Nutrition Vol. 14, Nos.

7/8, 1998
Immunonutrition: The Role of Arginine
DENIS EVOY, FRCSI, MICHAEL D. LIEBERMAN, MD, THOMAS J. FAHEY III, MD,
AND JOHN M. DALY, MD, FACS
From the Department of Surgery, The New York Hospital, Cornell Medical Center, New York, New York, USA
ABSTRACT
Arginine, a non-essential amino acid, has a role in stimulating the hosts immune system. Animal and human studies suggest
outcome benet to the use of supplemental dietary arginine. Nutrition 1998;14:611617. Elsevier Science Inc. 1998
Key words: arginine, macrophage, nitric oxide, immunity, infection
INTRODUCTION
Immunonutrition may be dened as the effect of the provi-
sion of specic nutrients on immune function. The amino
acid arginine is of particular interest in this regard as it has
been demonstrated to have an array of desirable biological
properties. Arginine stimulates anabolic hormone release, im-
proves nitrogen balance, and has been demonstrated to be
immunostimulatory and thymotrophic.
13
Arginine has funda-
mental roles in nitrogen metabolism, creatine, and polyamine
synthesis, and is the major substrate for the production of nitric
oxide.
Arginine was rst isolated in crystalline form and named in
1886. Its presence in animal protein was documented in 1895.
4
In
1930, Scull and Rose
5
demonstrated that arginine was synthesized
by the growing rat. They showed that arginine in the carcasses of
rats fed a low arginine diet contained two to three times as much
arginine as had been consumed.
5
In both children and adults arginine is regarded as a nonessen-
tial amino acid.
6
A deciency of any indispensable amino acid
leads to a decrease in food intake, reduced growth, and negative
nitrogen balance. Rats deprived of arginine do not lose weight, but
gain weight more slowly than rats allowed arginine in the diet.
Rose stated that arginine can be synthesized by the rat but not at
a sufciently high rate to meet maximum growth. Its classica-
tion, therefore, as essential or nonessential is purely a matter of
denition.
7
However, rats fed diets without arginine develop
fatty livers and altered glucose tolerance as well as abnormalities
of nitrogen metabolism.
8,9
In rats, mice, hamsters, guinea pigs,
and rabbits, the excretion of citric and orotic acid is a sensitive
indicator of arginine availability. Orotic acid production is re-
duced or prevented by inclusion of the urea cycle intermediates,
arginine, citrulline, or ornithine, in the diet.
10
For many mammals,
arginine is essential for normal growth and development of the
young and is regarded as nonessential only in the fully grown
adult.
11
ARGININE BIOCHEMISTRY
The biochemistry of arginine is complex and involves many
key metabolic pathways and organ systems (Fig. 1). Glutamate
and glutamine are the amino acids that allow the incorporation of
ammonia into amino acids and other organic biomolecules in the
eukaryotic cell. In most cell types one or both of these amino acids
are present at elevated concentrations, often a half log higher than
other amino acid levels. In animals, glutamate is synthesized from
the substrates of -ketoglutarate and NH
4

by the action of
L-glutamate dehydrogenase, and plasma glutamate levels are
maintained by the transamination of -ketoglutarate during amino
acid metabolism. Glutamine is a nonessential amino acid that can
be synthesized by the addition of NH
3
to glutamate, and is a major
constituent of normal dietary protein intake. Glutamine is the
preferred energy source of gastrointestinal mucosal cells. Much of
the glutamine utilized by the intestine is metabolized to citrulline
and released into the portal circulation. Citrulline is taken up by
the kidney and converted into arginine. The production of citrul-
line by the intestine, arginine by the kidney, and glucose and urea
by the liver are metabolically linked and this cycle (Fig. 2) is
regulated by differential activity of enzymes present in each of
these tissues.
12
Arginine is an integral constituent of the urea cycle. In 1932,
Krebs
4
identied the urea cycle and noted that urea production
from ammonia by the liver was greatly accelerated by adding any
one of three amino acids; arginine, citrulline, or ornithine. The
addition of ammonia to ornithine synthesizes citrulline; the addi-
tion of ammonia to citrulline synthesizes arginine; the loss of these
two NH groups in the form of urea from arginine is used to
synthesize ornithine. Arginase activity in the liver is very high;
therefore, hepatic arginine levels are very low, and there is very
little arginine released into the circulating amino acid pool by the
liver. Tissue arginase activity and tissue arginine content are
inversely related. Kidney and muscle have 1% the arginase con-
tent of the liver and 10 times the arginine content. Most of the
arginine formed in the liver is cleaved to form urea.
