1 Laboratory of Autonomic Neuroscience, Pennington Biomedical Research Center, Baton Rouge, Louisiana 70808; and 2 Department of Neuroscience, Ohio State University, Columbus, Ohio 43210
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ABSTRACT |
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Our previous studies suggested that
the cytokine tumor necrosis factor- (TNF-
) may act within the
neural circuitry of the medullary dorsal vagal complex (DVC) to affect
changes in gastric function, such as gastric stasis, loss of appetite,
nausea, and vomiting. The definitive demonstration that endogenously
generated TNF-
is capable of affecting gastric function via the DVC
circuitry has been impeded by the lack of an antagonist for TNF-
.
The present studies used localized central nervous system applications
of the TNF-adsorbant construct (TNFR:Fc; TNF-receptor linked to the Fc
portion of the human immunoglobulin IgG1) to attempt to neutralize the
suppressive effects of endogenously produced TNF-
. Gastric motility
of thiobutabarbital-anesthetized rats was monitored after systemic
administration of lipopolysaccharide (LPS) to induce TNF-
production. Continuous perfusion of the floor of the fourth ventricle
with TNFR:Fc reversed the potent gastroinhibition induced by LPS, i.e.,
central thyrotropin-releasing hormone-induced increases in motility
were not inhibited. This disinhibition of gastric stasis was not seen
after intravenous administration of similar doses of TNFR:Fc nor
ventricular application of the Fc fragment of human immunoglobulin.
These results validate our previous studies that suggest that
circulating TNF-
may act directly within the DVC to affect gastric
function in a variety of pathophysiological states.
tumor necrosis factor-; gastric stasis; nausea
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INTRODUCTION |
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ACTIVATION OF A SYSTEMIC
IMMUNE response by injury, infection, radiation, or chemotherapy
is often accompanied by gastric stasis (which is perceived as nausea),
loss of appetite, and vomiting (7, 32, 37). These
pathophysiological symptoms are correlated with high circulating levels
of proinflammatory cytokines, especially tumor necrosis factor-
(TNF-
) (10, 24, 32, 37). Indeed, systemic injections of
TNF-
into human volunteers can mimic these characteristics of
illness (20). Whereas it has been recognized that TNF-
plays a role in the anorexia associated with these different
conditions, it is not clear whether these gastric effects are:
1) due to the direct effects of TNF-
or other cytokines triggered in the cytokine cascade or 2) mediated via central
or peripheral sites of action of TNF-
.
The medullary dorsal vagal complex [DVC; composed of the sensory nuclei of the solitary tract (NST), the area postrema (AP), and the dorsal motor nucleus (DMN) of the vagus nerve] is the locus of the vagovagal reflex circuits that provide overall control of gastric motility (28). This brain stem area is considered to be a circumventricular organ in that it is essentially devoid of a blood-brain barrier (1, 12, 36). Additionally, dendritic endings of neurons in both the NST and the DMN have been reported to penetrate the AP and the floor of the fourth ventricle (26, 27, 30). Thus the DVC is in a position to monitor blood-borne and cerebrospinal fluid-borne factors and to change vagally mediated autonomic functions accordingly (5, 19, 28).
The brain stem has a high density of TNF- binding sites (17,
23). Therefore, we have hypothesized that the DVC may be a site
at which circulating TNF-
acts to provoke gastric stasis and the
other prodromata of illness, such as nausea and emesis. Indeed, our
earlier studies have already shown that nanoinjection of TNF-
directly into the DVC can: 1) completely suppress centrally mediated increases in gastric motility (14) even at doses
of <1 fmol; 2) provoke Fos activation of neurons in the NST
(8); and 3) activate NST neurons belonging to
gastric vagovagal reflex control circuits (7). This
neurophysiological study also revealed that, once these gastric NST
neurons were exposed (and responded) to TNF-
, subsequent responses
of these neurons to otherwise innocuous visceral stimuli were highly
potentiated. This finding coincides with the observation that
cytokines, or agents that provoke cytokine production, evoke
persistent, conditioned visceral aversion behavior (16).
Perhaps the potentiating effect of TNF-
on NST neuron responses to
visceral afferent input is critical to the production of such long-term
changes in the responsiveness to visceral afferent input as learned
taste aversion.
