activity of immune system constituents and inflammatory cells in vitro, their action depends not only on the kind of lipid but also its concentration and the research model used (e.g. types of cells or the immunological parameter measured). The results of animal studies are even more varied and cannot be directly transferred to humans. Finally, the effects of lipid emulsions on the human immune system under clinical conditions depends not only on the kind of a preparation, its dose or route of administration but also (which is often neglected in analyses) on the type of an underlying disease and individually assessed condition of a patient. The wide range of lipid effects on various human cells, including the immune system, poses a question about the usefulness of the notion of immunomodulation in the clinical practice. Therefore, it seems more appropriate to talk about the effects of lipid emulsions on the functions of the immune system and inflammatory processes accompanying the underlying diseases.
IMMUNOLOGICAL DISORDERS IN CRITICALLY ILL AND UNDERNOURISHED PATIENTS
Both the primary and secondary immune responses to severe diseases are changed by the nutritional condition. Initially, at the site of infection or trauma, the inflammatory reaction develops, caused by, among other things, activation of the alternative pathway of the complement or coagulation system as well as the inflow and activation of macrophages/monocytes (with the pro-inflammatory Toll-like receptors involved). This reaction is protective in nature and beneficial for the body. The local reaction is augmented by e.g. pro-inflammatory mediators and cytokines, which may lead to the development of the systemic inflammatory response syndrome (SIRS), when released to circulation in high amounts.
The properly developing inflammatory reaction should subside once the damaging factor has been eliminated; however, if proper repair mechanisms (autoregulatory) are lacking or the infection (trauma) persists, the excessive systemic reaction develops [4, 5]. Its clinical manifestations include acute respiratory distress syndrome (ARDS), septic shock, disseminated intravascular coagulation (DIC) or multiple organ failure. The secondary immunological response develops within several hours/days after the primary response and consists in macrophage or dendritic cell presentation of antigens to T lymphocytes involved in the cell response and B lymphocytes involved in the humoral response. Moreover, this stage of immune response potentiates the ongoing inflammation (by activation of inflammatory cells through specific mechanisms), which desirable effects, for instance, will be the effective elimination of the inflammatory factor. In critically ill patients, compensatory anti-inflammatory response syndrome (CARS) is observed, characterized by dysfunction and increased apoptosis of lymphocytes, inhibited activity of monocytes and macrophages and intensified factors suppressing the immune system ( e.g. production of IL-10)
. In critically ill patients after severe, multi-organ trauma, the ‘immunological paralysis’ was observed, i.e. decreased ability to present the antigen due to reduced expression of HLA-DR antigens and impaired interaction between monocytes and T lymphocytes. The phenomena described are responsible for inhibited activity of the immunological response; they can lead to such clinical symptoms as skin allergy, hypothermia, leucopoenia and increased susceptibility to nosocomial infections; dysfunction of internal organs can result in death [7, 8, 9].
Therefore, the immunological response in critically ill and undernourished patients is likely to be markedly disturbed but the type (activation/excitation) and the extent of disturbances are diverse and depend on the disease and its stage.
STRUCTURE OF LIPIDS AND THEIR EFFECTS ON THE IMMUNE SYSTEM
Lipids are the compounds that include fatty acids, waxes, sterols, glycerolipids, and glycerophospholipids. Lipids are involved in the storage of energy, formation of biological membranes and transduction of signals. The essential constituents of lipid emulsions in terms of their effects on the immune system are fatty acids, which are composed of the hydrocarbon chain of various lengths – from 4 to over 30 carbon atoms in a molecule . Fatty acids can be divided according to the presence of a double bond: saturated fatty acids (SFAs) do not contain double bonds, mono- and polyunsaturated fatty acids (MUFA, PUFA) contain one or more double bonds. The presence of double bonds induces cis-trans isomerism, which directly affects the fluidity of biological membranes thus determining the biological action of acids and their metabolites.
Both saturated and monounsaturated, but not polyunsaturated acids may be synthesised de novo in the human body. Thus, they are typical EFA, which have to be delivered with food. The most important fatty acids contained in emulsions are listed in Table 1. The metabolism pathways of two basic types of fatty acids - Ω-3 and Ω-6 are presented in Fig. 1.
EFFECTS OF LIPID EMULSIONS ON THE INFLAMMATORY PROCESSES AND IMMUNE SYSTEM
Fatty acids used in lipid emulsions can affect the immune system via several mechanisms (Fig. 2). The first mechanism involves incorporation of lipids into the structure of membranous cells and thus affecting the fluidity of cell membranes, permeability of ion channels and functions of membranous receptors. The second mechanism is associated with penetration of fatty acids to the cell where they can affect the production of eicosanoids, resolvins, cytokines, pathways responsible for signal transduction into the cell, and expression of genes. Moreover, fatty acids can alter cell apoptosis and production of reactive oxygen species.
Different lipid emulsions have different biological properties depending on their composition. The fatty emulsions available on the market contain various, yet sufficient amounts of Ώ-3 and Ώ-6 acids, except for 100% fish oil-based emulsions, which are added to other mixtures of fatty acids. The differences in the effects on the immune system are largely dependent on the composition of lipid mixtures, particularly the content of MUFA, Ώ-6 or Ώ-3 PUFA. The in vitro effects of the main types of emulsions are listed in Table 2.
