1 Second Department of
Medicine, Central neuropeptides play important roles in
many instances of physiological and pathophysiological
regulation mediated through the autonomic nervous system. In regard to
the hepatobiliary system, several neuropeptides act in the brain to
regulate bile secretion, hepatic blood flow, and hepatic proliferation.
Stressors and sympathetic nerve activation are reported to exacerbate
experimental liver injury. Some stressors are known to stimulate
corticotropin-releasing factor (CRF) synthesis in the central nervous
system and induce activation of sympathetic nerves in animal models.
The effect of intracisternal CRF on carbon tetrachloride
(CCl4)-induced acute liver
injury was examined in rats. Intracisternal injection of CRF dose
dependently enhanced elevation of the serum alanine aminotransferase (ALT) level induced by CCl4.
Elevations of serum aspartate aminotransferase, alkaline phosphatase,
and total bilirubin levels by CCl4
were also enhanced by intracisternal CRF injection. Intracisternal injection of CRF also aggravated
CCl4-induced hepatic histological changes. Intracisternal CRF injection alone did not modify the serum
ALT level. Intravenous administration of CRF did not influence CCl4-induced acute liver injury.
The aggravating effect of central CRF on
CCl4-induced acute liver injury
was abolished by denervation of hepatic plexus with phenol and by
denervation of noradrenergic fibers with 6-hydroxydopamine treatment
but not by hepatic branch vagotomy or atropine treatment. These results
suggest that CRF acts in the brain to exacerbate acute liver injury
through the sympathetic-noradrenergic pathways.
sympathetic nerve; noradrenergic nerve; peptide; hepatic damage; central nervous system
ABUNDANT ANATOMIC AND physiological evidences have
suggested a role of the central and autonomic nervous systems in the
regulation of hepatic function (25, 27, 39). However, little is known about neurotransmitters that may mediate these effects in the central
nervous system. Neuropeptides have been recognized as neurotransmitters
in the central and peripheral nervous systems (4, 5, 41), and centrally
acting neuropeptides have been reported to regulate a variety of
physiological functions (29, 31, 47). Corticotropin-releasing factor
(CRF) is one of the brain neuropeptides, and the effects of central CRF
on physiological, pharmacological, and pathophysiological regulations
of the gastrointestinal tract have been recognized. Injection of CRF
into the cerebrospinal fluid and brain nuclei, such as the
paraventricular nucleus and locus ceruleus, inhibited gastric motility
and secretion (14, 28, 44) and enhanced colonic motility through the
autonomic nervous system (32, 34). Physiological stressors are reported to increase CRF mRNA expression and CRF immunoreactivity in the hypothalamus and amygdala (26, 32, 34), and stress-induced alterations
of gastrointestinal functions are blocked by central administration of
CRF antagonist (31, 33, 51), suggesting involvement of endogenous CRF
in these alterations of the gastrointestinal tract. In regard to the
hepatobiliary system, the autonomic nervous system affects hepatic
metabolism and hemodynamics (1, 3, 12, 13, 27). Moreover, some
physiological stressors, electrical stimulation of hypothalamus, and
continuous activation of the sympathetic nerve enhance liver injury in
animal models (11, 20-23).
These findings led us to speculate that CRF acts in the central nervous
system to influence experimental liver injury through the autonomic
nervous system. The present study addresses this question by
examining the effect of intracisternal injection of CRF on carbon
tetrachloride
(CCl4)-induced acute liver
injury in rats.
Animals.
Male Wistar rats weighing 280-320 g (Charles River Japan,
Yokohama, Japan) were housed in group cages under conditions of controlled temperature (22-24°C) and illumination (12-h light cycle starting at 6:00 AM) for at least 7 days before experiments. Animals were maintained on laboratory chow and water. Experiments were
performed in rats deprived of food for 12 h (starting at 6:00 PM) but
given free access to water up to the beginning of the study. Protocols
describing the use of rats were approved by the Animal Care Committee
of Asahikawa Medical College and were in accordance with the National
Institutes of Health Guide for the Care and Use of
Laboratory Animals.
