Center for Surgical Research, Brown University School of Medicine and Rhode Island Hospital, Providence, Rhode Island 02903
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ABSTRACT |
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Although plasma norepinephrine (NE) increases and
hepatocellular function is depressed during early sepsis, it is unknown whether gut is a significant source of NE and, if so, whether gut-derived NE helps produce hepatocellular dysfunction. We subjected rats to sepsis by cecal ligation and puncture (CLP), and 2 h later (i.e., early sepsis) portal and systemic blood samples were collected and plasma levels of NE were assayed. Other rats were enterectomized before CLP. Hepatocellular function was assessed with an in vivo indocyanine green (ICG) clearance technique, systemic levels of tumor
necrosis factor (TNF)-, interleukin (IL)-1
, and IL-6 were determined, and the effect of NE on hepatic ICG clearance capacity was
assessed in an isolated, perfused liver preparation. Portal levels of
NE were significantly higher than systemic levels at 2 h after
CLP. Prior enterectomy reduced NE levels in septic animals. Thus gut
appears to be the major source of NE release during sepsis. Enterectomy
before sepsis also attenuated hepatocellular dysfunction and
downregulated TNF-
, IL-1
, and IL-6. Perfusion of the isolated livers with 20 nM NE (similar to that observed in sepsis) significantly reduced ICG clearance capacity. These results suggest that gut-derived NE plays a significant role in hepatocellular dysfunction and upregulating inflammatory cytokines. Modulation of NE release and/or
hepatic responsiveness to NE should provide a novel approach for
maintaining hepatocellular function in sepsis.
indocyanine green clearance; enterectomy; isolated, perfused rat liver; cecal ligation and puncture; inflammatory cytokines
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INTRODUCTION |
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DESPITE REFINEMENTS
in the management of septic patients, sepsis, septic shock, and
multiple organ failure remain major causes of death in surgical
intensive care units (3, 23). It is possible that the
subtle alterations in cellular functions that occur early after the
onset of sepsis are not identified and are consequently missed, leading
to inadequate or delayed treatment of the septic patient
(40). The animal model of polymicrobial sepsis induced by
cecal ligation and puncture (CLP) has been extensively used to study
the pathophysiology of sepsis. This model of sepsis is characterized by
an early, hyperdynamic phase (which includes increased cardiac output,
tissue perfusion, and oxygen delivery, decreased vascular resistance,
hyperglycemia, and hyperinsulinemia) followed by a late, hypodynamic
phase (which includes reduced cardiac output, tissue perfusion, and
oxygen delivery, hypoglycemia, and hypoinsulinemia) (6, 10, 40,
44). Although hepatic failure during sepsis is generally thought
to be a late complication following pulmonary and renal failures
(2), our studies have indicated that hepatocellular
dysfunction occurs early after the onset of sepsis (36)
and is further depressed with the progression of sepsis
(34). Furthermore, the depression in hepatocellular function does not appear to be due to a disturbance of hepatic perfusion or microcirculatory failure (34, 35, 42). In
this regard, proinflammatory cytokines such as tumor necrosis factor (TNF)- have been implicated as important mediators responsible for
producing cellular dysfunction and metabolic alteration during sepsis
(30, 32).
It has been suggested that the gastrointestinal tract may be the
"motor" for initiating multiple organ dysfunction following injury
(25). Although the gut is capable of producing
inflammatory cytokines, it appears that organs other than the gut, such
as the liver, are responsible for the upregulated proinflammatory cytokines during polymicrobial sepsis (19). However, the
gut may play a crucial role during sepsis through the release of other mediators, such as norepinephrine (NE), that stimulate Kupffer cells
(KC) and increase inflammatory cytokine release. To this end,
studies from our laboratory (12), as well as by Kovarik et
al. (20), have indicated that systemic levels of NE
increase significantly during sepsis. Moreover, Spengler et al.
(29) have demonstrated that stimulation of
2-adrenoceptors augments the production of
macrophage-derived TNF-
. In this regard, KC are known to be a major
source of proinflammatory cytokine release during sepsis as well as
under other adverse circulatory conditions (4, 17,
27). However, the mechanism by which KC are upregulated to produce increased proinflammatory cytokines remains unknown. We
therefore hypothesize that the gut is a significant source of NE during
sepsis and that increased gut-derived NE is responsible for depressing
hepatocellular function via upregulating inflammatory cytokine
production by KC during the early stage of sepsis.
