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Proceedings of the Nutrition Society
(2000),
59
, 553–563
553
CAB InternationalPNSProceedings of the Nutrition Society (2000)© Nutrition Society 2000 59
PNS 00-054Nutrition in the severely-injured patientU. Suchner
et al
.553
563
11© Nutrition Society 2000
A joint meeting of the Clinical Nutrition and Metabolism Group of the Nutrition Society and the British Association of Parenteral and Enteral
Nutrition was held at the Bournemouth International Centre on 7–9 December 1999
Clinical Nutrition and Metabolism Group Symposium on
‘Nutrition in the severely-injured patient’
The scientific basis of immunonutrition†
U. Suchner
1
*, K. S. Kuhn
2
and P. Fürst
2
1
Clinic of Anesthesiology, Grosshadern, Ludwig Maximilians University, Marchioninistrasse 15, 81377 Munich, Germany
2
Institute of Biological Chemistry and Nutrition, University of Hohenheim, Garbenstr. 30, 70593 Stuttgart, Germany
Dr U. Suchner, present address Fresenius Kabi Deutschland GmbH, Else-Kröner-Strasse 1, 61352 Bad Homburg v.d.H., Germany, fax +49 6172 686 5505, email ulrich.suchner@fresenius-kabi.com
Substrates with immune-modulating actions have been identified among both macro- and
micronutrients. Currently, the modes of action of individual immune-modulating substrates, and
their effects on clinical outcomes, are being examined. At present, some enteral formulas are
available for the clinical setting which are enriched with selected immune-modulating nutrients.
The purpose of the present paper is to review the scientific rationale of enteral immunonutrition.
The major aspects considered are mucosal barrier structure and function, cellular defence function
and local or systemic inflammatory response. It is notable that in critical illness the mucosal
barrier and cellular defence are impaired and a reinforcement with enteral immunonutrition is
desirable, while local or systemic inflammatory response should be down regulated by nutritional
interventions. The results available from clinical trials are conflicting. Meta-analyses of recent
trials show improvements such as reduced risk of infection, fewer days on a ventilator, and
reduced length of intensive care unit and hospital stay. Thus, a grade A recommendation was
proclaimed for the clinical use of enteral immune-modulating diets. Improvement in outcome was
only seen when critical amounts of the immune-modulating formula were tolerated in patients
classified as being malnourished. However, in other patients with severe sepsis, shock and organ
failure, no benefit or even disadvantages from immunonutrition were reported. In such severe
conditions we hypothesize that systemic inflammation might be undesirably intensified by
arginine and unsaturated fatty acids, directly affecting cellular defence and inflammatory
response. We therefore recommend that in patients suffering from systemic inflammatory
response syndrome great caution should be exercised when immune-enhancing substrates are
involved which may aggravate systemic inflammation.
Immunonutrition: Immune-modulating substrates: Enteral nutrition
EPA, eicosapentaenoic acid; GSH, glutathione; IL, interleukin; LT, leukotriene; NOS, NO synthase; PUFA, polyunsaturated fatty ac ids; SIRS, systemic inflammatory response syndrome
The interrelationship between nutrition and the immune
system has become the focus of ever increasing attention as
an increasing number of substrates are being identified as
having an immune-modulating function. Immunonutrients
might be identified among macro- and micronutrients.
Amino acids such as glutamine, arginine, cysteine and
taurine, as well as nucleotides, are important immune-
modulating substrates. Lipids that may be involved include
monounsaturated and polyunsaturated fatty acids (PUFA),
as well as short-chain fatty acids. Numerous substrates that
interact
among vitamins and trace elements (vitamins A, C and E,
Zn and Se). Based on experimental observation, many
immunomodulatory effects have been claimed for a long
time, but their clinical significance has only been recognized
since the early 1980s. Indeed, the levels of inclusion of
immune-modulating substrates clearly exceeds the amount
used in a simple prevention of deficits. However,
‘pharmacological’ immunonutrition should simultaneously
satisfy both the metabolic and immunological needs of the
patient. The rationale for writing the present review is to
examine the scientific basis of immunonutrition in the
with
the
immune
system
have
been
identified
Abbreviations:
EPA, eicosapentaenoic acid; GSH, glutathione; IL, interleukin; LT, leukotriene; NOS, NO synthase; PUFA, polyunsaturated fatty acids;
SIRS, systemic inflammatory response syndrome.