Correspondence to: John M. Daly, MD, FACS, Lewis Atterbury Stimson Professor and Chairman, Department of Surgery, The New York Hospital, Cornell
Medical Center, 525 East 68th Street, Room F-739, New York, NY 10021, USA.
Nutrition 14:611617, 1998
Elsevier Science Inc. 1998 0899-9007/98/$19.00
Printed in the USA. All rights reserved. PII S0899-9007(98)00005-7
The urea cycle straddles the mitochondrial-cytoplasmic divide
(Fig. 3). Ammonia is transported in the blood stream to the liver
from the periphery in the form of glutamine (transaminated glu-
tamate) or alanine (transaminated pyruvate).
13
It is then delivered
to the mitochondria of the hepatocyte and is immediately utilized
with bicarbonate to form carbamoyl phosphate. The enzyme cat-
alyzing this reaction is a mitochondrial enzyme, carbamoyl phos-
phate synthetase I. This is a key regulatory step in the urea cycle
that is ultimately controlled by the concentration of arginine.
Arginine may be regarded as a urea cycle intermediate that accu-
mulates when urea production is insufcient to accommodate the
ammonia produced by amino acid catabolism. The accumulation
of arginine upregulates the urea cycle.
Citrulline is a major end product of intestinal glutamine me-
tabolism and is released by the intestine into the circulating amino
acid pool. It is estimated that more than 25% of intestinal glu-
tamine is released as citrulline. Renal citrulline uptake is approx-
imately 80% of the amount released by the intestine.
14
The kidney
then synthesizes arginine from citrulline,
15
and releases it into the
blood stream allowing peripheral uptake of arginine and protein
synthesis. The kidney, therefore, is the primary organ responsible
for maintenance of the plasma arginine level. In our laboratory the
standard fasting plasma arginine level approximates 75 M/L
(preoperative patients) and uctuates according to the fasting or
fed state.
3
The average intake of arginine in the diet is estimated
to be 5 g daily.
11
ARGININE AND IMMUNE FUNCTION
Two pathways of arginine metabolism have been identied as
being critical to the immunomodulatory actions of arginine in
vivo. First, the arginase pathway, in which arginine is con-
verted to urea and ornithine, generates polyamines by the action of
ornithine decarboxylase. This route of polyamine synthesis may
be the mechanism whereby arginine augments lymphocyte mito-
genesis.
16
Induction of arginase has also been proposed as the
effector pathway in arginine-dependent macrophage-mediated tu-
mor cell cytotoxicity.
17
Second, arginine is the sole substrate for nitric oxide synthesis
in biologic systems. Nitric oxide is synthesized from arginine by
the action of nitric oxide synthase resulting in the formation of
nitric oxide and citrulline. Nitric oxide is a ubiquitous molecule
with important roles in the maintenance of vascular tone, coagu-
lation, the immune system, and the gastrointestinal tract, and has
been implicated as a factor in disease states as diverse as sepsis,
hypertension, and cirrhosis.
18,19
Arginine is the starting substance in the synthesis of poly-
amines, which include spermine. Polyamines appear to play a key
role in cell division, DNA replication, and regulation of the cell
cycle.
20,21
Arginine is also the only amino acid that provides the
amidino group for synthesis of creatine, a major reserve of high
energy phosphate for regeneration of ATP in muscle. The path-
ways for de novo biosynthesis of pyrmidines and arginine are
interrelated by the common substrate, carbamoyl phosphate. In
FIG. 1. The biochemistry of arginine.
FIG. 2. The intestinal production of citrulline, the kidney production of
arginine, and the liver production of glucose and urea are regulated by the
differential activities of an array of enzymes present in each tissue.
IMMUNONUTRITION: THE ROLE OF ARGININE 612
addition, the urea cycle intermediate, arginosuccinate, has impor-
tant links with the citric acid cycle.