Soybean oil-based lipid emulsions
Soybean oil-based lipid emulsions were the first ones to be widely used for parenteral nutrition. Their main constituent is Ώ-6 linoleic acid, whose amount is much higher than of Ώ-3 α-linolenic acid. Although they are a good source of energy, their effects on the immune system and inflammatory processes are not clear. They show both immunosuppressive (inhibiting the constituents of immunological response) and pro-inflammatory action (e.g. increased production of pro-inflammatory cytokines and adhesion molecules). Considering increased production of pro-inflammatory eicosanoids and enhanced oxidative stress, their indications for use in patients with sepsis or after trauma should be carefully considered . Ώ-6 polyunsaturated fatty acids reduce the migration and phagocytic activity of neutrophils and macrophages, decrease the lymphocyte response to bacterial antigens and inhibit antibody-dependent cell cytotoxicity . The immunosuppressive properties of fatty acids contained in soybean oil can be associated with higher prevalence of infections, hence with longer treatment and hospitalisation [13, 14]. Recently, the issues of their side effects, e.g. infections, peroxidation of lipids and increased oxidative stress, have been discussed . The study evaluating the effects of lipid emulsions on outcomes of treatment in patients with alimentary carcinoma revealed reduced SIRS reactions and shortened hospitalisation in those receiving fish oil lipid emulsions compared to the group on soybean oil .
Due to doubts concerning the safety of soybean oil-based emulsions, some attempts have been made to replace them with mixtures of medium-chain fatty acids.
Mixtures of medium-chain triglycerides (MCTs) and soybean oil
Medium-chain triglycerides are capable of penetrating directly the cell interior without binding with transporting proteins; unlike long-chain fatty acids, they do not require carnitine during transport to the mitochondrion and are resistant to peroxidation . They cannot be used without long-chain fatty acids, as the human body does not tolerate pure MCTs and they do not contain EFAs.
It was initially thought that MCTs had no regulatory properties and only limited impact on the course of inflammatory processes; the recent data, however, indicate that they are not indifferent to the functioning of the immune system [16, 17]. The effects of mixtures of medium-chain triglycerides combined with soybean oil and those containing additionally fish oil were compared in patients with SIRS or developed sepsis. There were no differences in the duration of artificial lung ventilation, ITU stay and mortality; however, the use of fish oil resulted in shortened hospitalization of survivors and increased PO2/FIO2 .
Olive oil-based lipid emulsions
Olive oil-based mixtures contain oleic acid, Ω-9 monounsaturated acid constituting about 65% of their composition, polyunsaturated acids with predominance of Ω-6 in relation to Ω-3, sterols, alcohols and antioxidants. Oleic acid is resistant to peroxidation processes and to a slight degree affects the synthesis of eicosanoids, the mediators of inflammation. Polyphenolic compounds present in the olive oil have anti-inflammatory properties [19, 20]. It appears that olive oil has slight, generally immunosuppressive effect on the immune system. The animal studies demonstrated decreased numbers of natural killer (NK) cells responsible for protection against viruses and neoplastically transformed cells .
The clinical findings indicated that the mixtures might be neutral or have anti-inflammatory effects in some diseases. Patients treated with lipid emulsions in the home setting had no increased levels of oxidative stress while patients with rheumatoid arthritis showed reduced inflammation [19, 22, 23]. Thanks to their neutral effects on lymphocytes, NK cells and neutrophils and inhibition of chemokine release, olive oil-based emulsions can be used in the majority of patients, except for those with excessive inflammatory reaction [24, 25]. The study findings did not reveal significant side effects in patients receiving olive oil-based emulsions. The double blind trial in critically ill neonates showed better tolerance of nutrition based on olive oil emulsions compared to soybean oil emulsions . In another study regarding long-term therapy of patients in the home setting, olive oil-based emulsions were demonstrated to be better tolerated and safe without directly affecting the inflammatory process [27, 28].
The safety and good tolerance of olive oil-based emulsions was observed in premature newborns, patients requiring long-term home treatment, those undergoing haemodialysis and after trauma or burn .
Fish oil-based emulsions
Fish oil-based emulsions contain mainly long-chain Ω-3 polyunsaturated fatty acids, consisting of 18-carbon α-linolenic acid, 20-carbon eicosapentaenoic acid (EPE) and 22-carbon docosahexaenoic acid (DHA) plus a small amount of α-linolenic acid.
The emulsions in question are not neutral for the immune system. EPA and DHA easily penetrate the cell interior and are components of tissues. They modify lipid membranes, affect the profile of synthesised eicosanoids by their increased production with EPA instead of arachidonic acid (AA). EPA-based eicosanoids and inflammation mediators are less active [30, 31]. Emulsions based on fish oil have also inhibitory effects on signal transduction and expression of genes involved in the inflammation. In patients with sepsis, the use of fish oil-based emulsions resulted in reduced concentrations of pro-inflammatory cytokines IL-6 and IL-10. Fish oil was found to modify significantly the cytokine profile and to increase the EPA levels in serum . Moreover, its use was demonstrated to enhance the production of DHA and EPA metabolites without affecting the production of AA, whose products show pro-inflammatory effects . The use of fish oil shortened the hospitalisation of patients after major abdominal surgeries compared to patients receiving soybean oil-based emulsions .