*Corresponding author:
Dr U. Suchner, present address Fresenius Kabi Deutschland GmbH, Else-Kröner-Strasse 1, 61352 Bad Homburg v.d.H., Germany,
fax +49 6172 686 5505, email ulrich.suchner@fresenius-kabi.com
†The other papers presented at this meeting were published in
Proceedings of the Nutrition Society
(2000)
59
no. 3.
554
U. Suchner et al.
context of enteral feeding interventions in the severely
injured patient.
exchange, vascular permeability, coagulation, as well as
substrate utilization, and thus may influence organ function.
Thus, a selective quantitative and qualitative choice of the
supply of certain defined nutritional substrates which serve
as the precursors of mediators may modulate the severity of
the inflammatory immune response.
The actions of pathogens on the systemic immune
response are illustrated in Fig. 2. Although a boost of
cellular defence functions may initially take place; in the
long term this boost is followed by the suppression of
these functions, an effect described by the term ‘immune
paralysis’. Within the framework of these events
experimental and clinical data lend credence to the idea of
understanding defined substrates as ‘pharmacologically
effective agents’ by which the cellular defence function
can be restored or the systemic inflammatory response
alleviated. Consequently, glutamine, arginine, nucleotides
and PUFA are considered of primary relevance.
Areas of immune defence and their modulation by
defined substrates
In order to simplify this task, the immune defence system
can be subdivided into three sites of action representing
potential targets for specific nutritional substrates: (1)
mucosal barrier function; (2) cellular defence function; (3)
local or systemic inflammation (Fig. 1).
The mucosal barrier function of the intestinal mucosa
represents the first line of defence against translocating
pathogens, and it is already considered important in relation
to early enteral nutrition of critically ill patients (Gardiner
et al
. 1995). Indeed, sufficient availability of suitable
substrates is currently considered the major tool in
maintaining the structure and functionality of the mucosal
barrier.
Cellular defence function includes the specific and
non-specific cellular immune response. Following invasion
of pathogens it represents the second line of defence,
consisting of granulocytes, macrophages, lymphocytes and
plasma cells. The complex interactions between these
effector cells are coordinated through the release of
cytokines and other mediators. Nutritional substrates can
modulate the cellular and humoral defence system via
modified mediator formation or by interference with signal
transduction.
Essential components of the inflammatory immune
response are represented by the activation of cascade
systems, such as the coagulatory or the complementary
system. Moreover, mediators are involved which include
cytokines, eicosanoids, platelet-activating factor and NO, as
well as vasoactive amines and kinines. Systemic inflam-
matory response is manifest at the endothelium, the smooth
vascular and bronchial muscles, and at platelet aggregation.
This response may impair microcirculation, pulmonary gas
Glutamine
Glutamine is the most prevalent free amino acid in the
human body. In skeletal muscle glutamine constitutes
> 60 % of the total free amino acid pool (Bergström
et al
.
1974). It is a precursor that donates N for the synthesis
of purines, pyrimidines, nucleotides, amino sugars and
glutathione (GSH), and is the most important substrate for
renal ammoniagenesis (regulation of the acid–base balance).
