Glutamine: Mode of action in critical illness

Paul E. Wischmeyer, MD
A
recent editorial in Critical
Care Medicine was titled Glu-
tamine, a life-saving nutrient,
but why? (1). The question this
review will attempt to address is: How
might glutamine (Gln) be acting to be life-
saving?
Initial clinical data in the past 15 yrs
have begun to show that Gln may be
benecial in improving outcomes in clin-
ical trials of critically ill patients. A num-
ber of trials of Gln in critical illness have
revealed that Gln could improve infec-
tious morbidity and mortality in critically
ill patients (26). Differences in methods
in trials showing benet vs. trials that
have not shown benet (7) seem to relate
to the dose and, in some cases, the route
of administration of Gln. The benecial
trials gave larger doses of Gln (typically
0.5 gkg
1
day
1
), and most gave the
Gln intravenously. This trend toward
larger parenteral doses of Gln being ben-
ecial was supported by a recent meta-
analysis of Gln in critical illness (8).
Based on these initial clinical trials, and
in an attempt to understand why Gln might
be lifesaving, the history of the explanations
for Gln supplementation in critical illness
must be examined. Gln is now known to be
conditionally essential in states of serious
illness or injury (9). In catabolic states,
large amounts of amino acids are released
from muscle tissue (10). One described hy-
pothesis for the release of Gln after stress is
that Gln provides a vital fuel source for
enterocytes of the small bowel, rapidly di-
viding leukocytes and macrophages in the
immune system, for its essential role in
nucleic acid synthesis, and for acidbase
homeostasis in the kidney (11, 12). Despite
this signicant release of Gln, Gln levels do
not seem to increase after critical illness or
injury; in fact, signicant decreases in
plasma Gln levels have been observed in
states of severe critical illness (13, 14). Of
note, this deciency has recently been as-
sociated with increased mortality in criti-
cally ill patients (15).
Recent mechanistic research reveals
that long-held beliefs about Glns mech-
anism as just a metabolic fuel or protein
precursor for rapidly dividing cells are
being challenged. Recent research reveals
that Gln may serve as a vital cell-
signaling molecule in states of illness and
injury (16). Gln has been shown to regu-
late the expression of many genes related
to metabolism, signal transduction, cell
defense, and repair and to activate intra-
cellular signaling pathways (16). It is pos-
sible that the release of Gln from muscle
and other sources after stress, illness, and
injury serves as a stress signal to the
organism to turn on genes vital to cellu-
lar protection and immune regulation.
These new data are beginning to provide
attractive explanations for the mecha-
nisms by which Gln may exert lifesaving
properties after severe injury and illness.
Further, this mechanistic data may help
us understand what patients and in what
dose Gln therapy may be most benecial.
RECENT MECHANISTIC
STUDIES OF GLN IN CRITICAL
ILLNESS
The aforementioned editorial (1) pro-
posed four potential mechanisms by which
Gln may be acting. These included the fol-
lowing: 1) tissue protection, 2) immune
modulation, 3) preservation of glutathione
and antioxidant capacity, and 4) preserva-
tion of metabolism. Our laboratory and
others have recently published data on all
these possible mechanisms, and based on
these recent data, this author would like to
rene this list to include the following:
From the Department of Anesthesiology, University
of Colorado Health Sciences Center, Denver, CO.
Dr. Wischmeyer has received speaking fees from
Fresenius Kabi AG.
For information regarding this article, E-mail:
Paul.Wischmeyer@UCHSC.edu
Copyright 2007 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000278064.32780.D3
A recent editorial in Critical Care Medicine was titled Glutamine,
a life-saving nutrient, but why? (2003; 31:25552556). This review
will attempt to utilize new understanding of genenutrient interac-
tions and molecular medicine to address potential mechanisms by
which glutamine may be lifesaving after critical illness and injury.
Recent meta-analysis data reveal that glutamine seems to exert a
benecial effect on mortality in critically ill patients. However, this
effect seems to be dose and route dependent. The questions that
remain to be answered are in what settings and via what method of
administration does this phamaconutrient show optimal benet? It is
likely that examination of the molecular mechanisms by which
glutamine exerts its effects will lead to an understanding of how best
to utilize glutamine as both a pharmacologic and a nutritional agent.