Furthermore, the use of fish oil in patients undergoing stent implantation resulted in lower incidences of atrial fibrillation and shorter ITU and hospital stay, compared to the therapy with soybean oil-based emulsions .
The study on EPA effects on the clinical condition of patients awaiting endarterectomy disclosed that EPA incorporating into the atheromatous plaque decreased the number of foam cells and T lymphocytes, reduced the inflammatory process and increased the stability of platelets . Their use can also prove beneficial for patients at risk of excessive inflammatory reaction . The multi-centre prospective double blind trial carried out in the group of 200 patients undergoing abdominal and thoracic surgeries revealed safety and good tolerance of fish oil-based emulsions . According to another study, the early administration of fish oil emulsions did not reduce the number of internal organs damaged during sepsis .
NON-NUTRITIONAL EFFECTS OF LIPID EMULSIONS
Surgery and trauma
The functions of the immune system are impaired in surgical patients. This mainly regards reduced proliferation of T lymphocytes, skin allergies, and decreased production of IL-2, IFN-γ [37, 38]. The disturbances observed within the T cell receptor (TCR) are believed to result from reduced arginine concentration . The immunosuppressive action leads to more frequent infections and higher mortality rates in surgical patients.
The use of fish oil for prophylaxies of impaired immunological response is widely considered. Ω-3 fatty acids contained in it increase the arginine concentration by inhibition of argininase-1. Moreover, EPA and DHA reduce the inflammatory reaction by competing with AA for metabolism induced by cyclooxygenase and lipoxygenase, which results in a decrease in synthesis of pro-inflammatory eicosanoids, such as PGE2 and LTE4. EPA and DHA also inhibit the expression of genes and reduce the ability of leucocytes and platelets to adhere to the endothelium [4, 39].
Patients after surgical procedures receiving fish oil recovered more quickly. The introduction of treatment before surgery resulted in its higher effectiveness [40, 41].
Sepsis/critically ill patients
The use of supplementary diet modulating the functions of the immune system in critically ill patients arouses controversies. The systemic inflammatory response in their bodies is associated with metabolic stress, excessive production of reactive oxygen species, resistance to insulin, metabolic disturbances leading to hyperglycaemia, lipolysis, enhanced proteolysis and negative oxygen balance [42, 43].
Soybean oil-based emulsions should be administered cautiously in patients with sepsis. It is believed that pure soybean oil emulsions should not be used, particularly in patients with high risk of inflammatory processes or those with the ongoing processes (after trauma, surgery, burns, with sepsis). They ought to be partially replaced with MCTs, olive oil containing MUFA or fish oil containing EPA or DHA . The meta-analysis involving 24 studies in 3013 patients (12 in ITU patients, 5 in burn patients and 7 in patients after trauma) demonstrated that the use of fish oil for supplementary therapy in ITU patients resulted in lower mortality, lower incidence of infections and shorter hospitalisation; in patients after trauma and burns, only decreased incidences of infections were observed .
Patients with burns develop extremely heavy inflammatory processes. Therefore, preparations stimulating the inflammatory response, e.g. soybean oil-based lipid emulsions are not recommended in such cases . In the double blind study carried out in patients with severe burns, there were no differences found in metabolism and tolerance of soybean oil and olive oil emulsions. The latter, however, showed better effects on proper liver function .
Patients treated chronically/in home setting
The patients requiring long-term use of parenteral nutrition are at risk of numerous complications, ranging from electrolyte abnormalities to the parenteral nutrition-associated liver disease (PNALD). PNALD is a severe complication of long-term nutrition with lipid emulsions. The precise mechanism remains unclear yet it is known that the use of emulsions with Ώ-6 polyunsaturated fatty acids of plant origin and phytosterols involved are hepatotoxic. The use of fish oil-based emulsions is believed to be safer . Some other studies confirm the relation between soybean oil-based emulsions and liver diseases and recommend the use of different lipid emulsions .
Under standard care conditions, it is difficult to anticipate the clinical effects resulting from immunoregulatory properties of the emulsion administered. The use of properties of lipid emulsions in particular clinical situations should be based on the individual evaluation of the immune system and weighing potential benefits against risks. If the evaluation of the condition and functions of the immune system is unequivocal, the use of lipid emulsions that do not markedly affect its activity (immunologically neutral) is the optimal management ensuring safety of patients.
Further studies are required to formulate the guidelines concerning the choice of emulsions for long-term therapy and to confirm their safety in parenteral nutrition.
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*Marek L. Kowalski
Klinika Immunologii, Reumatologii i Alergii UM w Łodzi
Łódź 92-213, ul. Pomorska 251
tel.: +48 42 675 73 09, fax: +48 42 678 22 92
received: 25.04.2011 r.
accepted: 28.06.2011 r.