Glutamine serves as a N transporter between various
tissues, and represents the major metabolic fuel for the
cells of the gastrointestinal tract (enterocytes, colonocytes;
Windmueller, 1982; Souba, 1991) as well as for many
rapidly proliferating cells, including those of the immune
system (Calder, 1994). Consequently, the morphological
and functional integrity of the intestinal mucosa appears to
be protected by sufficient availability of glutamine. There is
much evidence that hypercatabolic and hypermetabolic
situations are accompanied by marked depressions in
muscle intracellular glutamine. This response has been
shown to occur after elective operations, major injury,
burns, infections and pancreatitis, irrespective of nutritional
attempts at the time of repletion. A reduction in the muscle
free glutamine pool (approximately 50 % of the normal
level) thus appears to be a hallmark of the response to
injury, infection and malnutrition (for references, see
Fürst, 1994
a
). This response creates a glutamine-depleted
environment, the consequences of which include enterocyte
and immunocyte starvation (Bode & Souba, 1994). It has
been suggested that glutamine becomes a conditionally
essential amino acid during episodes of catabolic stress such
as injury and sepsis.
Numerous experimental studies support this hypothesis.
Glutamine-supplemented enteral or parenteral nutrition
solutions are associated with increased intestinal mucosal
thickness and DNA and protein content, reduced bacterial
translocation after radiation (Souba, 1991), weakened
adverse effects of experimentally induced enterocolitis
(Rombeau, 1990), preserved intestinal mucosa during
parenteral nutrition (Babst
et al
. 1993) and enhanced rat
mucosal hyperplasia after small bowel resection (Klimberg
et al
. 1990).
In vitro
, glutamine has been shown to induce
Mucosal
barrier
integrity
Immune
nutrients
Cellular
defence
function
Systemic
inflammatory
response
Fig. 1.
Schematic representation of the three areas of immune
defence affected by immunonutrients.
Nutrition in the severely-injured patient
555
Systemic invasion of
bacteria
toxins
Systemic immune reponse
Cellular
defence function
Systemic
inflammatory response
Mediators
Eicosanoids (PGE, LTB)
Cytokines (IL, TNF)
NO
Degranulation : Polymorpho-
nuclear neutrophil
leucocytes
Phagocytosis : Macrophages
Cytotoxicity : Lymphocytes
Lymphopoiesis : Cell proliferation
Smooth vascular : Microcirculation
muscle
Smooth bronchial : Ventilation
muscle
Endothelium : Permeability
Platelets : Aggregation
Substrates
Fig. 2.
Effects of invading pathogens on the systemic immune response and its modulation by
substrates with immune-modulating action. PGE, prostaglandin E; LTB, leukotriene B; IL, interleukin;
TNF, tumour necrosis factor.
heat shock protein 70 and its RNA transcription in intestinal
epithelial cells, thereby reducing cytolysis, induced by heat
and oxidation (NH
2
-Cl; Wischmeyer
et al
. 1997; Chow &
Zhang, 1998). Thus, glutamine supplementation reduced
heat shock-induced cell death. This effect, together with the
maintenanceofcellgrowth,mayplayakeyroleinthe
prevention of intestinal mucosal atrophy.
In addition, glutamine supplementation has been reported
to restore mucosal immunoglobulin A and enhance upper
respiratory tract immunity (Li
et al
. 1997), prevent gut-
derived sepsis in obstructive jaundice (Houdijk
et al
. 1997),
reverse gut-derived sepsis due to prednisone administration
(Gennari
experimentally induced intestinal GSH deficiency has been
shown to be associated with impaired mucosal integrity and
function (Martensson
et al
. 1990; Kelly, 1993). It has also
been shown that lumen and lymphatic concentrations of
lipid hydroperoxides were related to intestinal GSH status
(Aw, 1997). Experimental feeding with glutamine results in
a considerable increase in its gut fractional uptake and a
marked increase in intestinal GSH fractional release,
indicating increased intestinal GSH production (Cao
et al
.
