Am J Physiol Endocrinol Metab 302: E265–E272, 2012.

First published November 8, 2011; doi:10.1152/ajpendo.00508.2011. Review

Ghrelin-mediated sympathoinhibition and suppression of inflammation

in sepsis
Cletus Cheyuo,1,2,3 Asha Jacob,2,3 and Ping Wang1,2,3
1
Elmezzi Graduate School of Molecular Medicine, 2The Feinstein Institute for Medical Research; and 3Department of
Surgery, Hofstra North Shore-LIJ Medical School, Manhasset, New York
Submitted 3 October 2011; accepted in final form 7 November 2011

Cheyuo C, Jacob A, Wang P. Ghrelin-mediated sympathoinhibition and suppres-

sion of inflammation in sepsis. Am J Physiol Endocrinol Metab 302: E265–E272, 2012.
First published November 8, 2011; doi:10.1152/ajpendo.00508.2011.—Sepsis, a sys-

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temic inflammatory response to infection, continues to carry a high mortality
despite advances in critical care medicine. Elevated sympathetic nerve activity in
sepsis has been shown to contribute to early hepatocellular dysfunction and
subsequently multiple organ failure, resulting in a poor prognosis, especially in the
elderly. Thus, suppression of sympathetic nerve activity represents a novel thera-
peutic option for sepsis. Ghrelin is a 28-amino acid peptide shown to inhibit
sympathetic nerve activity and inflammation in animal models of tissue injury.
Age-related ghrelin hyporesponsiveness has also been shown to exacerbate sepsis.
However, the mechanistic relationship between ghrelin-mediated sympathoinhibi-
tion and suppression of inflammation remains poorly understood. This review
assesses the therapeutic potential of ghrelin in sepsis in the context of the
neuroanatomical and molecular basis of ghrelin-mediated suppression of inflam-
mation through inhibition of central sympathetic outflow.
sympathoexcitation; ventrolateral medulla; ␣2A-adrenergic receptor; norepinephrine

DESPITE STRIDES IN CRITICAL CARE, the 751,000 annual cases of
sepsis in the United States continue to be costly, causing
215,000 deaths, with an estimated economic burden of 16.7
billion dollars on the United States annually. Multiple organ
failure, resulting in part from the deleterious effects of proin-
flammatory cytokines, is responsible for most deaths in sepsis
(5, 70). We discovered that norepinephrine released from the
gut causes early hepatocellular dysfunction in sepsis by stim-
ulating ␣2A-adrenoceptors on Kupffer cells, potentiating lipo-
polysaccharide (LPS)-stimulated NF-␬B-mediated cytokine re-
lease (56). The proinflammatory cytokines released by Kupffer
cells contribute to multiple organ failure. Thus, suppression of
sympathetic nerve activity and norepinephrine release repre-
sents a promising novel therapeutic approach to sepsis.
Ghrelin is a stomach-derived 28-amino acid peptide that
exerts anti-inflammatory effects in sepsis. Serum ghrelin levels
are reduced during sepsis, and administration of exogenous
ghrelin improves survival in sepsis (69, 85, 86). Ghrelin can act
centrally to inhibit peripheral sympathetic nerve activity fol-
lowing tissue injury (67, 73, 87). However, the mechanisms of
central ghrelin-mediated sympathoinhibition and how this
translates into suppression of systemic inflammation in sepsis
remain poorly understood. This review assesses the therapeutic
potential of ghrelin in sepsis by discussing the neuroanatomical
and molecular bases of ghrelin-mediated inhibition of central
sympathetic outflow and the relation to suppression of inflam-
mation and attenuation of tissue injury in sepsis. Guided by the
Address for reprint requests and other correspondence: P. Wang, Center for
Immunology and Inflammation, The Feinstein Institute for Medical Research,
350 Community Dr., Manhasset, NY 11030 (e-mail: pwang@nshs.edu).
http://www.ajpendo.org 0193-1849/12 Copyright © 2012 the American Physiological Society
current recommendations of the surviving sepsis campaign
(19), we make suggestions for further studies aimed at devel-
oping human ghrelin as a novel treatment for sepsis.
