1 Department of Internal Medicine, School of Medicine, Keio University, Tokyo, 160-8582 Japan; and 2 Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130 - 3932
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ABSTRACT |
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Whereas both ethanol and gut
ischemia/reperfusion (I/R) are known to alter hepatic microvascular
function, little is known about the influence of ethanol consumption on
the hepatic microvascular responses to I/R. The objective of this study
was to determine whether acute ethanol administration exacerbates the
hepatic microvascular dysfunction induced by gut I/R. Rats were exposed
to gut ischemia for 30 min followed by reperfusion. Intravital
videomicroscopy was used to monitor leukocyte recruitment and the
number of nonperfused sinusoids (NPS). Plasma alanine aminotransferase
(ALT), tumor necrosis factor- (TNF-
), and endotoxin
concentrations were monitored. In separate experiments, ethanol was
administered 15 min or 24 h before gut ischemia. In control rats,
gut I/R increased the number of stationary leukocytes and NPS. It also
elevated the plasma ALT, TNF-
, and endotoxin with a corresponding
increase in intestinal mucosal permeability. Low-dose ethanol
consumption 15 min before gut ischemia blunted the gut I/R-induced
leukostasis and elevations in plasma TNF-
and ALT. However,
high-dose ethanol consumption aggravated the gut I/R-induced increases
in leukostasis and increases in plasma endotoxin and ALT. When ethanol
was administered 24 h before, high-dose ethanol aggravated the gut
I/R-induced hepatocellular injury, but low-dose ethanol did not have
any effects on it. These results suggest that low-dose ethanol
consumption shortly before gut ischemia attenuates the hepatic
inflammatory responses, microvascular dysfunction, and hepatocellular
injury elicited by gut I/R, whereas high-dose ethanol consumption
appears to significantly aggravate these gut I/R-induced responses.
tissue hypoxia; intravital microscopy; intestinal mucosal
permeability; tumor necrosis factor-; endotoxin.
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INTRODUCTION |
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REPERFUSION OF THE ISCHEMIC liver and/or intestine is often associated with hepatocellular injury. A rate-limiting step in the pathogenesis of ischemia/reperfusion (I/R) injury of the liver and other organs is the adhesion of leukocytes to vascular endothelial cells (13, 14, 20). There is mounting evidence that leukocytes may contribute to the deleterious effects of gut I/R that extend beyond the bowel wall (20, 26). The lung and liver are two organs that appear to be particularly vulnerable to the negative consequences of gut I/R, presumably because the vasculature of these tissues is coupled in series with the intestinal circulation. Several reports describe an increased pulmonary vascular permeability after gut I/R, a response attenuated in animals pretreated with monoclonal antibodies (mAb) directed against leukocyte or endothelial cell adhesion molecules (3, 9).
Liver injury associated with gut I/R appears to be similarly dependent
on leukocyte adhesion and activation. The importance of leukocytes in
gut I/R-induced hepatic injury is demonstrated by 1) the
accumulation of leukocytes in the liver after gut reperfusion and
2) an attenuated gut I/R-induced leukocyte recruitment and hepatocellular dysfunction in animals treated with adhesion
molecule-specific mAb or in mice genetically deficient in adhesion
molecules (13, 14). Gut- and/or liver-derived mediators,
such as tumor necrosis factor- (TNF-
), have been implicated as
participants in the gut I/R-induced, leukocyte-mediated liver responses
(15, 37). There is also evidence suggesting that
gut-derived bacterial endotoxins contribute to the liver inflammation
associated by gut I/R (19, 28).
Ethanol is known to cause hepatic microcirculatory disturbances similar to those elicited by gut I/R (2, 25). These alterations in microvascular function as well as bacterial endotoxin, and changes in tissue lipid peroxides, oxygen tension, and redox state have all been implicated in the pathogenesis of ethanol-induced liver injury. For example, it was reported that acute ethanol administration leads to hepatic microvascular dysfunction in both the isolated perfused (5) and in situ rat liver (6, 22). Furthermore, it has been shown that daily feeding of lactobacilli, which results in much lower plasma endotoxin, virtually eliminates experimental alcohol-induced pathological changes in the liver (1, 24). The latter observations are consistent with other reports demonstrating that bacterial endotoxin can induce hepatic microvascular dysfunction and liver injury (11). Furthermore, in endotoxemic animals, even relatively low-dose ethanol that cannot cause hepatic microvascular dysfunction alone induced hepatic microvascular dysfunction (12). Thus interaction between ethanol and endotoxin on hepatic microcirculation has been recognized.