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MATERIALS AND METHODS |
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Experimental model of polymicrobial sepsis. Polymicrobial sepsis was induced by CLP as described in detail previously (6). Male Sprague-Dawley rats (275-325 g) were fasted overnight but allowed water ad libitum. The animals were then anesthetized with methoxyflurane inhalation, and a 4-cm midline incision was performed. The cecum was exposed, ligated just distal to the ileocecal valve to avoid intestinal obstruction, and then punctured twice with an 18-gauge needle. The punctured cecum was squeezed to expel a small amount of fecal material and returned to the abdominal cavity, and the abdominal incision was closed in two layers. Sham-operated rats underwent the same surgical procedure except that the cecum was neither ligated nor punctured. All animals received normal saline (3 ml/100 g body wt) subcutaneously immediately after operation (i.e., fluid resuscitation). The animals were divided into four groups: 1) sham operation, 2) enterectomy before sham operation, 3) CLP, and 4) enterectomy before CLP (see Experimental model of enterectomy for details). The four groups of animals were randomly selected and were studied at 2 h after CLP or sham operation. We have previously demonstrated that 2 h after CLP is the time point that is representative of the early stage of polymicrobial sepsis (39). The experiments described here were performed in adherence to the National Institute of Health guidelines for the use of experimental animals. This project was approved by the Institutional Animal Care and Use Committee of Rhode Island Hospital, Providence, RI.
Experimental model of enterectomy. Enterectomy was performed in animals immediately before CLP or sham operation in which the entire intestine from the third part of duodenum to the anus was excised (45). The first and second parts of duodenum were kept intact to maintain the normal bile and pancreatic fluid drainage. The ends of the duodenum and anus were ligated securely and cleaned with iodine, 75% ethyl alcohol, and normal saline one after another. The end of duodenum was then buried by a purse string suture, and the end of the anus was closed by suture. In animals undergoing CLP, the cecum was excised from the removed gut, stitched to the posterior peritoneum, and then punctured twice with an 18-gauge needle. The punctured cecum was squeezed to expel a small amount of fecal material, and the abdominal incision was closed in two layers. Sham-operated animals only underwent a total enterectomy.
Measurement of plasma levels of NE.
At 2 h after CLP, portal and systemic blood samples were
simultaneously collected into tubes containing EGTA and reduced
glutathione to prevent blood clotting and NE degradation. Plasma was
immediately separated and stored at 70°C until assayed. Plasma
levels of NE in both portal and systemic samples were determined
radioenzymatically, as previously described by us (12),
using a commercially available assay (CAT-A-KIT; Amersham, Piscataway, NJ).
Assessment of hepatocellular function. Hepatocellular function was assessed using an in vivo indocyanine green (ICG) clearance technique as previously described by us (39). It should be noted that the maximal velocity of ICG clearance (Vmax) represents the number of functional ICG receptors or carriers of the active hepatocellular ICG transport system and that the kinetic constant (Km) represents the efficiency of the active transport process (39).
Determination of inflammatory cytokines.
Following the determination of hepatocellular function, blood samples
were withdrawn by cardiac puncture. The blood samples were put on ice
for 10 min and then centrifuged at 1,200 g for 10 min, and
the serum was stored at 70°C until assay. The levels of TNF-
,
interleukin (IL)-1
, and IL-6 were measured with enzyme-linked immunosorbent assay kits (BioSource International, Camarillo, CA)
according to the manufacturer's instructions.
Isolated, perfused liver preparation and in vitro ICG clearance.
We used an isolated, perfused rat liver preparation similar to that
described and characterized previously by Wolkoff et al. (43) with modifications. In brief, rats were anesthetized
with methoxyflurane inhalation, and longitudinal midline and transverse subcostal incisions were made to expose the liver. The common bile duct
was isolated and cannulated with polyethylene-10 tubing for the
collection and determination of bile production throughout the
experiment. Sutures were then loosely placed around the inferior vena
cava above and below the right renal vein, around the portal vein above
the splenic vein, and around the portal vein and hepatic artery. The
distal renal vein and distal vena cava were then ligated. The portal
vein was then immediately cannulated with a 16-gauge silicon catheter,
and perfusion was begun within 1 min. This catheter was connected to a
three-limb tube that was attached to a perfusion pump and to a syringe
filled with 3 ml of normal saline with heparin (20 U/ml). A blood
pressure analyzer (Micro-Med, Louisville, KY) was connected to the
portal vein catheter using polyethylene-50 tubing for the monitoring of
perfusion pressure. While the portal vein catheter was being secured,
heparin saline was injected into the liver and the perfusion was
started. A 12-gauge silicone tube was inserted into the inferior vena
cava toward the heart, and the vena cava was ligated suprahepatically.