1998). The biochemical explanation for these findings is
based on the fact that the highly charged glutamic acid
molecule, one of the direct precursors of GSH, is poorly
transported across the cell membrane, whereas glutamine is
readily taken up by the cell. Glutamine is then deaminated
and thus can serve as a glutamic acid precursor (Hong
et al
. 1992). Obviously, glutamine-mediated GSH synthesis
might be one of the most important factors in the systemic
inflammatory response. It is proposed that tissue GSH
synthesis is a crucial factor in causing the reversal of the
clinical biochemical signs of critical illness.
Regarding the clinical application of glutamine,
impressive confirmation that enteral glutamine therapy is
effective in preventing infective complications has been
reported recently in sixty patients with severe multiple
trauma (Houdijk
et al
. 1998). In a randomized controlled
study enteral glutamine nutrition at 25–30 g/d (Houdijk,
1998) was commenced within 4 h of trauma via a naso-
duodenal tube for a minimum of 5 d. There was a significant
reduction (<
&
Alexander,
1997)
and
enhance
bacterial
clearance in peritonitis (Furukawa
et al
. 1997).
Glutamine supplementation augments the cytotoxic
activity of natural killer and lymphokine-activated killer
cells (Alverdy, 1990; Babst
et al
. 1993; Horig
et al
. 1993) as
well as adequate lymphocyte, killer cell and macrophage
proliferation (Griffiths & Keast, 1990; Parry-Billings
et al
.
1990) and function (Griffiths & Keast, 1990; Wallace &
Keast, 1992; Calder & Newsholme, 1992; Calder, 1994;
Juretic
et al
. 1994). Leucocyte glutaminase activity is high,
thus indicating a high rate of glutamine utilization (Calder,
1994). Recumbent immunocompetent cells already show a
distinctive glutamine metabolism, that further increases by
immunological provocation (Calder, 1994). All these effects
emphasize that cellular defence function can be reinstated
by glutamine repletion
in vitro
and
in vivo
.
In experimental studies supplemental glutamine
preserves hepatic and intestinal mucosal stores of GSH and
maintains plasma concentrations (Hong
et al
. 1992;
Harward
et al
. 1994; Denno
et al
. 1996; Yu
et al
. 1996).
In the gut GSH is involved in the detoxification of
reactive oxygen species and pro-oxidative nutrients. An
50 %) in the 15 d incidence of pneumonia,
bacteraemia and severe sepsis. As a measure of the systemic
inflammatory response, the group receiving glutamine
showed lower levels of soluble tumour necrosis factor
receptors. The strength of this study lies in the relatively
homogeneous population of patients studied, and that it does
−
556
U. Suchner et al.
not suffer the confounding factors present in multi-centre
studies (Griffiths, 1999). However, the results of this
fascinating study require confirmation. In a current study of
a more heterogeneous group of intensive care unit patients
able to tolerate enteral feeding (Jones
et al
. 1999), many of
whomwerealreadyinfectedonadmission,therewasno
suggestion of reduced mortality, but total post-intervention
hospital costs were significantly reduced in both enteral and
parenteral glutamine recipients.
In conclusion, the enteral route may be ideal when given
early to the non-infected patient to improve gut-associated
lymphoid tissue function and the immune defence against
infection. For the already-severely-stressed or infected
intensive care unit patient enteral supplements alone may be
inadequate, and parallel parenteral support is likely to be
required. It has been clearly demonstrated that during
intensive care, the patient’s parenteral supplementation of
enteral nutrition does not increase the risk to the patients and
may even ensure a better overall outcome (Bauer
et al
.
1998).
Kulkarni
et al
. 1989) as well as reduced IL-2 production
(VanBuren
et al
. 1994). Moreover, reduced phagocytosis
(Fanslow
et al
. 1988) and an impaired clearance of
experimentally applied pathogens (Kulkarni
et al
. 1986)
were induced by dietary removal of nucleotides. Most of
these effects could be reversed by resumption of the dietary
supply of nucleotides (Pizzini
et al
. 1990).