22
Arginine, therefore, plays an important role in protein synthe-
sis, urea cycle metabolism, the synthesis of the high-energy com-
pounds, creatine and creatine phosphate, polyamine synthesis, and
the production of nitric oxide. The use of arginine, therefore, is of
particular interest in the eld of immunonutrition and many stud-
ies have been undertaken attempting to exploit the desirable
biological properties of arginine.
Studies by Barbul et al.
23
have demonstrated that administra-
tion of dietary supplemental arginine to injured rats results in
accelerated wound healing. Increased wound tensile strength and
collagen deposition were demonstrated. Wound healing was im-
proved in the arginine parenterally supplemented group as as-
sessed by fresh wound strip breaking strength, xed breaking
strength, and the amount of reparative collagen deposition indexed
by the hydroxyproline content of the implanted sponges.
23
These
ndings are explained by the fact that in the growing animal,
arginine is used for protein synthesis; in the injured animal there
is an increased requirement for arginine to synthesize reparative
connective tissue. Arginine-supplemented rats also had improved
thymic function as assessed by thymic weight, the total number of
thymic lymphocytes in each thymus, and the mitogenic reactivity
of thymic lymphocytes to phytohemagglutinin and concanavalin
A. Thymic involution is usually associated with injury in the rat.
Of note, arginine supplementation in uninjured rats is associated
with an increase in thymic weight. This response was accompa-
nied by an increase in total lymphocyte counts and enhanced
blastogenic response in the noninjured rats. Only rarely has any
substance been identied that augments a normal cellular function.
The effect of arginine on wound healing in humans has also
been assessed. Barbul et al.
2
implanted polytetrauoroethylene
tubing into the subcutaneous tissue of volunteers. After 2 wk of
arginine supplementation (25 g/d), the amount of hydroxyproline
in the tubing was measured as an index of collagen synthesis.
Hydroxyproline levels doubled in arginine-supplemented subjects.
Arginine supplementation also increased peripheral lymphocyte
mitogenesis in response to phytohemagglutinin and concanavalin
A in humans.
2
Other studies have documented similar results in a
healthy elderly human population.
24
The benecial effect of argi-
nine on the immune system appears distinct from its more mod-
erate effect on nitrogen metabolism as only minor improvements
in postoperative nitrogen balance in patients are observed com-
pared to the more robust upregulation of immune parameters.
3
The effect of arginine supplementation in the postoperative
period has been investigated.
3
Thirty patients with gastrointestinal
cancer were randomized to receive either arginine 25 g/d or
isonitrogenous glycine 43 g/d for 7 d after surgery as part of an
enteral diet. Arginine supplementation resulted in an enhanced
response by peripheral blood lymphocytes to mitogens on the 7th
d after operation compared with the 1st d, and was also associated
with an increased number of circulating CD4 T cells. Arginine
supplementation increased plasma arginine levels from a base line
level of 75 M/L to 200 M/L after 7 d of arginine supplemen-
tation. There was a similar magnitude of increase in plasma
ornithine levels. There was no difference in clinical outcome
detected between groups in this study.
There has been a trend to supplement enteral diets with argi-
nine, RNA, and -3 fatty acids, in order to determine if these
agents in combination will be of greater benet to the patient than
any single agent. Sixty adult patients with gastrointestinal cancers
were randomized to receive supplemental or standard diet via
jejunostomy beginning on the rst postoperative day (goal 25
kcal kg
1
d
1
) until hospital discharge. Patients were also ran-
domized to receive or not receive enteral jejunostomy feedings in
the 12- to 16-wk recovery and radiation/chemotherapy periods.
FIG. 3. The urea cycle straddles the mitochondrial-cytoplasmic divide.
IMMUNONUTRITION: THE ROLE OF ARGININE 613
Infectious wound complications occurred in 10% of the supple-
mented group compared with 43% of the standard group. We
conclude that enteral feeding, supplemented with immune modu-
lating agents including arginine, decreases postoperative infec-
tious wound complications compared with standard enteral feed-
ing.
25
A multicenter, prospective, randomized clinical trial
26
using
early enteral administration of a standard formula supplemented
with arginine, nucleotides, and sh oil in intensive care unit
patients has been completed. From intensive care units in eight
different hospitals, 296 trauma, surgery, or septic patients were
eligible for analysis. Patients receiving the supplemented formula
had a signicant (P 0.0001) increase in plasma arginine and
ornithine concentrations by day 7. The mortality rate was not
different between groups. However, for patients stratied as sep-
tic, the median length of hospital stay was reduced by 10 d (P
0.05). In this study there was no signicant difference in infectious
TABLE I.