Control of Sympathetic Outflow
To understand the mechanism of sepsis-induced increase in
sympathetic nerve activity and how ghrelin treatment sup-
presses inflammation through sympathoinhibition, it is impor-
tant to understand the relevant anatomy involved in the regu-
lation of central sympathetic outflow. The sympathetic nervous
system consists of a central network of neurons that respond to
cardiovascular, metabolic, immune, and endocrine stress sig-
nals to maintain homeostasis in the body. There is a cross-
interaction between the sympathetic nervous system and the
functionally opposite parasympathetic nervous system in the
maintenance of homeostasis (60).
Central sympathetic network. The rostral ventrolateral me-
dulla (RVLM) is the major source of central sympathetic
outflow to the periphery. The RVLM consists of predominantly
glutaminergic neurons (70%), which project excitatory output
to sympathetic preganglionic neurons in the intermediolateral
column of the spinal cord. The RVLM serves as a point for
integration of information from many structures in the brain.
Among the structures modulating the output of RVLM are the
paraventricular nucleus (PVN), caudal ventrolateral medulla
(CVLM), and nucleus tractus solitarius (NTS). The PVN stim-
ulates sympathetic outflow by making excitatory connection
with RVLM or through direct excitatory output to sympathetic
preganglionic neurons in the intermediolateral column of the
spinal cord. The CVLM, which consists of interneurons, serves
as the main negative regulator of RVLM through the release of
E265
Review
E266 GHRELIN-MEDIATED SYMPATHOINHIBITION IN SEPSIS

the inhibitory neurotransmitter ␥-aminobutyric acid (GABA)
(29) (Fig. 1A). The NTS, which receives excitatory afferent
vagal input (61), can suppress sympathetic outflow by a direct
excitatory glutaminergic input to CVLM (4). The CVLM
interneurons then cause sympathoinhibition through the release
of GABA at RVLM (1, 3, 11). The NTS may also inhibit
RVLM sympathetic discharge via excitatory glutaminergic
projection to the nucleus ambiguus (NA) (2). The NA in turn
stimulates the CVLM (55), which then inhibits the RVLM
through GABA release (1). Thus, the vagus nerve-mediated
inhibition of sympathetic nerve activity, which has been dem-
onstrated in several studies (9, 33, 34, 78), may be explained by
the NTS-CVLM-RVLM inhibitory pathway.
Sympathetic efferents. Sympathetic efferents are classified
vasoconstrictors and result from the response of the rostral
ventromedial medulla to hyperventilation, hypothermia, and
emotional stimuli (29). Glucosensitive efferents are regulated
in part by the RVLM in response to hypoglycemia and mediate
epinephrine release from the adrenal medulla (58). Epinephrine
then elevates blood glucose levels by stimulating gluconeogen-
esis in the liver (20). Barosensitive efferents are controlled by
the RVLM and are activated by carotid and aortic barorecep-
tors, visceral nociceptors, and central chemoreceptors, as well
as disease states such as sepsis (32, 82). The primary and
secondary lymphoid organs, which are involved in the immune
functions of the body, are extensively innervated and regulated
by the sympathetic nervous system (49).