Recently, it was reported that ethanol consumption may alter the tissue responses to I/R (27, 29, 38). In a perfused liver model, ethanol enhanced gut I/R induced hepatotoxicity (an increase in blood levels of liver enzymes) and enhanced the production of reactive oxygen species (38). Similarly, in an in vivo gut I/R model, ethanol enhanced neutrophil accumulation in the intestinal wall (29). However, other studies indicate that ethanol may attenuate I/R-induced tissue injury. For example, in vivo experiments in the brain indicate that ethanol pretreatment attenuates cerebral I/R injury (27). It has also been reported that both acute and chronic ethanol consumption prevent I/R injury in the heart (17, 23, 39). Given the inconsistency in the I/R responses to ethanol pretreatment among different tissues, we chose to systematically examine the effects of both low- and high-dose ethanol consumption on the hepatic microvascular and inflammatory responses to gut I/R.
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MATERIAL AND METHODS |
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Animals and surgical procedures. Male Wistar rats (250-300 g) were fed a standard rat chow and starved for 18 h before the experiment. The rats were anesthetized with pentobarbital sodium (35 mg/kg) injected intraperitoneally. The left carotid artery was cannulated, and a catheter was placed in the aortic arch for monitoring blood pressure. The left jugular vein was also cannulated for drug administration. All experimental procedures were performed according to the criteria outlined by the National Institutes of Health and approved by the Keio University School of Medicine Committee on Animal Care and Use.
Intravital microscopy. After laparotomy, one lobe of the liver was observed under an inverted intravital microscope (model TMD-2S Diaphoto; Nikon, Tokyo, Japan) equipped with a silicon-intensified target camera (model C-2400-08; Hamamatsu Photonicus, Shizuoka, Japan). The liver was placed on an adjustable Plexiglas microscope stage with a nonfluorescent coverslip that allowed observation of a 2-cm2 segment of tissue. The liver was placed carefully to minimize the influence of respiratory movements, and the tissue surface was moistened and covered with cotton gauze soaked in saline. Images of the microcirculation were observed from the surface of the liver through a ×20 fluorescent objective. The microfluorographs were recorded on videotape using a videocassette recorder (model S-VHS-HQ; Victor, Tokyo, Japan).
Analysis of leukocyte accumulation and sinusoidal perfusion. Leukocytes were labeled in vivo with rhodamine-6G (1 mg dissolved in 5 ml of 0.9% saline) using a previously described method (14) that was based on the method used in the rat brain (35). It has recently been shown that rhodamine-6G selectively stains white blood cells and platelets but not endothelial cells (21). Thus the fluorochrome allows for differentiation between adherent leukocytes and endothelial cells. Rhodamine-6G (0.2 ml/100 g body wt) was injected before ethanol administration with subsequent injections every 30 min. The rhodamine-6G-associated fluorescence was visualized by epi-illumination at 510-560 nm, using a 590-nm emission filter. We selected a lobule with well-perfused sinusoids and the fewest stationary leukocytes. The lobule furthest from the edge of the liver was chosen when all the other conditions were equivalent.
Hepatic microcirculation, including rhodamine-6G-labeled leukocytes, was visualized for 90 min after the start of superior mesenteric artery (SMA) occlusion and recorded on a digital video recorder for a 1-min period at 0, 30, 60, and 90 min after reperfusion. The number of stationary leukocytes was determined off line during playback of the videotaped images. A leukocyte was considered stationary within the microcirculation (sinusoids) if it remained motionless for >10 s. Stationary leukocytes were quantified in both the midzonal and pericentral regions of the liver lobule and expressed as the number per field of view (2.1 × 105 µm2). The percentage of nonperfused sinusoids was calculated as the ratio of the number of nonperfused sinusoids to the total number of sinusoids per viewing field.Experimental protocols. The liver microcirculation was observed for 10 min before ligation of the SMA to ensure that all the parameters measured online were at a steady state. The SMA was then ligated with a snare created from polyethylene tubing for 0 (sham) or 30 min. Estimates of blood flow by laser Doppler flowmetry indicate that ligation of the SMA results in an ~70% reduction of blood flow in mouse liver (13). After the ischemic period, the ligature was gently released. Leukocyte accumulation and number of nonperfused sinusoids were measured before the induction of ischemia immediately after reperfusion and every 15 min for 1 h thereafter. In some experiments, the rats were fed ethanol (10%, 1 g/kg or 40%, 4 g/kg) through a gastric tube 15 min or 24 h before the induction of ischemia. These experiments were performed using five animals in each group.