The question of whether the demand for nucleosides and
nucleotides can exceed the endogenous synthetic capacity in
human subjects remains to be answered, and implications
with regard to impaired organ and system function are yet to
be evaluated (Grimble, 1994). Notably, there is no relevant
experimental
or
clinical
evidence
that
nucleotides
or
nucleosides
may
enhance
the
systemic
inflammatory
response.
Arginine
Arginine is a dibasic amino acid which the body obtains
from dietary sources and by endogenous synthesis via the
urea cycle. During trauma and sepsis endogenous
availability of arginine is reduced (Barbul
et al
. 1983;
Kirk & Barbul, 1990; Nirgiotis
et al
. 1991). Arginine is
metabolized within the enterocyte via the arginase pathway
to ornithine and urea. Arginine, via the formation of
glutamate, may yield increased amounts of proline and
hydroxyproline, which are required for the synthesis of
connective tissue. Moreover, arginine is the precursor of
polyamine, histidine and nucleic acid synthesis. It is a
promoter of thymic growth and an endocrinological
secretagogue stimulating release of growth hormone,
prolactin, insulin and anti-insulinaemic hormones (Barbul,
1986). Most importantly, however, via the arginine
deaminase pathway (Blachier
et al
. 1991), arginine has been
shown to be the unique substrate for the production of the
biological effector molecule NO. NO is formed by oxidation
of one of the two identical terminal guanidino groups of
L
-arginine by the enzyme NO synthase (NOS). Of the three
NOS isoenzymes characterized, two are constitutive, Ca
2+
-
dependent (endothelial and neuronal) and generate lesser
levels of NO than their inducible counterpart (Nathan &
Xie, 1994). Inducible NOS is prominent in inflammatory
conditions and it is also most often implicated as the
producer of NO during the immune response. According to
recent reports NO plays an essential role in the regulation of
inflammation and immunity (Albina, 1996).
Inhibition of NO synthesis increased intestinal mucosal
permeability in experimental models of ischaemia–
reperfusion intestinal injury (Kubes, 1993) and acute
necrotizing enterocolitis (Miller
et al
. 1993). In addition,
administration of
L
-arginine reversed the effect of NOS
inhibition (Kubes, 1993). These results suggest that basal
NO production is important in minimizing the mucosal
barrier dysfunction in these models.
Arginine may also be of significance in the critically ill
patient because of its potential role in immunomodulation
(Kirk & Barbul, 1990; Evoy
et al
. 1998). It is hypothesized
that arginine enhances the depressed immune response of
individuals suffering from injury, surgical trauma,
malnutrition or sepsis. In experimental animals as well as in
human studies supplementation with arginine resulted in an
Nucleotides
Nucleotides are important components for the synthesis of
DNA, RNA and adenine nucleotides. Adequate nucleotide
synthesis requires sufficient amounts of purines and
pyrimidines. In healthy subjects they are efficiently
absorbed from the diet which normally contains 1–2 g/d.
Purines and pyrimidines are either derived from
de novo
synthesis or from RNA turnover by means of so-called
‘salvage pathways’. In the case of adequate protein intake,
de novo
synthesis is the main source of nucleotides;
glutamine being the major N donor (Szondy & Newsholme,
1990). The role of nucleic acids is critical because
expression of the synthesizing enzymes in the
de novo
pathway is apparently impaired during catabolic stress
(Grimble, 1994). During episodes of infection following
injury and trauma the demand for nucleotides is increased in
order to facilitate the synthetic capacity of the immune cells
(Jyonouchi, 1994; Kulkarni
et al
. 1994). The absence of
nucleotides (purines and pyrimidines) in the diet results in a
selective loss of T-helper lymphocytes and a suppression of
interleukin (IL) 2 production (VanBuren
et al
. 1994).
Parenteral solutions and the majority of enteral diets do
not contain nucleotides. In clinical nutrition an adequate
supply of nucleotides may be a critical factor in promoting
intestinal function and immune status, as suggested by the
findings of numerous experimental studies (Kulkarni
et al
.