Chemicals.
The following substances were used: rat CRF (Peptide Institute, Osaka,
Japan), CCl4 (Wako Pure Chemical
Industries, Osaka, Japan), phenol (Wako), atropine methyl nitrate
(Sigma, St. Louis, MO), and 6-hydroxydopamine (6-OHDA; Aldrich,
Milwaukee, WI). CRF was dissolved in 0.9% saline (pH 7.4) before the
experiment and injected intracisternally in 10 µl using a 50-µl
Hamilton microsyringe (Hamilton, Reno, NV).
Experimental design.
After 12 h of fasting, rats were anesthetized with ether and mounted on
ear bars of a stereotaxic apparatus (model 900, David Kopf Instruments,
Tujunga, CA) and injected with CRF (0.5-20 µg) or saline
intracisternally or intravenously just before and 6 h after
CCl4 administration.
CCl4 was mixed with an equal
volume of olive oil and injected subcutaneously in a volume of 2 ml/kg. We chose the dose and administration method for
CCl4 by pilot experiments, because
2 ml/kg of mixed solution of CCl4
and olive oil injected subcutaneously induced mild and reproducible
liver damage 24 h after CCl4 in
12-h-fasted rats under our experimental conditions. Rats in the control
group were injected with olive oil at a dose of 2 ml/kg. Rats were kept
in individual cages, and blood samples were obtained from the jugular
vein before and 24 h after
CCl4
administration. Serum alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin
(T-Bil) levels were determined by commercially available kits (Wako).
The liver sample was obtained from the hepatic median lobe 24 h after
CCl4 administration and fixed in 10% Formalin solution. The specimens were stained with hematoxylin and
eosin. Five fields per slide at ×75 magnification were blindly evaluated under a light microscope. The percentage of necrotic areas
surrounded by fatty degeneration (42) was measured by a computerized
image analyzer. Microscopic findings were photographed with color print
films (Super G 200, Fuji Film, Tokyo, Japan), converted to digital
signals by an image scanner (JX-330, Sharp Electric, Tokyo, Japan), and
analyzed by a computer (Power Macintosh 8100, Apple Computer,
Cupertino, CA) equipped with National Institutes of Health Image
analyzer software. To exclude the effect of intracisternal injection of
CRF on food intake, rats were pair fed with vehicle-treated rats.
Effect of hepatic plexus denervation, 6-OHDA, atropine, and hepatic
branch vagotomy on CRF-induced modulation of acute liver injury by
CCl4.
Either hepatic plexus denervation or vehicle treatment was performed
under pentobarbital anesthesia (Abbott, North Chicago, IL; 50 mg/kg ip)
7 days before the peptide injection, according to the method of Lautt
(27). Denervation of hepatic plexus (anterior plexus and posterior
plexus) was achieved rapidly (<20 min) by phenol (85%) applied to
the region where the hepatic artery and the portal vein run in close
apposition. 6-OHDA dissolved in saline was intraperitoneally injected
twice (100 mg/kg on the first day, 80 mg/kg on the fourth day), and
intracisternal injection of CRF was performed on the seventh day (50).
Atropine methyl nitrate (0.15 mg/kg) dissolved in saline was injected
intraperitoneally 30 min before the peptide injection in a 1.0 ml/kg
volume. Either hepatic branch vagotomy or sham operation was performed
under pentobarbital anesthesia (50 mg/kg ip) 72 h before the peptide injection. Hepatic branch vagotomy was achieved under a dissection microscope by selective section of the hepatic branch of the vagus nerve branching off from the anterior vagal trunk a few millimeters proximal to the cardia (49). To exclude the effect of hepatic plexus
denervation, 6-OHDA, atropine methyl nitrate, and hepatic branch
vagotomy on food intake, rats were pair fed with respective vehicle-treated or sham-operated rats.
Statistical analysis.