We have also shown that these same motility (15) and
Fos-activation results (13) occur after endogenous
production of TNF- in response to systemic administration of the
endotoxin lipopolysaccharide (LPS). It is of interest to note that
Fos-activation of NST and AP neurons occurred even when both cervical
vagal trunks were transected, indicating that endogenous TNF-
is
capable of accessing and activating neurons in the DVC directly
(13).
Together, these studies strongly suggest that one of the sites of
TNF- action is directly within the DVC to affect vagal sensory
activity and, ultimately, gastric motility. Although compelling, direct
proof would be more convincing. At present, no TNF-
antagonists are
available. However, TNF-
-adsorbing constructs (e.g., TNFR:Fc; Enbrel) have been used clinically to bind and inactivate the
proinflammatory effects of TNF-
in rheumatoid arthritis
(21). Therefore, we hypothesized that if TNF-
is the
active agent within the DVC to produce the above-cited changes in
gastric motility, then local application (i.e.,
intracerebroventricularly) of TNFR:Fc should specifically block the
effects of TNF-
endogenously generated after systemic
administration of LPS. That is, endogenously produced TNF-
should be specifically inactivated by the TNFR:Fc construct in the DVC and centrally mediated activation of gastric motility should, again, be demonstrable.
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METHODS AND MATERIALS |
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Drugs and chemicals.
Rats were anesthetized with thiobutabarbital (100 mg/ml, 200 mg/kg ip;
Inactin, Sigma, St. Louis, MO) dissolved in saline. This
thiobutabarbital compound has been shown not to interfere with brain
stem autonomic reflexes (2), the generation of cytokines after the administration of LPS (18), or the activation of
DVC neurons after exposure to cytokines (7, 8, 14).
Endogenous production of TNF- was induced by systemic administration
of LPS. LPS was derived from Escherichia coli serotype
0111:B4 (Sigma; Ref. 35) and suspended in PBS (124 mM
NaCl, 26 mM NaHCO3, 2 mM KH2PO4,
304 mosmol/kgH2O, pH 7.4). Gastric motility can be stimulated centrally by exposing the floor of the fourth ventricle to 2 µl of a 100-µM solution of thyrotropin releasing hormone (TRH;
Bachem, Torrance, CA) dissolved in PBS (14).
Animals. Male Long-Evans rats (200-400 g body wt; Simonsen Laboratories) were maintained in a temperature-controlled vivarium with a 12:12-h light-dark cycle. Animals had ad libitum access to food and water. All experimental procedures were performed according to guidelines set forth by the National Institutes of Health and were approved by the Ohio State University Institutional Laboratory Animal Care and Use Committee.
Surgical preparation. Rats (n = 26) were anesthetized and received tracheal cannulae to ensure the maintenance of an open airway for the duration of the experiment. Animals were equipped with sterile jugular cannulae for intravenous administration of LPS. An abdominal laparotomy was performed, and a miniature strain gauge (RB Products, Madison, WI) was secured to the ventral surface of the antral portion of the stomach, in parallel with the circular smooth muscle (14, 15, 19). After the initial surgical preparations were complete, the animal was mounted in a stereotaxic frame in a nose-down orientation. The dorsal spinomedullary junction was exposed by resecting the dorsal cervical musculature, removing the occipital plate, and resecting both the dura mater and arachnoid meninges. Rats were randomly assigned to receive systemic injections of either 25 µg/kg or 1,000 µg/kg iv LPS and fourth ventricular applications of either TNFR:Fc or Fc fragment. One control group was surgically prepared as described above, received no intravenous LPS, and was subjected to repetitive ventricular applications of TNFR:Fc. An additional control group was subjected to the low dose of LPS (25 µg/kg iv) and received 40 µg iv TNFR:Fc according to the same delivery schedule as described below for the ventricular applications of TNFR:Fc. These two doses of systemic LPS were chosen because the 25 µg/kg dose was shown to evoke a significant c-Fos activation of NST neurons in our previous study (13) and does not produce hypotensive side effects. The higher LPS dose (1,000 µg/kg) is frequently cited in the literature as a dose appropriate to elicit a variety of systemic pathophysiological illness effects [e.g., hypotension and fever (39)] and had been used in our earlier studies (15) to elicit suppression of centrally stimulated gastric motility.