The liver was perfused at a rate of 36 ml/min for 60 min with
Krebs-Henseleit buffer with 0.1% glucose and 0.5% bovine serum
albumin (fraction V) that was gassed with 95% O2-5%
CO2. NE (20 nM) was added to the perfusate and was present
throughout the entire period of perfusion. Temperature (37°C),
perfusion pressure (14 cmH2O), perfusate pH
(7.3-7.4), and PO2 (
500 mmHg) were
monitored and maintained. Before ICG clearance determination, the liver
was perfused for 30 min with Krebs-Henseleit buffer without
recirculation. The liver was then perfused with an additional 400 ml of
perfusate containing 8 mg ICG with recirculation for an additional 30 min. Samples of effluent (1 ml each) were collected every 5 min for 30 min after ICG administration. The ICG concentration in the effluent was
determined by a spectrophotometer (U-3210; Hitachi) at a wavelength of
800 nm (33) followed by interpolation against a standard
curve. The difference in ICG content between different time points was
the amount of ICG taken up by the liver. Samples of effluent were
assayed for alanine aminotransferase (ALT) with Sigma assay kits
according to the manufacturer's instructions. The bile production was
also recorded. At the end of the experiment, the liver was harvested
for determination of dry weight. Hepatic ICG clearance was expressed as
micrograms per gram dry tissue.
Histology of the isolated, perfused liver. The alterations in liver morphology were examined at 60 min after perfusion. Hepatic tissue was harvested and fixed in 10% neutral buffered formalin (Sigma, St. Louis, MO) and later embedded in paraffin. The tissue was then sectioned at a thickness of 5 µm and stained with hematoxylin and eosin. Slides were evaluated by light microscopy and documented by photographs.
Statistical analysis.
Data are presented as means ± SE. One-way ANOVA and Tukey's test
were employed for comparison among different groups of animals. The
differences were considered significant at P 0.05.
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RESULTS |
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Portal and systemic levels of NE and the effect of enterectomy on
circulating NE.
As shown in Fig. 1, the portal NE level
was 74% higher than the systemic level in sham-operated animals
despite the fact that statistical analysis did not show significant
difference. Although both systemic and portal levels of NE increased
significantly at 2 h after CLP, the levels of NE in portal blood
were significantly higher than NE in systemic blood (Fig. 1).
Enterectomy before the onset of sepsis, however, reduced systemic NE
levels by 51% (P < 0.05) at 2 h after CLP (Fig.
1). To determine whether prior enterectomy causes liver injury, plasma
levels of ALT were measured. The results in Table
1 indicate that enterectomy does not
significantly increase ALT levels at 2 h after operation.
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Alterations in in vivo ICG clearance.
As indicated in Fig. 2A,
enterectomy in sham-operated animals did not significantly affect the
Vmax values of in vivo ICG clearance. In
contrast, Vmax decreased by 67%
(P < 0.05) at 2 h after CLP compared with
sham-operated animals (Fig. 2A). Enterectomy before the
onset of sepsis, however, partially prevented the reduction in
Vmax (Fig. 2A). Similar to
Vmax values of ICG clearance, enterectomy in
sham-operated animals did not alter Km (Fig.
2B). Km values of ICG clearance,
however, were reduced by 69% (P < 0.05) at 2 h
after CLP, which was prevented by enterectomy immediately before the
onset of sepsis (Fig. 2B).
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Alterations in ICG clearance in isolated, perfused liver
preparation.
The perfused livers isolated from sham-operated animals demonstrated
effective ICG clearance (Fig. 3). In
contrast, in vitro ICG clearance decreased significantly in the livers
isolated from those animals that underwent sepsis for 2 h.
Similarly, perfusion with 20 nM NE also caused a significant decrease
of ICG clearance in the livers isolated from sham-operated animals
(Fig. 3). Determination of ALT levels present in the effluent
demonstrated no significant change throughout the 60-min perfusion
period in sham-operated animals (Fig.
4A). Additionally, bile
production was not different between livers isolated from sham-operated
animals, septic animals, and those perfused with NE throughout the
perfusion period (Fig. 4B). The morphological findings
indicate that compared with livers from normal rats (Fig.
5A), the isolated, perfused
rat liver at 60 min after perfusion shows normal liver histology, with
the exception of moderate sinusoidal dilation (Fig. 5B). The
normal hepatic morphology, effective ICG clearance, and normal liver enzyme and bile formation suggest that the viability of the isolated livers were maintained throughout the 60-min perfusion.
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Alterations in inflammatory cytokines.
The results in Fig. 6 indicate that
circulating levels of the measured cytokines (i.e., TNF-, IL-1
,
and IL-6) increased by 520-869% (P < 0.05) at
2 h after CLP. Prior enterectomy, however, significantly
attenuated the increase of these cytokines during early sepsis.
Enterectomy in sham-operated animals did not significantly affect sham
levels of plasma TNF-
, IL-1
, and IL-6 (Fig. 6).