Electrophysiological and histochemical studies indicate that

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into three main groups: thermosensitive, glucosensitive, and RVLM neurons are organized topographically into separate
barosensitive efferents. The main neurotransmitters of sympa- groups that control specific organs and vascular beds (organo-
thetic efferents at the target organs are norepinephrine and typic arrangement) (53). Based on these studies, the muscle
epinephrine. Thermosensitive efferents innervate cutaneous vasoconstrictor (MVC), cutaneous vasoconstrictor (CVC), vis-

Fig. 1. Schematic representation of the anatomic and molecular mechanisms of sepsis-mediated sympathoexcitation and ghrelin’s anti-inflammatory effect via
sympathoinhibition. A: sepsis-mediated sympathoexcitation is represented by blue arrow. Bacterial sepsis leads to the release of lipopolysaccharide (LPS), which
reaches the liver via the portal vein. In the liver, LPS stimulates toll-like receptor-4 (TLR4) on Kupffer cells (KC) leading to NK-␬B-mediated release of
proinflammatory cytokines such as TNF-␣ and IL-6. Pyrogenic cytokines such as IL-6 and IL-1␤ enter the brain through the circumventricular organs, where
they stimulate vascular endothelial cells (EC) to release prostaglandin E2. Prostaglandin E2 stimulates neurons of the preoptic area (POA) of the hypothalamus,
leading to an excitatory output to the paraventricular nucleus (PVN), which in turn stimulates the rostral ventrolateral medulla (RVLM). Excitatory glutaminergic
output from the RVLM stimulates sympathetic preganglionic neurons in the intermediolateral column of the spinal cord, which in turn stimulates sympathetic
postganglionic neurons in the sympathetic chain, leading to the release of norepinephrine (NE) at target organs, including the gut. NE binds to ␣2A-adrenergic
receptor (␣2A-AR) on Kupffer cells in the liver, leading to activation of p38 MAP kinase pathway. The p38 MAP kinase pathway, acting synergistically with
the LPS-induced NF-␬B pathway, leads to augmented proinflammatory cytokine secretion by Kupffer cells (see inset of Kupffer cell). Proinflammatory cytokines,
together with sepsis-associated hypoglycemia (2Glucose) and acidosis, contribute to norepinephrine release by activation of the RVLM. B: ghrelin-mediated
sympathoinhibition is represented by red arrow. Ghrelin, produced mainly in the stomach, reaches the brain by crossing the blood-brain barrier. At the nucleus
tractus solitarius (NTS), ghrelin stimulates growth hormone secretagogue receptor type 1a (GHSR-1a) on vagal afferents, leading to suppression of glutamate
release (see inset of NTS neuron-vagal afferent synapse). The effect of ghrelin signaling at the NTS may be transmitted, by as yet unclear mechanisms, directly
or indirectly [via nucleus ambiguus (NA)] to the interneurons of the caudal ventrolateral medulla (CVLM), leading to GABAergic inhibition of sympathetic
outflow from the RVLM. Ghrelin may also inhibit sympathetic outflow by stimulating agouti-related protein (AgRP)-neuropeptide Y (NPY) neurons of the
arcuate nucleus (ARC). Ghrelin-mediated phosphorylation of AMPK leads to activation of calcium channels. The resulting calcium influx could trigger the
release of GABA from synaptic vesicles (see inset of AgRP-NPY neuron-PVN neuron synapse). This results in GABAergic inhibition of the PVN, leading to
dampening of the stimulating effect of the PVN on the RVLM. The overall effect of ghrelin-mediated sympathoinhibition is suppression of norepinephrine-
induced cytokine release.

AJP-Endocrinol Metab • doi:10.1152/ajpendo.00508.2011 • www.ajpendo.org


GHRELIN-MEDIATED SYMPATHOINHIBITION IN SEPSIS
ceral vasoconstrictor (VVC), and renal sympathetic (RSN)
groups of RVLM neurons have been identified (53). The
neurotransmitters of sympathetic efferents act on adrenergic
receptors on target cells. Adrenergic receptors are subdi-
vided into ␣1A, ␣1B, ␣1C, ␣2A, ␣2B, ␣2C, ␤1, ␤2, and ␤3
receptors, with different affinities for norepinephrine and
epinephrine (10). The physiological effects of adrenergic
receptors are mediated through the G protein intracellular
signaling system (35).