1994; VanBuren
et al
. 1994; LeLeiko & Walsh, 1995;
Cosgrove, 1998). In the experimental setting dietary
nucleotide removal was associated with impaired mucosal
integrity and function, which could be partly prevented or
reversed by oral or intravenous supply of these substrates
(LeLeiko
et al
. 1987; Nunez
et al
1990; Iijima
et al
. 1993).
Decreased availability of nucleotides is associated with
impaired T-cell function (VanBuren
et al
. 1983, 1990;
Carver
et al
. 1990; Pizzini
et al
. 1990), weakened natural
killer cell activity (Carver
et al
. 1990), delayed rejection of
allogenic transplants (VanBuren
et al
. 1983), decreased
mortality from graft
v
. host reactions (Kulkarni
et al
. 1984),
suppressed lymphocyte proliferation (VanBuren
et al
. 1983;
Nutrition in the severely-injured patient
557
improved cellular response, a decrease in trauma-induced
reduction in T-cell function and a higher phagocytosis rate
(Kirk & Barbul, 1990).
It is notable that 5 years ago parenteral arginine was
considered a novel and valuable tool to improve immunity
and to beneficially influence metabolism and patho-
physiology in cancer and trauma. Remarkably, in the current
literature the intravenous arginine approach is almost
absent, while emphasis is laid on enteral arginine nutrition.
Presumably the prominent reports of the drawbacks and
disadvantages of large amounts of parenteral arginine have
been slowly recognized and considered (for references see
Fürst & Stehle, 1995). In healthy human subjects and
surgical and intensive care unit patients enteral arginine
supplementation was accompanied by increased lymphocyte
and monocyte proliferation as well as enhanced T-helper
cell formation (Daly
et al
. 1988; Barbul, 1990; Cerra
et al
.
1990). Clinical studies have demonstrated moderate net N
retention and enhanced protein synthesis compared with
isonitrogenous diets in critically ill and injured patients.
Following surgery for certain malignancies in elderly post-
operative patients, supplemental arginine (25 g/d) enhanced
T lymphocyte responses to phytohaemagglutinin and
concanavalin A, and increased the CD
4
phenotype number
(Daly
et al
. 1988). Interestingly, insulin-like growth factor-1
levels were about 50 % higher, reflecting the growth
hormone secretion induced by arginine supplementation. A
high load of oral arginine (30 g/d) improved wound healing
(Barbul
et al
. 1990) and enhanced blastogenic response to
several mitogens (Sodeyama
et al
. 1993). Some of these
studies were also associated with
in vitro
evidence of
enhanced immunoactivity (Kirk & Barbul, 1990; Brittenden
et al
.1994
a
,
b
;Beaumier
et al
. 1995). Thus, it is probable
that the observed beneficial effects of these substrates were
due to improved function of the immune system rather than
improved gut barrier function.
Results available from clinical trials failed to demonstrate
improvements in patient outcome (for references, see Lin
et al
. 1998). There is also some concern that arginine
may enhance the systemic inflammatory response due to
an enhanced NO release in patients with severe systemic
inflammatory response syndrome (SIRS) or sepsis. This
response would lead to a negative iono- and chronotropism
of the myocardium (Lowenstein
et al
. 1994), impaired
coagulation (Radomski
et al
. 1990; deGraaf
et al
. 1992) and
vascular dilatation leading to refractory hypotension (Lee
et al
. 1984; Lorente
et al
. 1993). Apparently, NO may exert
cytotoxic effects as a non-specific effector inhibiting growth
or killing off cells in an untargeted fashion (Lepoivre
et al
.
1991; Wink
et al
. 1991; Lowenstein
et al
. 1994). On the
other hand, according to current knowledge, NOS and NO-
mediated immunofactors as well as intracellular arginase
are restricted to distinct compartments, thus supplemental
arginine may not
cological agents provided through nutrition. This situation
appears to be particularly true for the
n
-3 PUFA.