All results are expressed as means ± SE. Comparison between two
independent groups was made by Mann-Whitney
U-test. Comparison of the values
before and after CCl4 was made by
paired Student's t-test. Multiple
group comparisons were performed by ANOVA followed by Fisher's least
significant difference test. P < 0.05 was considered statistically significant.
Effect of intracisternal CRF administration on
CCl4-induced acute liver injury.
Twenty-four hours after administration of
CCl4 (2 ml/kg), the serum ALT
level was significantly elevated, from 6 ± 1 to 29 ± 8 IU/l
(P < 0.01). Intracisternal
administration of CRF (10 µg) just before and 6 h after
CCl4 injection enhanced the
elevation of serum ALT levels induced by
CCl4, although intracisternal
administration of CRF either just before or 6 h after
CCl4 did not
influence serum ALT levels (Fig. 1). Intracisternal
injection of CRF (just before and 6 h after
CCl4 injection) dose dependently
enhanced the CCl4-induced
elevation of serum ALT levels (means ± SE, in IU/l: saline, 29 ± 8; 0.5 µg CRF, 38 ± 8; 1 µg CRF, 55 ± 11; 3 µg CRF,
85 ± 38; 5 µg CRF, 119 ± 36; 10 µg CRF, 140 ± 28; 20 µg CRF, 135 ± 39; n = 7-10; Fig. 2). Elevation of serum AST, ALP, and
T-Bil levels induced by CCl4 was
also enhanced by intracisternal CRF injection (Fig. 3).
Histological studies showed marked fatty degeneration (steatotic
hepatocytes) with minimal necrosis (Fig. 4,
A and
B). Intracisternal CRF (10 µg)
injection increased necrotic areas surrounded by fatty degeneration
(Fig. 4, C and
D, and Table 1). Intracisternal CRF (10 µg) injection
alone did not influence serum ALT level when CRF was injected with
olive oil vehicle (2 ml/kg sc) instead of
CCl4 (Table 2).
Intravenous administration of CRF (10 µg) did not influence the
CCl4-induced elevation of serum
ALT level (Table 3).
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Fig. 1.
Effect of intracisternal corticotropin-releasing factor (CRF) on
CCl4-induced elevation of serum
alanine aminotransferase (ALT) levels (means ± SE). Saline or CRF
(10 µg) was injected intracisternally just before and 6 h after
CCl4 (2 ml/kg) administration.
Control animals were intracisternally injected with saline just before
and 6 h after CCl4 administration.
Blood samples were collected before and 24 h after
CCl4 administration.
** P < 0.01 compared with
respective control group.
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Fig. 2.
Dose response of intracisternal CRF effect on
CCl4-induced elevation of serum
ALT levels (means ± SE). Saline or CRF (0.5, 1, 3, 5, 10, or 20 µg) was injected intracisternally just before and 6 h after
CCl4 (2 ml/kg) administration.
* P < 0.05, ** P < 0.01 compared with
saline injection group.
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Fig. 3.
Dose response of intracisternal CRF effect on
CCl4-induced elevation of serum
aspartate aminotransferase (AST; A),
alkaline phosphatase (ALP; B), and
total bilirubin (T-Bil; C) levels
(means ± SE). Saline or CRF (0.5, 1, 3, 5, 10, or 20 µg) was
injected intracisternally just before and 6 h after
CCl4 (2 ml/kg) administration.
* P < 0.05, ** P < 0.01 compared with
respective saline injection group.
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Fig. 4.
Effect of intracisternal CRF on
CCl4-induced hepatic histological
changes. Saline or CRF (10 µg) was injected intracisternally just
before and 6 h after CCl4 (2 ml/kg) administration, liver tissues were obtained 24 h after
CCl4 administration, and specimens
were stained with hematoxylin and eosin.
A: intracisternal saline injection
(×75). B: intracisternal saline
injection (×150). C:
intracisternal CRF injection (×75).
D: intracisternal CRF injection
(×150).
Table 1.
Aggravating effect of intracisternal CRF injection on degeneration
and necrosis in liver 24 h after CCl4 administration
Table 2.