Clearly, clinical critical illness leads to a marked deciency in glu-
tamine that is correlated with mortality in the intensive care unit
setting. It makes obvious sense that the deciency of this vital stress
nutrient should be replaced. In addition, recent laboratory data reveal
glutamine may act via mechanisms independent of its role as a
metabolic fuel. These include enhanced stress protein response,
attenuation of the inammatory response, improved tissue metabolic
function, and attenuation of oxidant stress. Present data indicate that
glutamine functions as a metabolic fuel and stress-signaling mol-
ecule after illness and injury. Thus, deciencies observed in critical
illness demand replacement for both pharmacologic and metabolic
optimization. Presently, randomized, multicenter, clinical trials utiliz-
ing glutamine as a pharmacologic and a nutritional agent are ongo-
ing. (Crit Care Med 2007; 35[Suppl.]:S541S544)
KEY WORDS: critical care; metabolic dysfunction; mortality; mo-
lecular mechanism; nutritional pharmacology; heat shock protein;
inammation
S541 Crit Care Med 2007 Vol. 35, No. 9 (Suppl.)
1) tissue protection, 2) anti-inammatory/
immunologic, 3) metabolic, and 4) antiox-
idant/inducible nitric oxide synthase atten-
uation (Table 1). This reviewwill attempt to
cover the recent literature supporting each
of these mechanisms.
Tissue Protection
Enhanced Heat Shock Protein Ex-
pression. The initial data that led to this
proposed mechanism were generated by
our laboratory in cellular models of in-
jury (17) and in animal models of shock
(1820). We and other laboratories have
improved on these data with recent pub-
lications. We recently completed a trial of
intravenous Gln therapy in a cecal liga-
tion and puncture model of sepsis in the
rat. In this study, Gln (0.75 g/kg) was
given as posttreatment 1 hr after the ini-
tiation of sepsis. This trial revealed a sin-
gle dose of Gln enhanced lung tissue heat
shock protein (HSP)-70, HSP-25 expres-
sion, and serum HSP-70 expression. The
activation of the transcription factor for
HSP-70, heat shock factor-1, was also in-
creased in Gln vs. placebo after sepsis. Gln-
mediated enhancement of HSP-70 led to
the prevention of acute respiratory distress
syndrome. Marked attenuation of tissue
metabolic dysfunction was observed after
Gln administration as measured by lung
tissue adenosine 5'-triphosphate/adenosine
5'-diphosphate ratio and the oxidized form
of nicotinamide adenine dinucleotide. Fi-
nally, a signicant decrease in mortality was
observed after Gln administration (p .05 vs.
placebo) (21). Treatment with quercetin
(a chemical inhibitor of HSP-70) blocked
all benecial effects of Gln administra-
tion.
Another recent study revealed that sim-
ilar Gln administration as a single dose
(0.75 g/kg) enhanced heme oxygenase-1
content in multiple cell types in the colon
of rats exposed to endotoxemia (22). This
study indicated that Gln could reduce gut
cell apoptosis and gut injury via histologic
postendotoxemic shock. Finally, Gln ther-
apy improved survival in this model. The
benecial effects of Gln treatment were
abolished by treatment with heme oxygen-
ase-1 inhibitor tin mesoporphyrin.
Given these data, our laboratory hypoth-
esized that Gln may act as a heat shock
factor-1 activator and increase the entire
family of HSPs after stress or injury. We
have recently published data that indicate
that in heat shock factor-1 knockout cells,
Glns ability to generate an HSP response is
lost and the protection conferred by Gln is
also completely abrogated (23). Utilizing
HSP-70 knockout mice, we have also
shown that HSP-70 expression is vital for
rodent survival after sepsis (24). Utilizing
these mice, we have found that Gln pro-
tects HSP-70 wild-type mice after sepsis
but is unable to provide a survival advan-
tage in mice with a gene deletion of HSP-70
from experimental sepsis (25).
In an attempt to translate these nd-
ings to critically ill patients, we recently
completed a pilot trial examining the po-
tential for Gln to enhance HSP-70 expres-
sion in critically ill patients. This double-
blind trial examined patients in the
surgical intensive care unit (ICU) who
required total parenteral nutrition for 5
days and were randomized to receive Gln
(given as alanyl-Gln, 0.5 gkg
1
day
1
) or
an isonitrogenous control. This subtrial
specically examined the expression of
HSP-70 at 7 days after initiation of Gln or
isonitrogenous control and correlated this
level with outcome. Gln treatment en-
hanced serum HSP-70 expression (3.7-fold
increase vs. isonitrogenous control; 95%
condence interval, 1.511.9; p .029),
and this enhanced HSP-70 expression cor-
related with a decrease in ICU length of stay
(p .009 vs. control) (26). This study dem-
onstrated Gln as the rst nontoxic, clini-
cally relevant enhancer of HSP-70 expres-
sion in critically ill patients.
Prevention of Enhanced Gut Perme-
ability. A recent meta-analysis examined
the question of Glns effect on gut per-
meability (27). The authors presented
data indicating that in a small number of
studies of burn patients and patients under-
going major abdominal surgery, Gln ad-
ministration leads to an improvement in
gut permeability as measured via lactose/
mannitol ratios (27). It is difcult to make
any inferences from these limited data. The
role of Gln in preventing injury to the gut
barrier still requires further study.