THE INCIDENCE OF SEPTIC COMPLICATIONS IN PROSPECTIVE RANDOMIZED TRIALS COMPARING ARGININE-SUPPLEMENTED
PATIENTS TO NONSUPPLEMENTED CONTROLS
Study cohort Author Year N Experimental diet Control diet
Infectious complications
Experimental Control
Postop cancer Daly
25
1992 85 Ent* Ent 11%** 37%
Postop cancer Daly
25
1995 60 Ent* Ent 10%** 43%
Postop cancer Braga
27
1996 60 Ent* Ent 10%
NS
15%
Mixed Bower
26
1995 296 Ent* Ent per patient
mean SD
0.74 0.97
NS
per patient
mean SD
0.98 1.27
Trauma patients Brown
29
1994 37 Ent Ent 16%** 56%
Trauma patients Kudsk
28
1996 33 Ent* Ent 6%** 41%
Trauma patients Moore
42
1994 98 Ent* Ent 0%**
Intra-abdominal abcess
11%
Intra-abdominal abcess
Burn patients Gottschlich
43
1990 50 Ent* Ent per patient
mean 0.4**
per patient
mean 1.1
* Ent: Arginine, -3 fatty acids and nucleotide supplementation.
** P 0.05 (References: 2529, 4243).
NS, not signicant.
FIG. 4. In A/J mice, bearing C1300 murine neuroblastoma, arginine supplementation signicantly (P 0.05) retarded tumor growth.
IMMUNONUTRITION: THE ROLE OF ARGININE 614
complications between the total numbers of supplemented and
non-supplemented patients (200). However, a subgroup of pa-
tients who were able to complete the total planned intake of
supplemental diet in the rst 7 d of enteral supplementation were
compared to patients who received the same quantity of standard
enteral formula; a total of 100 patients. There was a signicant
reduction in infectious complications (mean SD 0.54 0.78
versus 0.94 0.87) in this supplemented subgroup.
26
Braga et
al.
27
demonstrated no difference in the incidence of infectious
complications in patients undergoing surgery for malignancy sup-
plemented postoperatively with arginine, RNA, and -3 fatty
acids compared to control patients receiving standard enteral nu-
trition. However, the infectious complications were assessed as
being signicantly less severe in the supplemented group.
27
Kudsk et al.
28
prospectively randomized 35 severely injured
trauma patients to an enteral diet containing glutamine, arginine,
-3 fatty acids, and nucleotides or to an isonitrogenous, isocaloric
diet to investigate the effect of septic outcome. A third group of
patients, without enteral access but eligible by severity of injury,
served as unfed controls and were studied prospectively to deter-
mine the risk of infection. Patients were evaluated for septic
complications, antibiotic usage, and hospital and intensive care
unit stay. Signicantly fewer major infectious complications (6%)
developed in patients who received the supplemented diet than
patients in the isonitrogenous group (41%, P 0.02) or the
control group (58%, P 0.002). Hospital stay was also signi-
cantly lower in patients receiving the supplemented diet than the
other two groups. Unfed patients had the highest complication rate
in this study.
28
Other prospective, randomized clinical trials in an intensive
care setting have demonstrated similar results using arginine,
linolenic acid, beta-carotene, and hydrolyzed protein for up to
10 d.
29,30
The results of prospective, randomized clinical trials
involving the use of supplemental arginine are summarized in
Table I.
Innate host cellular cytotoxicity, mediated in part by natural
killer (NK) and lymphokine-activated killer (LAK) cells, is
thought to play an important role in the inhibition of tumor growth
and the reduction of metastatic spread. Arginine supplementation
has been shown to enhance NK and LAK cytotoxicity.
31
The effect of arginine on tumor growth has been examined
over the past 50 y. In vivo animal studies have demonstrated both
stimulation and inhibition of tumor growth.
32
Park et al.
33
has
described an increase in tumor proliferation markers in patients
with breast cancer treated with dietary arginine supplements.