Sepsis and Sympathetic Activation
The pathogenesis of sepsis involves a systemic inflammatory
response to an infection. Severe sepsis, which has a high
mortality, is associated with multiple organ failure. Hepatocel-
lular dysfunction occurs early in sepsis (13, 83, 84) and
subsequently contributes to the failure of other vital organs
such as the lungs. Sepsis-associated hepatocellular dysfunction
is mediated by proinflammatory cytokines (41), which cause
hepatocyte injury evidenced by elevations of aminotrans-
ferases, and dysfunction of the cytochrome P-450 enzyme-
metabolic pathway (44). In addition, the release of cytokines
by Kupffer cells leads to overproduction of nitric oxide. Curran
et al. (17) found that the specific combination of TNF-␣,
IL-1␤, interferon-␥, and endotoxin resulted in upregulation of
nitric oxide production through the L-arginine-dependent bio-
chemical pathway within hepatocytes. Increased production of
nitric oxide resulted in decreased hepatocyte protein synthesis.
Nitric oxide overproduction suppresses hepatic glucose output
(75), which may explain the hypoglycemia observed in early
bacterial sepsis.
We have previously shown that increased norepinephrine
secretion during sepsis aggravated hepatocellular dysfunction
by driving the production of cytokines through ␣2A-adrenergic
receptor-mediated activation of p38 MAP kinase pathway in
Kupffer cells (90, 94) (Fig. 1A). The sympathoexcitation asso-
ciated with sepsis results from stimulation of the central sym-
pathetic network by a variety of stimuli. Pyrogenic cytokines
IL-1␤ and IL-6, produced by Kupffer cells and other macro-
phages, enter the brain through the circumventricular organs
and stimulate vascular endothelial cells to produce prostaglan-
din E2 (PGE2). PGE2 stimulates its receptor subtype 3 (EP3R)
on neurons in the preoptic area of the hypothalamus. EP3R
stimulation leads to excitatory signals to the PVN and subse-
quently to the RVLM, leading to increased sympathetic out-
flow (23, 66, 92). LPS-induced hypoglycemia, resulting from
nitric oxide overproduction (44), also activates the central
sympathetic network, leading to glucosensitive sympathetic
efferent output, which stimulates epinephrine release from the
adrenal medulla (58). Sepsis may also be complicated by
metabolic acidosis and respiratory acidosis (59). Decreased pH
is sensed by chemoreceptors in the brain, leading to stimulation
of barosensitive sympathetic efferent output from the RVLM
(40) (Fig. 1A). Sepsis-induced activation of the RVLM has
been confirmed by the finding that intravenous injection of LPS
increased c-fos immunoactivity at the RVLM (22). Thus, a
variety of sepsis-associated stimuli cause sympathoexcitation
and systemic catecholamine release. In addition to centrally
mediated stimulation of catecholamine release, the increase in
circulating catecholamine levels in sepsis could also be partly
due to decreased clearance. The liver and the gut are respon-
AJP-Endocrinol Metab • doi:10.1152/ajpendo.00508.2011 • www.ajpendo.org
Review
E267
sible for metabolizing 86 –93% of catecholamines on first pass
(14). Thus, hepatocellular dysfunction and gut dysfunction in
sepsis will decrease catecholamine metabolism, resulting in
increased circulatory levels of norepinephrine and epinephrine.
The increased levels of catecholamines will then cause further
hepatic damage. This may account, in part, for the finding of
Beloeil et al. (8), who in the assessment of norepinephrine
kinetics in septic shock found a negative correlation between
norepinephrine clearance and sepsis severity.
Proinflammatory Role of Catecholamines in Sepsis
We have previously established a predominantly deleterious
proinflammatory role of norepinephrine in sepsis, mediated by
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␣2A-adrenergic receptors (56). Using a rat model of polymi-
crobial sepsis by cecal ligation and puncture (CLP), we found
that sepsis resulted in upregulation of ␣2A-adrenergic receptor
gene expression in Kupffer cells (56). Moreover, in the same
study, the binding capacity and affinity of ␣2-adrenergic re-
ceptor were increased by sepsis (56). Norepinephrine binding
to ␣2A-adrenergic receptor dramatically potentiated LPS-in-
duced secretion of TNF-␣ by Kupffer cells. We demonstrated
that the potentiation of TNF-␣ release by norepinephrine was
mediated by activation of the p38 MAP kinase pathway.