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DISCUSSION |
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Because of its important role in metabolism and host defense mechanisms, the liver has been extensively studied during sepsis and septic shock and is thought to be a major organ in the development of multiple organ failure under such conditions (39). Although hepatic failure is generally thought to be a late complication following pulmonary and renal failures (2), our studies have indicated that hepatocellular function is depressed early after the onset of sepsis and that this depression does not appear to be due to a reduction in hepatic perfusion (34-36, 42). Thus it is important to determine the mediators (which are released early after the onset of sepsis) responsible for producing hepatocellular dysfunction. In this regard, studies have indicated that levels of NE increase significantly during early sepsis (12, 20). Additionally, mesenteric organs (primarily the gut) are thought to contribute substantially to total body NE production (~50% of the NE formed in the body under normal conditions) (1, 7). Therefore, the present study was conducted to determine whether the gut is a significant source of NE during early sepsis and, if so, whether gut-derived NE plays any role in producing hepatocellular dysfunction under such conditions.
Our results indicate that both portal and systemic levels of NE were
markedly elevated at 2 h after the onset of sepsis. The portal
levels of NE, however, were significantly higher than systemic levels
in septic animals. Although the fact that levels of NE in portal blood
were significantly higher than those in systemic blood indicated that
the gut is a major source of NE during early sepsis, the strong piece
of evidence supporting this comes from animals that were enterectomized
before the induction of sepsis. The results from this group of animals
demonstrate that removal of gut before the CLP prevents the increase in
NE seen after the onset of sepsis. Thus the gut appears to be the major
source of NE production during the early stage of sepsis. The data also indicate that hepatocellular function was markedly depressed at 2 h after CLP. Prior enterectomy, however, attenuated hepatocellular dysfunction during early sepsis, as evidenced by increased
Vmax and Km of in vivo
ICG clearance. Furthermore, the increased levels of TNF-, IL-1
,
and IL-6 observed at 2 h after CLP were significantly reduced in
animals undergoing enterectomy immediately before the onset of sepsis.
To further confirm the role of gut-derived NE in hepatocellular
dysfunction, we used an isolated, perfused liver preparation for
determining in vitro ICG clearance. The isolated, perfused rat liver
preparation permits one to study hepatic function in a system that
approaches normal physiological conditions in which alterations in
blood flow, blood pressure, or hormonal milieu can be minimized
(43). Our results have demonstrated that the ICG clearance
was significantly reduced in livers isolated at 2 h after CLP
compared with livers isolated from sham-operated animals. Moreover,
perfusion of the isolated liver with 20 nM NE, similar to that observed
during sepsis (12), reduced ICG clearance capacity to a
level similar to that seen at 2 h after the onset of sepsis.
Together, these results indicate that the gut is a major source of NE
release during the early stage of sepsis and that gut-derived NE
appears to play a significant role in producing hepatocellular
dysfunction, which may be mediated via the upregulation of inflammatory
cytokine production.
Previous studies have suggested that the occurrence of hepatocellular
dysfunction during the early stage of sepsis appears to be due to
upregulation of inflammatory cytokines such as TNF- (37). It has been demonstrated that infusion of TNF-
at
a dose that does not decrease cardiac output and hepatic perfusion
produces hepatocellular dysfunction similar to that observed during the early stage of sepsis (32). Studies have also indicated
that inhibition of TNF-
biological activity by its monoclonal
antibodies or reduction of its synthesis by pharmacological agents such
as pentoxifylline is beneficial during sepsis (24, 31).
Thus cellular dysfunctions such as hepatocellular dysfunction observed early after the onset of sepsis may be a consequence of upregulated proinflammatory cytokines such as TNF-
(37, 39).
Although the gut is indeed capable of being a cytokine-producing organ (26) and although inflammatory cytokines such as TNF-
,
IL-1
, and IL-6 are upregulated during early sepsis (9),
our recent studies have indicated that organs other than the gut appear
to be responsible for the upregulated proinflammatory cytokine release during sepsis (19). In this regard, studies have
demonstrated that KC are the major source of inflammatory cytokine
release during sepsis or under other adverse circulatory conditions
(4, 17, 27, 37). Because of their position in splanchnic
circulation, KC are among the first cells to come into contact with
gut-derived products. Since KC constitute 80-90% of the fixed
macrophage population, their activation and subsequent release of
inflammatory cytokines have great effects on the systemic response
during sepsis (21). Previous studies have indicated that
upregulation of KC proinflammatory cytokine gene expression occurs
early after the onset of sepsis, with increased circulating levels
shortly thereafter (37). Moreover, the increased gene
expression and plasma inflammatory cytokines occur before the
depression in hepatocellular function during early sepsis. Furthermore,
our studies indicate that the reduction and blockade of phagocytic
activity in vivo by gadolinium chloride prevents the increase in
inflammatory cytokines and prevents hepatocellular dysfunction during
early sepsis (17). Thus it appears that KC are the major
source of inflammatory cytokine release during early sepsis. Because of
the anatomic relationship between the gut and liver via portal
circulation, gut-derived mediators such as NE should play an important
role in stimulating KC and releasing proinflammatory cytokines under
pathophysiological conditions. Although gut-derived NE appears to be
responsible for producing hepatocellular dysfunction via an
upregulation of TNF-
release by KC, endotoxin also plays an
important role in upregulating proinflammatory cytokines and depressing
hepatocellular function during polymicrobial sepsis. Thus further
studies are necessary to determine the individual roles of NE and
endotoxin in producing hepatocellular dysfunction as well as the
synergistic effects that these factors may possess.