Experimental design.
Gastric motility was continuously monitored once the animal was secured
in the stereotaxic frame. A minimum of 20 min of baseline gastric
motility was collected before the intravenous administration of LPS
(1,000 µg/kg, n = 8; 25 µg/kg, n =12; 0 µg/kg, n = 6) at time 0. The total volume
of intravenous LPS injections was ~0.3 ml; it was delivered over
60-90 s. Simultaneous to the intravenous LPS injection and every
10 min for the next 90 min, 2 µl of either TNFR:Fc (2 µg/µl icv)
or Fc fragment (2 µg/µl) were applied to the exposed floor of
the fourth ventricle or TNFR:Fc (4 µg/0.1 ml iv) was
injected. This intracerebroventricular dose of TNFR:Fc has been shown
to neutralize TNF- in the central nervous system (CNS) in other
models (34).
Data collection and analysis. Gastric motility was continuously monitored via the miniature strain gauge connected to a Wheatstone bridge-based amplifier (14). Each strain gauge was calibrated before the experiment by hanging known masses (0.1-2.0 g) on the gauges at the points where they would be sutured to the stomach. Calibrated output from the strain gauge amplifier was directed to a Grass polygraph and to the analog-to-digital converter inputs of a waveform storage/analysis system (Datapac 2000; Laguna Hills, CA). Gastric motility data could be displayed in real time and digitized for subsequent analysis or graphic display.
Motility records were analyzed in 300-s epochs. Peak voltage data (i.e., maximal contractions) during the 300-s epoch being analyzed were determined. Maximal gastric contraction amplitudes were compared (i.e., post- vs. pre-TRH application to the floor of the fourth ventricle) and expressed as peak motility ratios. Thus each animal served as its own control; motility ratio values >1 represent an increase in motility in response to TRH exposure, whereas motility ratio valuesTNF- assay and data analysis.
Concentrations of plasma TNF-
were determined via a double-sandwich
ELISA protocol as recommended by R&D Systems (Minneapolis, MN). All
incubations were done at room temperature. Microwells were washed three
times with wash buffer (i.e., PBS, pH 7.4, with 0.05% Tween 20)
between each addition/incubation step. Briefly, microwells of 96-well
immunoplates (Nunc; Fisher Scientific, Pittsburgh, PA) were precoated
with monoclonal anti-rat TNF-
antibody (R&D Systems) in PBS and
incubated overnight. Nonspecific binding was blocked with PBS
containing 1% BSA. Fifty to one-hundred microliters of unknown sera
samples or TNF-
standards (rat recombinant TNF-
; R&D Systems)
that had been diluted by 1:2-1:100 with Tris-buffered saline (TBS,
pH 7.3) plus 0.05% Tween 20 and 0.1% BSA was added to the microwells
and incubated for 2 h. TNF-
was detected via 2-h incubation
with biotinylated anti-rat TNF-
antibody (R&D Systems; diluted in
TBS with 0.1% BSA), streptavidin horseradish peroxidase conjugate
(Zymed, San Francisco, CA; with 20-min incubation), and a final 20-min
incubation in the dark after the addition of K-Blue Max substrate
(Neogen, Lexington, KY). The reaction was stopped by the addition of 1 M H2SO4. The optical absorbance of each well
was read within 30 min using a microplate reader set to 450 nm.
Absorbance values were converted to TNF-
concentrations by
comparison with a simultaneously generated standard curve. The minimum
and maximum limits of detection per well of this assay were
15-1,000 pg/ml.
Statistical analyses.
Plasma levels of TNF- in response to systemic administration of LPS
(i.e., 0, 25, or 1,000 µg/kg body wt iv) across all six experimental
groups were log transformed for normalization before statistical
analysis (22). Normalized data were subjected to one-way
overall ANOVA. Statistical significance was defined as an overall
P < 0.05; selected Bonferroni multiple comparison
posttests were applied.
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RESULTS |
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Plasma levels of TNF-.
Circulating levels of TNF-
are undetectable by ELISA in normal,
healthy, unchallenged animals (11, 13, 35). Intravenous challenges of either dose of LPS induced elevated plasma levels of
TNF-
in Inactin-anesthetized rats (Fig.