Prevention of Apoptosis. A number of
recent in vitro studies (28, 29) have ex-
amined the role of Gln in preventing ap-
optosis after stress or injury. These stud-
ies were reviewed in a recently published
article (30).
Anti-inammatory/Immune
Regulation
Previous literature has examined the
role of Gln in regulating the immune re-
sponse (18, 31, 32). Focus of recent studies
has been on Glns ability to attenuate the
inammatory response via effects on the
nuclear factor-B and inhibitor factor IB
signaling pathways. Our laboratory recently
completed a trial in the cecal ligation and
puncture model of sepsis in the rat showing
a single dose of Gln (0.75 g/kg) can attenuate
nuclear binding/activation of nuclear fac-
tor-B and prevent the degradation of its in-
hibitory protein IB (33). This study also
revealed that Gln could inhibit the activation
of the stress kinase pathway, including p38
mitogen-activated protein kinase and extra-
cellular signal-regulated kinase. This effect
led to attenuated tumor necrosis factor-,
interleukin-6, and interleukin-18 expres-
sion after sepsis. These ndings have been
supported by data showing Gln can atten-
uate interleukin-6 release in septic mice
after cecal ligation and puncture (34).
These ndings have been conrmed in a
recently published rodent model of hemor-
rhagic shock. These new data reveal that
Gln-based uid resuscitation can attenuate
tumor necrosis factor- and interleukin-1
expression in the liver after shock (35).
This anti-inammatory effect may, in
part, depend on HSP expression. Utilizing the
HSP-70 knockout mice described previously,
we have shown that mice with a deletion of
the HSP-70 gene do not demonstrate atten-
uated nuclear binding/activation of nuclear
factor-B after Gln treatment. Further-
more, Gln-mediated attenuation of tumor
necrosis factor- and interleukin-6 expres-
sion is lost in the HSP-70 knockout mice
(25).
Specic to the gut, Kozar et al. (37) have
performed a number of elegant studies ex-
amining the role of Gln and other nutrients
Table 1. Proposed molecular mechanisms by
which glutamine may improve outcome in criti-
cal illness
Tissue protection
Enhanced HSP expression (1726)
Attenuated gut barrier dysfunction (27)
Decreased cellular apoptosis (2830)
Anti-inammatory/immune regulation
Attenuation of cytokine release (18, 25, 31
37)
Attenuation of NF-B/stress kinase
activation (25, 33)
Preservation of tissue metabolic function in
stress states
Preservation of ATP levels following sepsis
and I/R injury (20, 21, 26, 27, 39)
Attenuation of insulin resistance (4042)
Antioxidant/attenuation of iNOS expression
Enhanced GSH levels after stress (39, 43)
Attenuation of iNOS activation after sepsis
and I/R injury (33, 35, 44)
HSP, heat shock protein; NF-B, nuclear fac-
tor-B; ATP, adenosine 5'triphosphate; I/R in-
jury, ischemia/reperfusion injury; iNOS, induc-
ible nitric oxide synthase; GSH, glutathione.
S542 Crit Care Med 2007 Vol. 35, No. 9 (Suppl.)
on gut ischemia/reperfusion (I/R) injury.
Their data reveal that after gut I/R injury,
Gln can activate peroxisome proliferator-
activated receptorDNA binding. Peroxi-
some proliferator-activated receptor- is a
vital transcription factor known to attenu-
ate the inammatory response by interfer-
ence with proinammatory pathways (such
as nuclear factor-B and activator protein-
1). This activation was correlated with at-
tenuation of injury via gut histology and
myeloperoxidase activity (which reects in-
ammation in the gut) (36). Kozar et al.
(37) also showed that Gln, but not alanine,
maintains small-bowel barrier function af-
ter gut I/R injury in rats.
Preservation of Tissue Metabolic
Function and Insulin Sensitivity
A recent hypothesis indicates that mul-
tisystem organ failure after shock and sep-
sis may be due to tissue metabolic dysfunc-
tion (38). We have shown that Gln can
preserve tissue level metabolic function in
the face of sepsis, shock, and I/R injury (20,
21, 39). This effect seems to be tied to
enhanced HSP expression (26, 27).
Further evidence has revealed that Gln
can attenuate the insulin resistance and sub-
sequent hyperglycemia observed after critical
illness. Clinical trials in multitrauma patients
(40) and critical care patients (41) reveal
improved insulin sensitivity in patients re-
ceiving Gln supplementation. Gln is also
known to directly enhance the release of
insulin by the -cell (42).