Although the increase in intracellular cAMP levels following
stimulation of 2-adrenoceptors by epinephrine
(epinephrine has much higher selectivity for
2-adrenoceptors than NE) downregulates TNF-
gene
expression and its release (11, 28), studies by Spengler
et al. (29) have demonstrated that the
2-adrenergic agonists NE and UK-14304 increase
endotoxin-stimulated TNF-
production by peritoneal macrophages. In
this regard, NE production and release have been found to be
significantly correlated with the spontaneous secretion of TNF-
by
alveolar macrophages (16). The presence of macrophage
2-adrenergic receptors has previously been confirmed (13, 29). Moreover,
2-adrenergic agonists
increase TNF-
mRNA accumulation at the transcriptional level that
can be blocked with the
2-adrenergic antagonist
yohimbine (29). In vivo studies indicate that
2-adrenergic antagonists inhibit TNF-
production following endotoxemia (8, 14). Thus gut-derived NE appears to play a major role in upregulating proinflammatory cytokines, such as
TNF-
, by KC through an
2-adrenoceptor pathway. The
findings that enterectomy before the onset of sepsis reduces
gut-derived NE production and circulating levels of inflammatory
cytokines in the present study support this notion. Since we
(32) have previously demonstrated that administration of a
low dose of recombinant TNF-
, which does not reduce cardiac output
and hepatic perfusion, produces hepatocellular dysfunction, it is
likely that NE depresses hepatocellular function through the increase
in TNF-
production by KC during the early stage of sepsis.
Although the findings of this study support the notion that the
increase in gut-derived NE plays a major role in hepatocellular dysfunction, the results of our preliminary experiments using 2-adrenoceptor antagonists both in vivo and with
perfusion experiments in relation to hepatocellular function and
inflammatory cytokine production and release strongly support this
hypothesis. These preliminary findings show that administration of NE
via the portal vein upregulates KC TNF-
gene expression as well as
KC and plasma levels of this cytokine. However, the coadministration of
NE and the
2-adrenergic antagonist yohimbine prevented
the increase of TNF-
in KC and in plasma (46).
Moreover, in vivo administration of the
2-adrenergic antagonist rauwolscine protects
hepatocellular function and attenuates the upregulation in TNF-
during early sepsis (preliminary data). In isolated, perfused liver
experiments, administration of NE in combination with the
2-adrenergic antagonist rauwolscine prevented the
depression of ICG clearance and attenuated the NE-induced upregulation
of TNF-
(preliminary data). These results, together and in
combination with the findings of the present study, suggest that the
increased gut-derived NE release during the early stage of sepsis is
responsible for depressing hepatocellular function through upregulation
of KC TNF-
production, which is mediated through an
2-adrenoceptor pathway.
It could be argued that the enterectomy procedure may significantly alter hepatic hemodynamics. Although it is evident that portal blood flow decreases markedly following enterectomy, our recent study indicates that oxygen delivery to the liver is well maintained (45). In that study, enterectomy reduced portal blood flow by 85%, which was accompanied by an increase in hepatic arterial blood flow by 367%, resulting in no significant changes in hepatic oxygen delivery and consumption (45). Furthermore, the results of this study indicate that enterectomy alone in sham-operated animals did not alter hepatocellular function or cytokine release. It can also be argued that the addition of erythrocytes to the perfusate of the isolated liver preparation is necessary to maintain hepatic viability. However, the monitoring of PO2 in our preparation indicates a significant reduction in effluent PO2 compared with that in the perfusate (data not shown), demonstrating that oxygen use is maintained despite an absence of erythrocytes in the perfusate. Morphological observations also support the viability of the isolated livers after 60 min of perfusion. It could also be argued that since NE is known to be a vasoconstrictor, its effects on portal circulation may be of concern. In the isolated, perfused liver preparations, we determined portal pressure throughout the experiment. These results show that portal pressure was not altered as a result of NE perfusion through the isolated liver. Moreover, we have performed preliminary studies of NE infusion via the portal vein and these results show that NE infusion does not alter mean arterial pressure. Together, these results suggest that NE does not significantly affect portal circulation.