Effect of intracisternal CRF injection on serum ALT levels with
olive oil treatment instead of CCl4
Table 3.
Effect of intravenous injection of CRF on CCl4-induced
elevation of serum ALT level
Effect of hepatic plexus denervation, hepatic branch vagotomy,
6-OHDA, and atropine on intracisternal CRF-induced enhancement of acute
liver injury by CCl4.
Denervation of hepatic plexus by 85% phenol (7 days before) or
denervation of noradrenergic fibers by 6-OHDA intraperitoneal injection
(100 mg/kg injected 7 days before and 80 mg/kg injected 4 days before)
completely abolished the aggravating effect of intracisternal
administration of CRF (10 µg) on the
CCl4-induced elevation of serum
ALT level (Fig. 5, A
and B) and the histological changes
(Fig. 6). On the other hand, hepatic branch vagotomy (3 days before) or atropine methyl nitrate (0.15 mg/kg ip; 30 min before)
did not influence the aggravating effect of intracisternal injection of
CRF (10 µg) on the CCl4-induced
elevation of serum ALT level (Fig. 5,
C and
D).
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DISCUSSION |
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In the present study, we demonstrated that intracisternal injection of CRF exacerbated CCl4-induced acute liver injury in rats. We measured serum ALT, AST, T-Bil, and ALP levels and also examined hepatic histological changes. Intracisternal CRF dose dependently enhanced the CCl4-induced elevation of serum ALT levels. Similarly, intracisternal CRF enhanced the CCl4-induced elevation of serum AST, T-Bil, and ALP levels. The increase of serum ALT levels by intracisternal injection of CRF was dose related in doses ranging from 0.5 to 10 µg. Administration of 20 µg of CRF did not further enhance the CCl4-induced increase of serum ALT level, indicating that the maximal effective dose of CRF injected intracisternally on CCl4-induced liver injury is 10 µg. In contrast, when injected intravenously at the dose that was maximally effective when given intracisternally, CRF did not influence CCl4-induced liver injury. These results indicate that CRF injected into the cisterna magna acts in the central nervous system to aggravate CCl4-induced acute liver injury and not through leakage into the peripheral circulation (35). Intracisternal administration of CRF (10 µg) alone just before and 6 h after olive oil vehicle administration instead of CCl4 did not influence serum ALT level, suggesting that CRF does not have any ability to cause liver injury by itself. Although intracisternal injection of CRF (10 µg) just before and 6 h after CCl4 administration aggravated CCl4-induced acute liver injury, CRF injection either just before or 6 h after CCl4 administration did not influence the liver injury. These results indicate that continuous stimulation by CRF is essential to enhance CCl4-induced acute liver injury. This effect of central CRF on liver injury is supported by previous reports that showed CCl4-induced liver injury was aggravated by continuous stress for 6 h (22).
The pathways through which central administration of CRF enhanced CCl4-induced acute liver injury were investigated. Previous reports have shown that central CRF affects peripheral organs in part through the autonomic nervous system (46). In regard to the digestive system, central CRF inhibits gastric secretion and motility and exocrine secretion of the pancreas through the sympathetic-noradrenergic nervous systems (2, 14, 30, 44). Meanwhile, central CRF stimulates colonic motility through the parasympathetic nervous system (32, 34). In the present study, the enhancement of CCl4-induced acute liver injury by intracisternal injection of CRF was completely abolished by denervation of hepatic plexus by phenol and by 6-OHDA pretreatment, whereas hepatic branch vagotomy or atropine methyl nitrate treatment had no effect. Because the treatment of hepatic plexus with phenol is known to dominantly denervate the hepatic sympathetic nerve and because 6-OHDA treatment chemically depletes noradrenergic nerve fibers via biosynthetic adrenergic intermediates (27, 50), these results indicate that CRF acts in the brain to enhance CCl4-induced acute liver injury in rats through the sympathetic-noradrenergic nervous systems.