Significantly, suppression of the effects of norepinephrine
using BRL-44408 maleate, a specific ␣2A-adrenergic receptor
antagonist, resulted in attenuation of multiple organ failure and
significant improvement in sepsis survival (56). Other investi-
gators have similarly demonstrated deleterious effects of cat-
echolamines in sepsis and other inflammatory conditions. Ani-
nat et al. (6) showed that various catecholamines induced
proinflammatory cytokines in human hepatocytes and potenti-
ated the effects of LPS. The augmenting effect of norepineph-
rine on LPS-induced TNF-␣ secretion may further be ex-
plained by the discovery of Kotlyarov et al. that MAPKAP
kinase-2 (MK2), which is a substrate of p38␣, is required for
TNF-␣ biosynthesis (42). The p38 MAP kinase pathway acti-
vates the TNF-␣ gene via the AU-rich element (ARE) (93).
Not only are catecholamines responsible for elevations in
cytokine levels, they have also been shown to suppress mac-
rophage and neutrophil phagocytosis leading to decreased
bacterial clearance in sepsis (26, 27, 36). These deleterious
effects of catecholamines may be partly responsible for the
continuing high mortality rates of sepsis in the face of advances
in other aspects of sepsis management such as the use of
vasopressors for hemodynamic support.
It is also worth noting that other investigators, focusing mainly
on ␤-adrenergic receptors on leukocytes, have described anti-
inflammatory effects of catecholamines (21). One explanation for
the seemingly contradictory effects of catecholamines with re-
gards to inflammation may be the differential receptor binding
preferences of norepinephrine at different concentrations. At
concentrations found in septic conditions (⬃20 nM), norepi-
nephrine has been shown to selectively bind ␣2-adrenergic
receptors (30, 57, 74). Our studies have shown that norepi-
nephrine at this concentration upregulates proinflammatory
cytokines (89). Other explanations could include the fact that
there is downregulation of ␤-adrenergic receptors with con-
comitant upregulation of ␣-adrenergic receptors, with in-
creased binding affinity, under inflammatory conditions
(51). Thus, proinflammatory effects, mediated by ␣2A-ad-
Review
E268 GHRELIN-MEDIATED SYMPATHOINHIBITION IN SEPSIS
renergic receptors, may be the predominant effect of cat-
echolamines in sepsis. Hence, suppression of this deleteri-
ous sepsis-associated sympathoexcitation is a promising
novel therapeutic approach.
Ghrelin-Mediated Sympathoinhibition and Anti-Inflammatory
Effects
Ghrelin is a 28-amino acid peptide produced mainly in the
fundus of the stomach. Ghrelin acts on the growth hormone
secretagogue receptor type 1a (GHSR-1a). GHSR-1a is a G
protein-coupled receptor that is widely distributed throughout
the body, with high expression in parts of the brain (15, 39, 72)
(Fig. 1B). We have previously shown (85, 86) that ghrelin
suppresses inflammation and sympathetic nervous system ac-
tivity in sepsis (87). We further found that ghrelin’s anti-
inflammatory action depends on its action on receptors in the
brain. Other investigators have similarly demonstrated ghre-
lin’s ability to suppress central sympathetic outflow (47).
However, the pathways of ghrelin-mediated sympathoinhibi-
tion and their link to ghrelin’s anti-inflammatory effects in
sepsis have not been previously explained. To act on its
receptors located in the brain, ghrelin must be able to cross or
circumvent the blood-brain barrier. Banks et al. (7) demon-
strated that human ghrelin is able to cross the blood-brain
barrier in mice through a saturable transport mechanism. How-
ever, recent evidence suggests that, even if such a transport
mechanism existed, it would be too slow, as it was shown that
a time lapse of 40 –50 min was required after intravenous
injection to increase cerebrospinal fluid ghrelin levels twofold
(28). Other investigators have suggested that ghrelin may act at
the circumventricular organs, where the blood-brain barrier is
nonexistent and ghrelin receptors are expressed (63, 95). In the
systemic inflammatory condition of sepsis, however, ghrelin is
likely to enter the brain easily, since it has been shown that
systemic inflammation disrupts the blood-brain barrier (48,
54). In the brain, ghrelin may act on its receptor GHSR-1a,
which is densely expressed at the NTS, and agouti-related
protein (AgRP)-neuropeptide-Y (NPY) neurons of the arcuate
nucleus (ARC) in the hypothalamus (15, 51).