ICG clearance technique assesses the cholephilic organic anion
transport function of the hepatocyte (22), which is an
important aspect of hepatocellular function, and ICG clearance has been shown to be an extremely sensitive and early indicator of alterations in hepatocellular function during sepsis and other adverse circulatory conditions (5, 15, 36, 41). This technique remains
distinct from the assessment of plasma liver enzymes because it
measures hepatocellular function rather than hepatocellular damage.
Moreover, the decrease in the hepatic clearance of this dye occurs as
early as 1.5 h after the onset of sepsis and is followed by an
increase in circulating levels of -glutathione
S-transferase at 5 h (18) and liver
transaminases at 10 h after CLP (38). Therefore, it appears that ICG clearance is an important and sensitive technique for
detecting alterations in hepatocellular function, which was not
significantly affected by enterectomy at 2 h after the procedure.
In summary, our results indicate that portal levels of NE are significantly higher than systemic levels during early sepsis and that enterectomy before the onset of sepsis significantly reduced circulating NE levels under such conditions. Thus the gut appears to be the major source of NE release during sepsis. Enterectomy before CLP significantly attenuated hepatocellular dysfunction and downregulated inflammatory cytokine release. Moreover, perfusion of the isolated livers with NE significantly reduced ICG clearance capacity. Therefore, it appears that gut-derived NE during early sepsis plays an important role in upregulating proinflammatory cytokine release and depressing hepatocellular function. Since it has been shown that NE upregulates proinflammatory cytokines, modulation of NE release and/or tissue responsiveness to NE should provide a novel approach for attenuating cell and organ dysfunction during sepsis.
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ACKNOWLEDGEMENTS |
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This study was supported by National Institutes of Health Grant GM-53008 (P. Wang). P. Wang is also the recipient of National Institutes of Health Independent Scientist Award KO2-AI-01461.
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FOOTNOTES |
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A portion of the data presented in this study has been published as an abstract (Shock 13: 9A-10A, 2000) and presented at the 20th Annual Meeting of the Surgical Infection Society, Providence, RI, April 27-29, 2000.
Address for reprint requests and other correspondence: P. Wang, Dept. of Surgery, Univ. of Alabama at Birmingham, School of Medicine, Volker Hall, Rm. G094P, 1670 University Blvd., Birmingham, AL 35294 (E-mail: ping.wang{at}ccc.uab.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.
Received 4 January 2000; accepted in final form 13 July 2000.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Aneman, A,
Eisenhofer G,
Fandriks L,
and
Friberg P.
Hepatomesenteric release and removal of norepinephrine in swine.
Am J Physiol Regulatory Integrative Comp Physiol
268:
R924-R930,
1995
2.
Baue, AE.
Multiple, progressive, or sequential systems failure: a syndrome of the 1970s.
Arch Surg
110:
779-781,
1975[ISI][Medline].
3.
Baue, AE.
Multiple organ failure, multiple organ dysfunction syndrome, and systemic inflammatory response syndrome: why no magic bullets?
Arch Surg
132:
703-707,
1997[Abstract].
4.
Callery, MP,
Kamei T,
Mangino MJ,
and
Flye MW.
Organ interactions in sepsis. Host defense and the hepatic-pulmonary macrophage axis.
Arch Surg
126:
28-32,
1991[Abstract].
5.
Chaudry, IH,
Schleck S,
Clemens MG,
Kupper TE,
and
Baue AE.
Altered hepatocellular active transport: an early change in peritonitis.
Arch Surg
117:
151-157,
1982[Abstract].
6.
Chaudry, IH,
Wichterman KA,
and
Baue AE.
Effect of sepsis on tissue adenine nucleotide levels.
Surgery
85:
205-211,
1979[ISI][Medline].
7.
Eisenhofer, G,
Aneman A,
Hooper D,
Rundqvist B,
and
Friberg P.
Mesenteric organ production, hepatic metabolism, and renal elimination of norepinephrine and its metabolites in humans.
J Neurochem
66:
1565-1573,
1996[ISI][Medline].
8.
Elenkov, IJ,
Hasko G,
Kovacs KJ,
and
Vizi ES.
Modulation of lipopolysaccharide-induced tumor necrosis factor- production by selective
- and
-adrenergic drugs in mice.
J Neuroimmunol
61:
123-131,
1995[ISI][Medline].
9.
Ertel, W,
Morrison MH,
Wang P,
Ba ZF,
Ayala A,
and
Chaudry IH.
The complex pattern of cytokines in sepsis: association between prostaglandins, cachectin and interleukins.
Ann Surg
214:
141-148,
1991[ISI][Medline].
10.
Fink, MP,
and
Heard SO.
Laboratory models of sepsis and septic shock.
J Surg Res
49:
186-196,
1990[ISI][Medline].
11.