Analysis of intestinal mucosal permeability. After laparotomy, a plastic catheter was secured in the lumen of the duodenum and the bowel was occluded just proximal to the opening of the plastic tube. The ileal end was transected, and the small intestine was gently lavaged with 10 ml saline. After ligation of the ileal end, ethanol (10%, 1 g/kg or 40%, 4 g/kg) or water (10 ml/kg body) was placed in the intestine. After 30 min, the small intestine was gently lavaged with 10 ml saline. Forty-five minutes after the administration of ethanol or water, the intestine was loaded with 5 ml of a solution (25 mg/ml) containing fluorescein isothiocyanate-dextran (FD4) with an average molecular mass 4,000 kDa (Sigma, St. Louis, MO). Blood samples were obtained from a femoral vein at 0, 15, 30, and 60 min after the administration of FD4 solution. The concentration of FD4 in plasma was determined using a fluorescence spectrophotometer (model RF-5300 PC; Shimadzu, Tokyo, Japan). In these experiments, both renal pedicles were ligated to prevent urinary excretion of the fluorescent probe (34).
Liver enzyme, TNF-, endotoxin, and ethanol assays.
Plasma samples were collected (105 min after the ethanol or saline
administration) from a catheter placed in the inferior vena cava at a
point distal to the hepatic veins with ligation of inferior vena cava
at a point proximal to the entry of the renal veins. This procedure
allowed only blood passing through the liver to be collected. The
plasma TNF-
concentration was also determined in a microtiter plate
using a commercial TNF-
assay kit (BioSource International,
Camarillo, CA), based on an ELISA. In another set of experiments,
alanine aminotransferase (ALT) activity was determined in the samples
collected 1 and 6 h after reperfusion by a spectrophotometric
assay using a commercial kit (Sigma). The plasma endotoxin
concentration was measured with endospecy, an endotoxin-specific
chromogen (Seikagaku, Tokyo, Japan), as described previously
(31). In some experiments, plasma ethanol concentration
was measured with a gas chromatograph (Perkin-Elmer, Yokohama, Japan),
according to a previous report (32).
Statistical analysis. All values were expressed as means ± SE. Statistical significance was determined by one-way ANOVA and Scheffé's post hoc test. Statistical significance was set at P < 0.05.
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RESULTS |
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Plasma ethanol concentration was 14.8 ± 1.7 mM at 45 min after low-dose (1 g/kg) ethanol administration, and 36.4 ± 1.7 mM at 45 min after high-dose (4 g/kg) ethanol administration.
Figure 1 summarizes the changes in
hepatic leukosequestration (number of stationary leukocytes) elicited
by gut I/R in untreated rats and in rats consuming either low-dose (1 g/kg) or high-dose (4 g/kg) ethanol. Although low-dose ethanol did not
change the number of stationary leukocytes under basal conditions, a
significant (277%) increase was noted after high-dose ethanol. A more
dramatic increase in hepatic leukosequestration (8-fold) was elicited
by gut I/R in untreated rats. After consumption of low-dose ethanol, the leukosequestration response to gut I/R was profoundly attenuated. However, high-dose ethanol consumption exerted the opposite effect, i.e., it exacerbated the leukocyte accumulation induced by gut I/R.
Changes in number of nonperfused sinusoids (NPS) (Fig.
2) that resulted from gut I/R followed a
pattern similar to that observed for leukocyte adhesion (Fig. 1). That
is, low-dose ethanol attenuated, whereas high-dose ethanol exacerbated,
the %NPS response to gut I/R. Furthermore, high-dose ethanol produced
a small but significant increase in %NPS under basal conditions, i.e.,
in the absence of gut I/R.
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Figure 3 summarizes the changes in plasma
FD4 concentration, a measure of intestinal mucosal permeability (IMP),
elicited by gut I/R in untreated rats and in rats consuming either
low-dose (1 g/kg) or high-dose (4 g/kg) ethanol. Although low-dose
ethanol did not alter plasma FD4 under basal conditions, high-dose
ethanol elicited a substantial (17-fold) increase in IMP in the absence of gut I/R. Indeed, the magnitude of the increase in plasma
FD4 produced by gut I/R in untreated rats was comparable with that caused by high-dose ethanol in the absence of gut I/R.
Ethanol consumption, at either dose, did not alter the mucosal
permeability response to gut I/R.
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Plasma endotoxin and TNF- concentrations were measured at 105 min
after ethanol or saline administration (Figs.