The pathophysiological effect of stressors and the autonomic nervous system on the liver has been reported. Some stressors and enhancement of the sympathetic nervous activity exacerbate experimental liver injury (11, 20-23). Recently, it has been shown that some physiological stressors increase CRF mRNA expression and CRF immunoreactivity in the hypothalamus and amygdala, which are important sites for the sympathetic nervous system (15, 16, 26) and that endogenous CRF regulates stress-induced alternation of the gastrointestinal functions through the autonomic nervous system (2, 31, 33, 43, 45, 51). In this study, we have investigated the relationship between central CRF and hepatic pathophysiological changes and demonstrated that CRF acts in the central nervous system and exacerbates CCl4-induced acute liver injury through the sympathetic-noradrenergic nervous systems in rats. This is further supported by previous reports that indicate that stimulation of the hypothalamus and activation of sympathetic nerves aggravate experimental liver injury (20, 21, 23). It is of interest to investigate the role of endogenous CRF in stress-induced aggravation of liver injury using a potent CRF antibody or antagonist in an experimental stress model.
CCl4 is a well-known hepatotoxic
chemical. The main cause of liver injury by
CCl4 is free radicals of its
metabolites. Cleavage of the
CCl3-Cl bond by superoxide
(O2) is thought to proceed via the
microsomal cytochrome P-450 reductase
and NADPH-dependent reductive pathways. Formation of free radicals may
cause lipid peroxidation and subsequent membrane injury (36). Decrease
in hepatic blood flow is suggested to be one of the important factors in aggravation of experimental liver injury induced by stimulation of
the hepatic sympathetic nerve (23, 24). Oxygen strongly inhibits the
hepatic cytochrome P-450-mediated
formation of free radicals from
CCl4, and
CCl4-induced liver injury is
protected against by hyperbaric oxygen in in vitro and in
vivo studies (6, 7). It may be suggested that activation of sympathetic
nerves by central CRF decreases hepatic blood flow and reduces oxygen supply to hepatocytes, inducing aggravation of
CCl4-induced liver injury. Because
stimulation of sympathetic nerves decreases activity of superoxide
dismutase (SOD), which is the scavenger of free radicals (19),
activation of sympathetic nerves by central CRF also may induce a
decrease of SOD and lead to accumulation of free radicals in the liver,
eliciting aggravation of liver injury.
The liver is known to be richly innervated (8, 9, 18, 37, 40), and abundant evidence indicates important roles of the central and autonomic nervous system in hepatic function (1, 3, 12, 13, 17, 25, 27, 39). Very little is known about the central neuropeptides involved in the modulation of hepatic function (10, 52, 54, 55). In the present study, we have found that central administration of CRF induces the enhancement of CCl4-induced acute liver injury through the sympathetic-noradrenergic pathways and have speculated that CRF acts in the brain as a neurotransmitter to induce central modulation of experimental acute liver injury. In a previous study, we have also shown that central thyrotropin-releasing hormone enhances hepatic blood flow (48) and hepatic proliferation (53) and protects against CCl4-induced acute liver injury through the vagal-cholinergic pathways in rats (38). It is very interesting that several neuropeptides act in the central nervous system and control physiological and pathological regulation of the liver through the different autonomic nervous pathways.
In conclusion, the present study indicates that CRF injected intracisternally acts in the brain to induce a potent enhancement of CCl4-induced acute liver injury in rats. The peptide action is mediated through the sympathetic-noradrenergic pathways. Central injection of CRF provides a useful tool to further investigate brain sites that influence sympathetic regulation of liver injury. It is also of interest to study the role of endogenous neuropeptide in stress-induced aggravation of liver injury by using CRF antagonists or antibodies.
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ACKNOWLEDGEMENTS |
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This research was supported in part by Ministry of Education, Science, and Culture of Japan Grants-in-Aid 0767554 and 09670503.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. Yoneda, Div. of Gastroenterology, Medical Center, International University of Health and Welfare, Kitakanamaru 2600-6, Otawara 324-0011, Japan (E-mail: yoneda{at}iuhw.ac.jp).
Received 31 March 1998; accepted in final form 5 November 1998.
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