Guirao, X,
Kumar A,
Katz J,
Smith M,
Lin E,
Keogh C,
Calvano SE,
and
Lowry SF.
Catecholamines increase monocyte TNF receptors and inhibit TNF through 2-adrenoreceptor activation.
Am J Physiol Endocrinol Metab
273:
E1203-E1208,
1997
12.
Hahn, PY,
Wang P,
Tait SM,
Ba ZF,
Reich SS,
and
Chaudry IH.
Sustained elevation in circulating catecholamine levels during polymicrobial sepsis.
Shock
4:
269-273,
1995[ISI][Medline].
13.
Handy, DE,
Johns C,
Bresnahan MR,
Tavares A,
Bursztyn M,
and
Gavras H.
Expression of 2-adrenergic receptors in normal and atherosclerotic rabbit aorta.
Hypertension
32:
311-317,
1998
14.
Hasko, G,
Elenkov IJ,
Kvetan V,
and
Vizi ES.
Differential effect of selective block of 2-adrenoreceptors on plasma levels of tumour necrosis factor-
, interleukin-6 and corticosterone induced by bacterial lipopolysaccharide in mice.
J Endocrinol
144:
457-462,
1995[Abstract].
15.
Hauptman, JG,
Wang P,
DeJong GK,
and
Chaudry IH.
Improved methodology for the evaluation of the velocity of clearance of indocyanine green in the rat.
Circ Shock
33:
26-32,
1991[ISI][Medline].
16.
Johnson, KM,
Garcia RM,
Heitkemper M,
and
Helton WS.
Polymyxin B prevents increased sympathetic activity and alveolar macrophage tumor necrosis factor release in parenterally fed rats.
Arch Surg
130:
1294-1299,
1995[Abstract].
17.
Koo, DJ,
Chaudry IH,
and
Wang P.
Kupffer cells are responsible for producing inflammatory cytokines and hepatocellular dysfunction during early sepsis.
J Surg Res
83:
151-157,
1999[ISI][Medline].
18.
Koo, DJ,
Zhou M,
Chaudry IH,
and
Wang P.
Plasma -glutathione S-transferase: a sensitive indicator of hepatocellular damage during polymicrobial sepsis.
Arch Surg
135:
198-203,
2000
19.
Koo, DJ,
Zhou M,
Jackman D,
Cioffi WG,
Bland KI,
Chaudry IH,
and
Wang P.
Is gut the major source of proinflammatory cytokine release during polymicrobial sepsis?
Biochim Biophys Acta
1454:
289-295,
1999[ISI][Medline].
20.
Kovarik, MF,
Jones SB,
and
Romano FD.
Plasma catecholamines following cecal ligation and puncture in the rat.
Circ Shock
22:
281-290,
1987[ISI][Medline].
21.
Kuiper, J,
Brouwer A,
Knook DL,
and
van Berkel TJC
Kupffer and sinusoidal endothelial cells.
In: The Liver: Biology and Pathobiology, edited by Arias IM,
Boyer JL,
Fausto N,
Jakoby WB,
Schachter DA,
and Shafritz DA.. New York: Raven, 1994, p. 791-818.
22.
Kullak-Ublick, GA,
Hagenbuch B,
Steiger B,
Wolkoff AW,
and
Meier PJ.
Functional characterization of the basolateral rat liver organic anion transporting polypeptide.
Hepatology
20:
411-416,
1994[ISI][Medline].
23.
Livingston, DH,
and
Deitch EA.
Multiple organ failure: a common problem in surgical intensive care unit patients.
Ann Med
27:
13-20,
1995[ISI][Medline].
24.
Lundblad, R,
Ekstrom P,
and
Giercksky KE.
Pentoxifylline improves survival and reduces tumor necrosis factor, interleukin-6, and endothelin-1 in fulminant intra-abdominal sepsis in rats.
Shock
3:
210-215,
1995[ISI][Medline].
25.
Meakins, JL,
and
Marshall JC.
The gastrointestinal tract: the `motor' of MOF.
Arch Surg
121:
197-201,
1986.
26.
Ogle, CK,
Guo X,
Hasselgren PO,
Ogle JD,
and
Alexander JW.
The gut as a source of inflammatory cytokines after stimulation with endotoxin.
Eur J Surg
163:
45-51,
1997[ISI][Medline].
27.
O'Neill, PJ,
Ayala A,
Wang P,
Ba ZF,
Morrison MH,
Schultze AE,
Reich SS,
and
Chaudry IH.
Role of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation.
Shock
1:
43-47,
1994[ISI][Medline].
28.
Severn, A,
Rapson NT,
Hunter CA,
and
Liew FY.
Regulation of tumor necrosis factor production by adrenaline and -adrenergic agonists.
J Immunol
148:
3441-3445,
1992
29.