4 and
5). Low-dose ethanol under basal
conditions did not affect plasma endotoxin and TNF-
concentrations;
however, the concentration of both inflammatory mediators was increased
after high-dose ethanol consumption in otherwise normal rats. Gut I/R
elicited significant increases in plasma endotoxin and TNF-
concentrations in untreated rats. Whereas consumption of low-dose
ethanol did not alter the gut I/R-induced increase in plasma endotoxin,
this treatment blunted the gut I/R-induced increase in plasma TNF-
.
High-dose ethanol consumption had the opposite effect on the responses
of these mediators to gut I/R, i.e., it aggravated the increase in
plasma endotoxin concentration but did not alter the elevation in
plasma TNF-
concentration.
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Plasma ALT activity was measured 1 and 6 h after reperfusion or
ethanol administration (Figs. 6 and
7). Neither low-dose nor high-dose
ethanol per se affected the plasma ALT activities in otherwise normal
animals. However, gut I/R elicited a significant increase in the plasma
ALT activities 6 h after reperfusion. Consumption of low-dose
ethanol blunted the gut I/R-induced increase in plasma ALT, whereas
high-dose exacerbated the increment the plasma ALT at 1 h after
the gut I/R.
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Figure 8 shows plasma ALT activities
6 h after reperfusion in rats pretreated with ethanol.
Pretreatment with low-dose ethanol 24 h before gut ischemia did
not affect gut I/R-induced increase in plasma ALT activities. On the
other hand, pretreatment with high-dose ethanol aggravated them.
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DISCUSSION |
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In the present study, gut I/R was shown to cause
leukosequestration in the liver, increase the %NPS, and result in
hepatocellular injury (as reflected in an elevated serum ALT). These
responses to gut I/R are consistent with previous studies of rat and
mouse liver (13-15). Accompanying these changes were
an increased IMP, and elevated plasma concentrations of endotoxin and
TNF-. On the basis of the latter observations, it is tempting to
speculate that the increased gut mucosal permeability caused by I/R
allows endotoxins produced by enteric bacteria to gain access into the mucosal interstitium and portal blood where it is transported to the
liver. It is also possible that endotoxin contributes to the elevated
plasma TNF-
concentration by stimulating macrophages in the gut
and/or liver to produce the cytokine. Indeed, it has been previously
reported that an increase in blood endotoxin concentration caused by
bacterial translocation across an injured gut mucosa stimulates Kupffer
cells to produce TNF-
(15). A role for Kupffer cells in
mediating the TNF-
and other hepatic inflammatory responses to gut
I/R was demonstrated in experiments using GdCl3 to
inactivate Kupffer cells (15). The importance of the
elevated TNF-
concentration in modulating the hepatic responses to
gut I/R is exemplified by previous work demonstrating that
immunoneutralization of circulating TNF-
significantly
reduces the liver inflammation and hepatic microcirculatory alterations
caused by gut I/R (15). Hence, the observations made in
the present study are largely consistent with previous studies designed
to define the mechanisms underlying the liver inflammation and
microcirculatory dysfunction caused by gut I/R.
The major objective of the present study was to determine whether and
how ethanol consumption alters the hepatic microvascular and
inflammatory responses to gut I/R. Our findings indicate that ethanol
consumption exerts a profound influence on the liver responses to gut
I/R and that the amount of ethanol consumed determines the nature
(protection vs. exacerbation) of these responses. We observed that
low-dose ethanol consumption, which did not affect the hepatic
microcirculation in otherwise normal animals, significantly blunted the
gut I/R-induced hepatic microvascular dysfunction and concomitant
hepatocellular injury (elevation of serum ALT levels). It also
attenuated the gut I/R-induced increase in the plasma TNF-
concentration but not the increase in IMP or blood endotoxin
concentration. These observations, coupled with previously reported
protection of a TNF-
mAb against gut I/R-induced hepatic dysfunction
(10), suggest that low-dose ethanol may exert its beneficial effects in this model by attenuating TNF-
production after gut I/R. Of potential relevance in this regard is a report describing an attenuated sensitivity of Kupffer cells to endotoxin after ethanol treatment in vivo in early period (7). On
the other hand, pretreatment with low-dose ethanol 24 h before the gut I/R did not affect the gut I/R-induced hepatocellular injury (increases in plasma ALT activities). This result suggests that the
low-dose ethanol administration did not cause tolerance of Kupffer
cells 24 h before the gut I/R.