Antioxidant/Attenuation of Inducible
Nitric Oxide Synthase Expression. Gln
has long been known to be an important
precursor of glutathione, a vital antioxi-
dant molecule, during I/R injury (39, 43).
Recent data reveal that Gln can attenuate
myocardial inducible nitric oxide syn-
thase expression after I/R injury and lung
inducible nitric oxide synthase expression
after sepsis (33, 44). However, recent data
indicate that Gln-based resuscitation af-
ter hemorrhagic shock leads to an in-
crease in messenger RNA for inducible
nitric oxide synthase in the liver (35).
This may indicate that Glns effects in
critical illness and injury are quite tissue
dependent. For example, the liver has
minimal Gln-mediated HSP-70 induction
after sepsis and shock (19), whereas the
heart and lung have signicant HSP ex-
pression after Gln treatment (19).
CONCLUSION
Critical illness and injury are often man-
ifested by the occurrence of sepsis and in-
ammation. Sepsis is the leading cause of
death in critical illness in the United States:
500,000750,000 patients develop sepsis
annually and 230,000 patients die of this
disease each year (4548). The death rate
from sepsis has increased 90% in the last
20 yrs, and the Centers for Disease Control
and Prevention indicates that septic death
rates have increased at a rate greater than
any other common cause of mortality in
the last year for which data were available
(49). Sepsis and inammation commonly
lead to the occurrence of multiple organ
dysfunction syndrome (47). Multiple organ
dysfunction syndrome is often the ultimate
cause of death in the ICU. Sepsis-induced
organ dysfunction, such as acute respira-
tory distress syndrome, is thought to be
associated with unchecked inammation
and a failure of cellular and tissue metabo-
lism (38). A therapeutic intervention that
could protect cells and tissues against in-
jury, attenuate inammation, and preserve
metabolic function may be of benet in the
prevention/treatment of multiple organ
dysfunction syndrome after sepsis or other
injuries.
As meta-analysis data are now indicat-
ing that Gln seems to reduce mortality in
critically ill patients and mechanistic data
are revealing that Gln may be to able
provide protection against injury, atten-
uate inammation, and preserve meta-
bolic function, a large, multicenter trial
of Gln administration (the REDOXS trial)
has begun. This trial will attempt to as-
sess the aforementioned mechanistic end
points in addition to clinical outcomes.
This author believes that we should be-
gin to look at Gln as both nutritional re-
placement therapy and a pharmacologic in-
tervention. The wide-ranging molecular
and gene-level effects of this amino acid
support this (16). We would advocate stud-
ies examining Gln as a pharmacologic sup-
plement given in large doses in short peri-
ods of time (24 hrs). We envision that Gln
may be able to be administered before sur-
gery or at the onset of sepsis (with admit-
tance to the ICU or emergency room) to
enhance HSP expression, prevent the oc-
currence of acute respiratory distress syn-
drome, and possibly decrease mortality
from sepsis and other severe injuries, such
as trauma and burn injury.
PERSPECTIVE
The rapid decrease in Gln concentra-
tions seen after critical illness may have a
number of causes; however, given that low
Gln levels may predict increased mortality
(15) in critical illness, it is possible that we
as humans have not evolved to retain ade-
quate stores of Gln to appropriately regu-
late our cells and tissues defenses beyond
2448 hrs. This would make teleological
sense, as the evolution of emergency
rooms, emergent operative intervention,
and ICUs is only a historically recent event.
It is impossible for us to have evolved the
appropriate reserve of stress substrates and
signaling molecules, such as Gln, to be
prepared for a prolonged ICU stay. As an
example, if a primitive man was attacked by
a predatory animal, he needed to put all of
his stress resources into surviving the
initial injury, preventing infection, and pro-
viding maximal cellular defense and repair
to combat the inevitable shock he faced. If
he was unable to do this in 2448 hrs, he
was almost assured a fatal outcome. Thus,
signicant stores of stress substrates and
signaling molecules would not be neces-
sary. This hypothesis is supported by the
fact that battleeld mortality rates have
changed very little in the last 150 yrs (50).
It is very possible that we as intensive care
physicians need to move toward under-
standing the importance of stress-signaling
molecules such as Gln and perhaps move
toward providing these molecules in a
pharmacologic method, much as we pro-
vide antibiotics for infection. In an era
when many of the therapies we consider as
standard of care are having their risk/
benet ratio questioned (51), perhaps it is
time we attempt to begin to take advantage
of the bodys own endogenous stress de-
fense mechanisms by utilizing stress-
signaling molecules that may not be able to
be produced by the severely stressed patient
in sufcient quantities given the extreme
level of critical care support we are now
able to provide.
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