Spengler, RN,
Allen RM,
Remick DG,
Strieter RM,
and
Kunkel SL.
Stimulation of -adrenergic receptor augments the production of macrophage-derived tumor necrosis factor.
J Immunol
145:
1430-1434,
1990
30.
Tracey, KJ,
Beutler B,
Lowry SF,
Merryweather J,
Wolpe S,
Milsark IW,
Hariri RJ,
Fahey TJ,
Zentella A, III,
Albert JD,
Shires GR,
and
Cerami A.
Shock and tissue injury induced by recombinant human cachectin.
Science
234:
470-474,
1986[ISI][Medline].
31.
Walsh, CJ,
Sugerman HJ,
Mullen PG,
Carey PD,
Leeper-Woodford SK,
Jesmok GJ,
Ellis EF,
and
Fowler AA.
Monoclonal antibody to tumor necrosis factor attenuates cardiopulmonary dysfunction in porcine gram-negative sepsis.
Arch Surg
127:
138-145,
1992[Abstract].
32.
Wang, P,
Ayala A,
Ba ZF,
Zhou M,
Perrin MM,
and
Chaudry IH.
Tumor necrosis factor- produces hepatocellular dysfunction despite normal cardiac output and hepatic microcirculation.
Am J Physiol Gastrointest Liver Physiol
265:
G126-G132,
1993
33.
Wang, P,
Ayala A,
Dean RE,
Hauptman JG,
Ba ZF,
DeJong GK,
and
Chaudry IH.
Adequate crystalloid resuscitation restores but fails to maintain the active hepatocellular function following hemorrhagic shock.
J Trauma
31:
601-608,
1991[ISI][Medline].
34.
Wang, P,
Ba ZF,
and
Chaudry IH.
Hepatic extraction of indocyanine green is depressed early in sepsis despite increased hepatic blood flow and cardiac output.
Arch Surg
126:
219-224,
1991[Abstract].
35.
Wang, P,
Ba ZF,
and
Chaudry IH.
Increase in hepatic blood flow during early sepsis is due to increased portal blood flow.
Am J Physiol Regulatory Integrative Comp Physiol
261:
R1507-R1512,
1991
36.
Wang, P,
Ba ZF,
and
Chaudry IH.
Hepatocellular dysfunction occurs earlier than the onset of hyperdynamic circulation during sepsis.
Shock
3:
21-26,
1995[ISI][Medline].
37.
Wang, P,
Ba ZF,
and
Chaudry IH.
Mechanism of hepatocellular dysfunction during early sepsis: key role of increased gene expression and release of proinflammatory cytokines tumor necrosis factor and interleukin-6.
Arch Surg
132:
364-370,
1997[Abstract].
38.
Wang, P,
Ba ZF,
Tait SM,
Zhou M,
and
Chaudry IH.
Alterations in circulating blood volume during polymicrobial sepsis.
Circ Shock
40:
92-98,
1993[ISI][Medline].
39.
Wang, P,
and
Chaudry IH.
Mechanism of hepatocellular dysfunction during hyperdynamic sepsis.
Am J Physiol Regulatory Integrative Comp Physiol
270:
R927-R938,
1996
40.
Wang, P,
and
Chaudry IH.
A single hit model of polymicrobial sepsis: cecal ligation and puncture.
Sepsis
2:
227-233,
1998.
41.
Wang, P,
Hauptman JG,
and
Chaudry IH.
Hepatocellular dysfunction occurs early after hemorrhage and persists despite fluid resuscitation.
J Surg Res
48:
464-470,
1990[ISI][Medline].
42.
Wang, P,
Zhou M,
Rana MW,
Ba ZF,
and
Chaudry IH.
Differential alterations in microvascular perfusion in various organs during early and late sepsis.
Am J Physiol Gastrointest Liver Physiol
263:
G38-G43,
1992
43.
Wolkoff, AW,
Johansen KL,
and
Goeser T.
The isolated perfused rat liver: preparation and application.
Anal Biochem
167:
1-14,
1987[ISI][Medline].
44.
Yang, S,
Cioffi WG,
Bland KI,
Chaudry IH,
and
Wang P.
Differential alterations in systemic and regional oxygen delivery and consumption during the early and late stages of sepsis.
J Trauma
47:
706-712,
1999[ISI][Medline].
45.
Yang, S,
Koo DJ,
Chaudry IH,
and
Wang P.
The important role of the gut in initiating the hyperdynamic response during early sepsis.
J Surg Res
89:
31-37,
2000[ISI][Medline].
46.
Zhou, M,
Koo DJ,
Ornan DA,
Chaudry IH,
and
Wang P.
Gut-derived norepinephrine (NE) upregulates TNF- production (Abstract).
Shock
13, Suppl:
10,
2000.