In a manner similar to gut I/R, high-dose ethanol administration per se
induced an increase in IMP and blood endotoxin levels, but it did so
without causing corresponding hepatocellular dysfunction or an elevated
plasma TNF-. These observations suggest that high-dose ethanol- and
gut I/R-induced hepatic microvascular dysfunction may involve both
common and distinct mechanisms. Both high-dose ethanol administration
and gut I/R have been reported to cause hepatic microvascular
dysfunction via inducing oxidative stress. There is an oxidative stress
that results from alcohol metabolism via cytochrome P-450
2E1 (4, 16). This enzyme, as well as others involved in
ethanol metabolism, such as alcohol dehydrogenase, aldehyde
dehydrogenase, and cytochrome P-450 2E1, are localized in
the pericentral region of the liver lobule (18, 33).
Hence, our findings that high-dose ethanol administration alone could cause an increase in NPS, and that high-dose ethanol-induced
leukostasis occurred to a greater extent in the pericentral region,
compared with the midzonal region, of the liver lobule is consistent
with the possibility that ethanol metabolism (oxidation)-induced
hypoxia and oxidative stress in the hepatic sinusoids contributes to
ethanol (high dose)-induced hepatic microvascular dysfunction.
Another interesting finding of the present study is that high-dose
ethanol consumption aggravated gut I/R-induced hepatic microvascular
and hepatocellular dysfunction, with an accompanying profound elevation
in blood endotoxin concentration. There is no significant difference in
IMP after gut I/R with or without ethanol administration. Either gut
I/R or high-dose ethanol administration substantially increased IMP.
Because either one already has substantial effects on IMP, it is not
surprising that gut I/R with high-dose ethanol administration did not
have synergical enhancement of an increase in IMP. Because the gut
I/R-induced increase in IMP was not further increased by high-dose
ethanol, it appears unlikely that more mucosal injury accounts for the
higher blood endotoxin concentration. It has been reported that
administration of high-dose ethanol decreases the clearance of
endotoxins (8). Reticuloendothelial function disturbed by
high-dose ethanol can decrease elimination capacity of endotoxin, which
causes the enhanced increase in plasma endotoxin levels by high-dose
ethanol administration (30). It is also noteworthy that
despite the more pronounced elevation in blood endotoxin noted in our
gut I/R model receiving high-dose ethanol, the plasma TNF-
concentration was not further elevated. This attenuated TNF-
response likely results from the reduced sensitivity of Kupffer cells
to endotoxins (7) mentioned above. Irrespective of why
TNF-
was not further elevated after gut I/R in the high-dose,
ethanol-treated animals, this observation suggests that mediators other
than TNF-
contribute to the exacerbation of gut I/R injury when
high-dose ethanol is consumed.
It was reported that after ethanol treatment, isolated Kupffer cells
exhibited tolerance to endotoxin early, whereas sensitization was
observed later (7, 36). Pretreatment with high-dose
ethanol aggravated gut I/R-induced increases in plasma ALT activities. Previous evidence and this result raise a possibility that pretreatment with high-dose ethanol induces tolerance of Kupffer cells at early points and their sensitization at later points. Although gut
I/R-induced increases in plasma endotoxin concentration were
aggravated, the high-dose, ethanol-induced tolerance of Kupffer cells
at early points may compensate for exdotoxin-induced elevation of
plasma TNF- concentration at early points. The high-dose
ethanol-induced sensitization of Kupffer cells at later points may
aggravate hepatocellular injury at later points.
In conclusion, the results of this study provide compelling evidence
that ethanol consumption modifies the liver injury response to gut I/R,
with low-dose ethanol providing protection against injury and high-dose
ethanol exacerbating the injury response. The mechanisms that underlie
these dose-dependent responses to gut I/R remain unclear. Our findings
suggest that whereas gut I/R-induced changes in plasma endotoxin and
TNF- concentrations are affected by ethanol consumption, these
factors alone cannot explain the differential responses to low- and
high-dose ethanol. Identification of these factors may lead to improved
therapeutic approaches for ischemic liver diseases.
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ACKNOWLEDGEMENTS |
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This study was supported by grants from the Japanese Ministry of Education, Science, and Culture and the Japanese owners association. D. N. Granger is supported by National Heart, Lung, and Blood Institute Grant HL-26441.
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. Ishii, Dept. of Internal Medicine, School of Medicine, Keio Univ., 35 Shinanomachi Shinjuku-ku, Tokyo 160-8582, Japan (E-mail: hishii{at}sc.itc.keio.ac.jp).
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.
10.1152/ajpgi.00171.2001
Received 24 April 2001; accepted in final form 7 November 2001.
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