Several studies have demonstrated sympathetic nervous sys-
tem suppression by centrally acting ghrelin. It has been shown
that ghrelin acts at the NTS to suppress renal sympathetic nerve
activity (52). Ghrelin has also been shown to suppress cardiac
(67, 73) and brown adipose tissue (91) sympathetic nerve
activity. Further evidence of ghrelin’s sympathoinhibition
comes from the work of Sato et al., who found that blood
norepinephrine and epinephrine levels were elevated in rodents
after chronic administration of the ghrelin receptor antagonist
[D-Lys3]-GHRP-6 (65). The NTS has been shown to make
direct and indirect (via NA) excitatory projection to the CVLM
(2, 4). Stimulation of CVLM interneurons results in inhibitory
GABAergic output to the RVLM, which is the main source of
sympathetic outflow. This may be one of the pathways by
which ghrelin decreases sympathetic nerve activity (Fig. 1B).
Another possible pathway by which ghrelin may act at the
NTS to cause sympathoinhibition is through the vagus nerve.
Vagus nerve stimulation has been shown to decrease sympa-
thetic nerve activity (34). Date et al. (18) showed that the
ghrelin receptor GHSR-1a is expressed at afferent vagus nerve
terminals and that stimulation of these receptors modulates
AJP-Endocrinol Metab • doi:10.1152/ajpendo.00508.2011 • www.ajpendo.org
vagal afferents, leading to increased c-fos activity in the brain.
Cui et al. (16) further elucidated the signaling of ghrelin at the
NTS when they discovered that ghrelin decreases the presyn-
aptic release of glutamate at the terminals of vagal afferents at
the NTS (Fig. 1B). The decreased glutamate release resulted in
inhibition of both catecholamine and noncatecholamine neu-
rons at the NTS. The mechanism by which the inhibitory effect
of ghrelin at the NTS leads to suppression of peripheral
sympathetic nerve activity awaits further research. Ghrelin’s
effects may also be mediated by efferent vagal signals. Shi-
mizu et al. (71) provided evidence that centrally administered
ghrelin activates the efferent vagus nerve, leading to increased
acetylcholine release in the heart. Peripherally released acetyl-
choline, acting on the ␣7-subunit of the nicotinic acetylcholine
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receptor, mediates the cholinergic anti-inflammatory pathway
(12). Thus, ghrelin’s anti-inflammatory effect appears to be
dependent on ghrelin’s ability to shift the autonomic balance:
suppressing sympathetic nerve activity on one hand and in-
creasing parasympathetic nerve activity on the other hand.
The AgRP-NPY neurons of the ARC of the hypothalamus,
which express GHSR-1a, have also been shown to make
synaptic connections with the PVN (25). Ghrelin stimulates the
phosphorylation of 5=-adenosine monophosphate-activated
protein kinase (AMPK) in AgRP-NPY neurons, leading to
activation of of N-type calcium channels (37, 38). The result-
ing inward calcium current could stimulate the release of
GABA from synaptic vesicles. Tong et al. (80) demonstrated
that ghrelin signaling at the ARC results in an inhibitory
GABAergic output. GABAergic inhibition of the PVN could
dampen the excitatory output of the PVN to the RVLM,
resulting in suppression of sympathetic outflow (Fig. 1B).
Indeed, we have previously demonstrated that ghrelin’s inhib-
itory effect on norepinephrine release and anti-inflammatory
effects were attenuated by GHSR-1a antagonist [D-Arg1,D-
Phe5,D-Trp7,9,Leu11]substance P, or an NPY/Y1 inhibitor (87).