Human pancreatic cancer cell growth is inhibited by the arginine
antimetabolite L-canavanine.
34
Arginine supplementation in the
tumor-bearing host may inhibit the growth and dissemination of
immunogenic tumors by upregulating NK and LAK function.
Reynolds et al.
35
demonstrated that in nontumor-bearing A/J
mice, 1% arginine supplementation signicantly enhanced thymic
weight and spleen cell mitogenesis. Supplemental 1% arginine,
when compared with 1.7% glycine, also enhanced interferon-
induced NK cell activity, LAK cell generation, and macrophage
cytotoxicity. In A/J mice, bearing C1300 murine neuroblastoma,
1% arginine enhanced splenocyte mitogenesis and IL-2 produc-
tion and signicantly (P 0.05) retarded tumor growth as shown
in Figure 4, and prolonged median survival time compared with
glycine or no supplementation.
35
A subsequent study assessed supplemental dietary arginine in
mice as a means to potentiate the host antitumor response to
interleukin-2 (IL-2) in the same murine neuroblastoma model. A/J
mice received 1% arginine or isonitrogenous glycine (1.7%) in
addition to a regular diet 14 d before subcutaneous inoculation
with C1300 neuroblastoma cells. Twenty-four hours later, animals
were administered IL-2 three times a day or saline intraperitone-
ally for 4 d. On days 4 and 10 post-C1300 neuroblastoma inocu-
lation, mice were killed for assessment of NK cell and tumor
specic cytotoxicity. Remaining animals were followed for tumor
incidence, tumor growth, and duration of host survival. IL-2
FIG. 5. IL-2 treated A/J mice, bearing C1300 murine neuroblastoma receiving supplemental dietary arginine compared with those receiving glycine results
in prolonged host survival.
36
GLY, glycerine; PBS, phosphate-buffered saline; ARG, arginine; IL-2, interleukin-2.
IMMUNONUTRITION: THE ROLE OF ARGININE 615
therapy in mice receiving dietary arginine compared with those
receiving glycine resulted in signicantly augmented NK cell
cytotoxicity. C1300 neuroblastoma engraftment and growth were
retarded, and prolonged host survival (P 0.05) were also dem-
onstrated in the IL-2, arginine-treated animals as shown in Figure
5. This study demonstrated that supplemental dietary L-arginine
enhances lymphocyte cytotoxic mechanisms and may potentiate
IL-2 immunotherapy.
36
A separate study by Yeatman et al.
37
examined the effects of
dietary arginine on the growth of a murine colon tumor, metastatic
to the liver in a model of advanced neoplastic disease. An argi-
nine-depleted diet inhibited tumor growth. This effect was attrib-
uted to the dependence of this particular tumor model on arginine
for growth in vitro and in vivo.
Arginine has multiple, potent secretagogue activities on several
endocrine glands.
22
The relationship of the metabolic effects to the
secretagogue properties of arginine is unclear. Arginine infusion
induces the secretion of growth hormone, insulin, glucagon, pro-
lactin, and somatostatin.
3841
An intact hypothalamo-pituitary
axis is essential in order for arginine to mediate its effects.
1
However, no signicant differences between arginine enterally
supplemented and nonsupplemented patient groups in mean insu-
lin, glucagon, cortisol, and growth hormone levels were found in
a separate study.
3
In this study, mean somatomedin C levels were
signicantly higher in the arginine group on day 7 suggesting a
stimulatory effect of arginine on the pituitary.
SUMMARY
Clearly, arginine has great potential as an immunomodulator
and may prove useful in catabolic conditions such as severe sepsis
and postoperative stress. There is a body of evidence suggesting
that supplemental arginine upregulates immune function and re-
duces the incidence of postoperative infection. More modest im-
provements in nitrogen balance have been observed. Tumor re-
sponse to arginine appears to depend on the immunogenicity of
the particular tumor and on the requirement of arginine by that
tumor as a growth substrate. Of note, ornithine shares the thy-
motrophic, immunostimulatory and secretagogue effects of argi-
nine.
3
It is, therefore, likely that these compounds share the same
cellular mechanism of action or that arginine acts via increasing
the concentration of available ornithine. The role of arginine in the
injured patient and in the tumor-bearing host demands additional
study based on the promising experimental evidence regarding the
supplemental use of arginine.
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