Fatty acids are characterized by the number of C atoms,
the number of double bonds and the position of the first
double bond, calculated from the methyl end of the
molecule. Thus, 18 : 2
n
-6 represents linoleic acid which
serves as the precursor for the formation of the most
important fatty acids of the
n
-6 series such as arachidonic
acid.
-linolenic acid, the parent
compound of
n
-3 PUFA, with the first double bond being at
C-3 from the methyl end. Whereas
n
-6 fatty acid deficiency
has been recognized and considered,
n
-3 fatty acid
deficiency is just now being appreciated. Delayed growth,
neurobiological symptoms, skin lesions, reduced visual
acuity, abnormal electroretinogram and reduced learning
ability represent signs of
n
-3 fatty acid deficiency. Long-
chain
n
-3 PUFA such as eicosapentaenoic (20 : 5
n
-3; EPA)
and docosahexaenoic acid (22 : 6
n
-3) are built up in algae
and plankton and the fish living on them, rendering deep-sea
fish and fish oils produced from them the main dietary
source of
n
-3 PUFA for human subjects.
With the enteral or parenteral intake of increased
quantities of
n
-3 PUFA, the
n
-3 :
n
-6 PUFA value in the
phospholipid spectrum of the cell membrane in various
tissues changes in favour of
n
-3 PUFA (Palombo
et al
.
1993; Morlion
et al
. 1996). Several laboratories have
demonstrated that dietary pretreatment with
n
-3 PUFA
favourably influences the pathophysiological response to
endotoxins (Mascioli
et al
. 1988; Seidner
et al
. 1989) and
exerts an important modulatory effect on eicosanoid and
cytokine biology. The most likely way in which lipids might
modulate pro-inflammatory cytokine biology is by changing
the fatty acid composition in the cell membrane. As a
consequence of the changes two interrelated phenomena
may occur: (1) alteration in membrane fluidity; (2) altera-
tions in products which arise from hydrolysis of membrane
phospholipids (Grimble, 1998).
Changes in fluidity may alter the binding of cytokines
and cytokine-inducing agonists to receptors (Stubbs &
Smith, 1984; Murphy, 1990). For example, fluidity changes
may alter G-protein activity, thereby changing adenylate
kinase, phospholipase A
2
and phospholipase C activity (for
references, see Fürst & Kuhn, 2000).
Alterations in membrane phospholipids will also directly
influence the synthesis of lipid-derived mediators such
as the eicosanoids, phosphatidic acid, platelet-activating
factor and the secondary messengers, diacylglycerol and
ceramide (Grimble, 1992, 1998; Ross
et al
. 1999). By the
action of the enzyme phospholipase A
2
,PUFAcanbe
released from the membrane phospholipids and either act as
a secondary messenger or alternatively serve as a precursor
for the cyclo-oxygenase pathway (Kinsella
et al
. 1990). The
latter pathway metabolizes arachidonic acid to the 2-series
of prostaglandins, especially prostaglandins E
2
and F
2α
and
thromboxane A
2
. EPA is also an excellent substrate for the
enzyme 5-lipoxygenase. The major advantages of EPA- and
docosahexaenoic acid-derived metabolites can be summa-
rized as follows: (1) EPA-derived thromboxane A
3
is less
active in platelet aggregation than thromboxane A
2
;(2)
leukotriene (LT) B
4
enhances chemotaxis, while other LT,
e.g. LTC
4
, LTD
4
,andLTE
4
, augment vascular permeability
18 : 3
n
-3
represents
α
affect
extracellular NO concentration
(Moncada
et al
. 1991).
n
-3 Polyunsaturated fatty acids
We are gradually understanding that lipids are more than
sources of energy and building blocks for cell membranes,
but may, in some circumstances, be considered as pharma-
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