We measured norepinephrine and cytokine release after treat-
ing septic rodents with intracerebroventricular injection of
ghrelin, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, or an
NPY/Y1 inhibitor and found that ghrelin treatment suppressed
sepsis-induced norepinephrine and TNF-␣ release. The inhib-
itory effect of ghrelin on norepinephrine and cytokine release
was abolished with intracerebroventricular administration of
[D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, or an NPY/Y1 in-
hibitor (87).
In other studies, we had previously linked the proinflamma-
tory effects of norepinephrine to activation of the p38 MAP
kinase pathway (56). Ghrelin administration in sepsis was
shown to antagonize the p38 MAP kinase pathway by upregu-
lating MAP kinase phosphatase-1 (31). Ghrelin, through its
mechanisms of sympathoinhibition and suppression of inflam-
mation, was shown to rescue rodents from sepsis-associated
multiple-organ failure by attenuating acute lung injury and
intestinal barrier dysfunction (85, 86). Sepsis may also be
aggravated in the presence of other kinds of tissue injury that
suppress the immune system. Radiation injury suppresses the
immune system, and Turai et al. (81) found in their studies that
sepsis was the main cause of death in recent incidents of
radiation accidents. Human ghrelin was shown to decrease
proinflammatory cytokine levels and improve survival in an
animal model of radiation combined with sepsis (69).

GHRELIN-MEDIATED SYMPATHOINHIBITION IN SEPSIS
A notable exception to the sympathoinhibitory effect of
ghrelin is the finding of Lambert et al. (43) that intravenous
infusion of ghrelin resulted in elevation of muscle sympathetic
nerve activity in both healthy lean and overweight individuals.
The exact mechanism for the seemingly opposite effects of
ghrelin on muscle sympathetic nerve activity compared with
other organs, such as kidney, is unknown. However, one may
speculate that the organotypically arranged groups of RVLM
neurons (53) are probably differentially regulated by ghrelin.
Further mechanistic studies are required to determine the
possible organotypic regulation of the RVLM by ghrelin.
Ghrelin and Age-Related Changes in Sympathetic Nerve
Activity
Sepsis in the elderly constitutes 65% of all cases of sepsis,
with a higher case fatality rate than in younger patients (50).
The increased severity of sepsis with age is partly due to an
exaggerated inflammatory response. Tateda et al. (79) showed
that aged rodents were more sensitive to LPS and produced
greater amounts of TNF-␣, IL-1␣, and IL-6 than younger
rodents after intraperitoneal LPS challenge. Roubenoff et al.
(64) reported similar findings in human subjects, with IL-6,
IL-1Ra, and C-reactive protein observed to be higher in elderly
patients than in their younger counterparts. The greater cyto-
kine release in the elderly during sepsis may be due to an
age-related increase in sympathetic nerve activity. Norepineph-
rine release driven by the central sympathetic network is
increased in older men, whereas epinephrine release from the
adrenal medulla has been shown to decrease with age (24, 68).
Nonetheless, epinephrine levels in the elderly are still higher
due to markedly decreased epinephrine clearance (68). Leong
et al. (45) have linked the hyperinflammatory response in the
elderly to ␣2A-adrenoceptor-mediated activation of the CD14/
TLR4 pathway. Starr et al. also discovered that the increased
mortality of sepsis in the elderly is related to a hypercoagulable
state mediated by age-related suppression of the protein C
anticoagulant pathway. This hypercoagulable state exacerbates
microvascular thrombosis associated with disseminated intra-
vascular coagulation in late sepsis (76). Increased release of
norepinephrine in sepsis may also contribute to disseminated
intravascular coagulation, as it has been shown that ␣2A-
adrenergic receptor stimulation promotes platelet activation
and aggregation, resulting in thrombosis (62).