1) at levels significantly above normal,
healthy, but comparably surgically prepared animals (ANOVA overall
P < 0.0001; Bonferroni selected posttests
**P < 0.001). Although the variability in the response
to systemic LPS challenge is larger at the higher dose of LPS, these
animals had higher plasma levels of TNF-
compared with those that
had received 25 µg/kg LPS (Fig. 1; *P < 0.01 Bonferroni selected posttests).
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Adsorption of endogenous TNF- within the fourth ventricle
permits central TRH stimulation of gastric motility.
Raw motility records (e.g., Fig. 2) were
quantitated for graphic and statistical purposes (Fig.
3). Maximal contraction indices (converted to peak voltage data) were determined for specific 300-s
(5-min) epochs of time during the experiment. The maximal contraction
indices from 0 to 5 min after TRH stimulation were compared with the
basal level of each animal (i.e., peak motility ratios = post-TRH/pre-TRH).
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DISCUSSION |
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Our previous studies (15) showed that endogenous
production of TNF- after systemic LPS challenge is associated with
suppression of centrally stimulated gastric motility. The present
experiment used the TNFR:Fc construct to specifically adsorb and
inactivate TNF-
within the brain stem perfusion area to determine
whether TNF-
action, within the medullary brain stem, is the
causative agent for the previous observations.
In this study, all animals challenged with intravenous LPS demonstrated
elevated plasma levels of TNF-. Under normal circumstances (i.e., no
LPS exposure), intracerebroventricular application of TRH evokes a
large, prolonged, and vagally mediated increase in gastric contractions
(14, 15, 28). Endogenous production of TNF-
after
systemic LPS challenge suppresses this centrally stimulated gastric
motility (15). In the present study, continuous perfusion
of the floor of the fourth ventricle with TNFR:Fc after systemic LPS
challenge disinhibited the centrally commanded (i.e., TRH) increase in
gastric motility. That is, TNFR:Fc specifically adsorbed and
inactivated circulating TNF-
in this medullary area and permitted
the TRH stimulation of the DVC to increase gastric motility. Thus these
results support the hypothesis that circulating TNF-
can act within
the brain stem DVC to inhibit gastric function. Furthermore, the
specific removal of TNF-
from the vicinity of vagovagal reflex
control circuitry is sufficient to restore a normal CNS-generated
increase in motility.
Therapeutic regimens that cause reductions in TNF- production are
well recognized for their antinausea and gastric prokinetic effects. Doses of glucocorticoids sufficient to cause immune
suppression through inhibition of TNF-
production can relieve nausea
and gastric stasis associated with cancer chemotherapy, which, by itself, can evoke very large increases in TNF-
production (4, 9). Furthermore, as we suggested in an earlier paper
(15), it is very likely that the antinausea properties of
thalidomide in emesis gravidarum (morning sickness) are due to the
effect of the drug to retard the synthesis of TNF-
(see Ref. 15). TNF-
is highly pleiotrophic and pleurifunctional (6,
32) and the case of thalidomide points out the potential for the
development of serious unintended consequences of the systemic
manipulation of the cytokine. Although thalidomide is safe and
effective in its role as an anti-inflammatory, e.g., treatment of
leprosy and lupus (39) and antinausea compound
(25), thalidomide used during early pregnancy reveals
severe teratogenic effects on fetal limb development due to the role of
TNF-
as a regulator of angiogenesis and limb bud development
(38).
Gastric stasis, and possibly the nausea, associated with the many
disease processes that involve the production of TNF- may, at least
partially, be explained by action of the cytokine directly on neurons
of the dorsal vagal complex. However, elimination of these
pathophysiological consequences of TNF-
action by blocking TNF-
action is a course that must be taken with caution.
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ACKNOWLEDGEMENTS |
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G. Hermann thanks John Hermann for encouragement and inspiration.
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FOOTNOTES |
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Enbrel was a generous gift from Immunex.
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-52142 and DK-56373.
Address for reprint requests and other correspondence: G. E. Hermann, Laboratory of Autonomic Neuroscience, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, LA 70808 (E-mail: HermanGE{at}pbrc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
April 24, 2002;10.1152/ajpgi.00412.2001
Received 24 September 2001; accepted in final form 18 April 2002.
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