The increased sympathetic nerve activity and exaggerated
cytokine release associated with sepsis in the elderly may be
explained by an age-related decrease in ghrelin receptor
GHSR-1a, in the brain. In our previous study (88), comparing
3-mo-old with 24-mo-old rodents, we found that in the aged
rodents GHSR-1a expression was decreased at the dorsal vagal
complex, which includes the NTS. We demonstrated that LPS
challenge in the aged rodents, with decreased GHSR-1a, re-
sulted in greater cytokine release compared with younger
rodents. Moreover, treatment of young rodents with GHSR-1a
antagonist resulted in increased cytokine release (88). The
effect of decreased GHSR-1a expression in aged rodents on
catecholamine release will be similar to chronic GHSR-1a
antagonism, which was shown by Sato et al. (65) to result in
elevated blood levels of norepinephrine and epinephrine.
Treatment of aged rodents with ghrelin, together with growth
hormone, restored GHSR-1a levels and attenuated cytokine
AJP-Endocrinol Metab • doi:10.1152/ajpendo.00508.2011 • www.ajpendo.org
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E269
release (88). Thus, ghrelin is a promising therapeutic agent for
the severe sepsis seen in the elderly.
Perspectives and Future Directions
The further development of sympathoinhibition as an anti-
inflammatory therapy for sepsis should be guided by the
current practice recommendations of the surviving sepsis cam-
paign (SSC). Among the SSC recommendations (19), adequate
fluid resuscitation is fundamental to the hemodynamic man-
agement of the septic patient. However, vasopressor support,
preferably norepinephrine or dopamine, is often required as an
early emergency measure in severe shock patients to maintain
mean arterial pressure. It is important to acknowledge that
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different pathogenic mechanisms are at play at various stages
of the sepsis-septic shock spectrum. Some of the early mech-
anisms in sepsis have a cascading effect, which leads to other
mechanisms in the late stage of septic shock. Sympathoexci-
tation is one of the early mechanisms of sepsis that contributes
to the late stages of the sepsis-septic shock spectrum. Early
norepinephrine-mediated hepatocellular dysfunction leads to
perturbation of the cytochrome P-450 enzyme-metabolic path-
way, which may severely affect antibiotic efficacy, one of the
cornerstones of sepsis management. Proinflammatory cyto-
kines, released by norepinephrine stimulation of ␣2A-adrener-
gic receptor, lead to overproduction of nitric oxide. Nitric
oxide contributes to vasoplegia and loss of mean arterial
pressure in the late stages of shock (46), requiring vasopressor
support. Thus, sympathoinhibition in early sepsis may be
beneficial in arresting some of the late developments of the
sepsis-shock cascade.
In summary, ghrelin ameliorates sepsis-associated organ
injury and improves survival through suppression of central
sympathetic outflow, resulting in suppression of inflammation.
The beneficial effects of ghrelin through sympathoinhibitory
suppression of inflammation have been demonstrated so far in
the rodent hypodynamic sepsis model. Some investigators also
advocate for experimental studies using the hyperdynamic
sepsis seen in higher-order mammals and humans (77), where
ghrelin’s beneficial effects on sepsis may be further tested. In
conclusion, ghrelin-mediated sympathoinhibition is a promis-
ing therapy for sepsis that needs further development. Future
preclinical research into ghrelin-mediated sympathoinhibition
may include more neurophysiological studies as well as dose-
response and time-course studies in animal models of sepsis.
ACKNOWLEDGMENTS
We are very thankful to Drs. Rongqian Wu and Mian Zhou for their
invaluable assistance in preparing the manuscript.
GRANTS
This work was supported by National Institutes of Health Grants R01
GM-053008, R01 AG-028352, and R33 A-1080536.
DISCLOSURES
Ping Wang, MD, has a pending patent on the use of ␣2A-adrenergic receptor
antagonist for the treatment of sepsis. PCT No. WO/2006/124770: “Treatment
of sepsis with alpha2A adrenergic antagonists”.
AUTHOR CONTRIBUTIONS
Author contributions: C.C., A.J., and P.W. conception and design of
research; C.C., A.J., and P.W. prepared figures; C.C. drafted manuscript; C.C.,
Review
E270 GHRELIN-MEDIATED SYMPATHOINHIBITION IN SEPSIS
A.J., and P.W. edited and revised manuscript; C.C., A.J., and P.W. approved
final version of manuscript.
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