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Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7365
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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To test the hypothesis that
leukocyte infiltration mediated by intercellular adhesion molecule
(ICAM)-1 is involved in early alcohol-induced liver injury, male
wild-type or ICAM-1 knockout mice were fed a high-fat liquid diet with
either ethanol or isocaloric maltose-dextrin for 4 wk. There were no
differences in mean urine alcohol concentrations between the groups fed
ethanol. Alcohol administration significantly increased liver size and
serum alanine aminotransferase levels in wild-type mice over high-fat
controls, effects that were blunted significantly in ICAM-1 knockout
mice. Dietary ethanol caused severe steatosis, mild inflammation, and focal necrosis in livers from wild-type mice. Furthermore, livers from
wild-type mice fed ethanol showed significant increases in the number
of infiltrating leukocytes, which were predominantly lymphocytes. These
pathological changes were blunted significantly in ICAM-1 knockout
mice. Tumor necrosis factor (TNF)-
mRNA expression was increased in
wild-type mice fed ethanol but not in ICAM-1 knockout mice. These data
demonstrate that ICAM-1 and infiltrating leukocytes play important
roles in early alcohol-induced liver injury, most likely by mechanisms
involving TNF-.
intragastric feeding; adhesion molecules
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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INTERCELLULAR ADHESION
MOLECULE (ICAM)-1, a member of the immunoglobulin superfamily, is
one of many critical adhesion molecules expressed on several cell
types, including endothelial cells, epithelial cells, and fibroblasts
and is induced by proinflammatory cytokines such as tumor necrosis
factor (TNF)- and interleukin (IL)-1 (17). ICAM-1
recruits leukocytes into inflammatory sites by binding to its ligands
LFA-1 or Mac-1, which are members of the leukocyte integrin family. The
activated leukocytes injure tissue by releasing oxidants and proteases.
Thus ICAM-1 could be involved in the pathogenesis of inflammatory liver
diseases such as ischemia-reperfusion injury and alcoholic
hepatitis because it is expressed on sinusoidal endothelial cells in
the liver (15, 21).
Inflammatory cell infiltration is one characteristic histopathological change in alcoholic liver disease. Indeed, chronic enteral ethanol administration increases the number of infiltrating neutrophils in the liver in the Tsukamoto-French model (9, 14). Furthermore, ICAM-1 mRNA expression was increased in the liver from rats fed enteral ethanol chronically (19). Therefore, it has been speculated that ICAM-1 plays an important role in early alcohol-induced liver injury by facilitating adhesion of leukocytes, which produce toxic mediators; however, hard evidence for or against this hypothesis is still lacking. Activated Kupffer cells also generate a wide range of inflammatory mediators, including cytokines, eicosanoids, and reactive oxygen species. Indeed, early alcohol-induced liver injury is attenuated by inactivation of Kupffer cells (1). However, it is still unclear whether early alcohol-induced liver injury is caused directly by inflammatory mediators from Kupffer cells or from infiltrating leukocytes. Therefore, the purpose of this study was to evaluate the hypothesis that ICAM-1 and infiltrating neutrophils are involved in early alcohol-induced liver injury by studying ICAM-1 knockout mice fed enteral alcohol.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Male wild-type (C57BL/6J) or ICAM-1 (129SV7 × C57BL/6J, backcrossed 12 times) knockout mice were obtained from Jackson Laboratory (Bar Harbor, ME). Animals were housed in a facility approved by the American Association for Accreditation of Laboratory Animal Care and received humane care in compliance with institutional guidelines. Specifically, 4-mo-old male mice (18-20 g body wt) were used in this study. Mice had free access to a chow diet and water ad libitum before the study.
Operative procedures and gastric cannulation. Mice were fasted for 24 h before surgery. A 45-cm PE-90 polyethylene tube (Becton Dickenson, Sparks, MD) with a small silicon tip (1.5 mm) on one end was used for gastric cannulation with aseptic surgical techniques (11, 25). Briefly, animals were anesthetized by inhalation of methoxyflurane and a vertical midline incision was made in the skin of the abdomen from the xiphoid cartilage extending to the midabdomen. A second small incision was made in the dorsal cervical area. A subcutaneous tunnel was exposed and 7-0 polypropylene sutures were passed 1 mm apart through the serosa and muscular layer of the stomach. After a small opening was made in the forestomach between sutures, the tip of the cannula was inserted 0.8 cm into the stomach. The tube was anchored to the stomach wall with Dacron felt, and the stomach was returned to the abdominal cavity. The small incision where the cannula exited through the abdominal wall was closed with 5-0 silk and tied around the cannula, resulting in tight fixation of the cannula to the abdominal wall. The abdominal wall and skin were closed with 5-0 silk. The mouse was placed in a prone position, an anchoring button was sutured to the muscles of the dorsal cervix, and the skin was closed around the button stem with 5-0 silk. The total surgical procedure took ~30 min. Gentamicin (8 mg/kg ip) and ampicillin (25 mg/kg ip) were administered postsurgically. The cannula exited through a flanged button (Instech Laboratories, Plymouth Meeting, PA) and a protective spring coil (Instech Laboratories) and was attached to a swivel (Lomir Biomedical, Nôtre Dame-de-L'Ile-Perrot, PQ, Canada). The use of a spring coil and swivel protected the cannula and allowed free movement of animals in individual metabolic cages. The animals' diet was delivered from syringes through the gastric cannula via infusion pumps. All animals were placed in a microorganism-free clean area during the experimental period.
Diet. A liquid diet described by Thompson and Reitz (22) supplemented with lipotropes as described by Morimoto et al. (18) was prepared fresh daily. It contained corn oil as fat (37% of total calories), protein (23%), carbohydrate (5%), minerals, and vitamins plus ethanol (35-40% of total calories) or isocaloric maltose-dextrin (control diet) as described elsewhere (24). Throughout the enteral feeding period, mice had free access to cellulose pellets as a source of fiber (Harlan Teklad, Madison, WI).
Experimental protocol.
Mice were randomly divided into four experimental groups and fed either
high-fat control or high-fat ethanol-containing diets intragastrically
continuously for up to 4 wk. The diet (1.29-1.31 kcal/ml) was
infused at a rate of 0.44 ml · g body
wt
1 · day1 with an infusion pump
(Harvard Apparatus, Natick, MA). All animals received humane care in
compliance with institutional guidelines, and severe alcohol
intoxication was assessed carefully to evaluate the development of
tolerance using a 0-3 behavioral scoring system (0, normal; 1, sluggish movement; 2, loss of movement but still moving if stimulated;
3, loss of consciousness) (11, 25). The amount of ethanol
in the diet was increased from 4% initially to 8% to obtain optimal
delivery of calories without compromising growth or survival. Ethanol
initially was delivered at 14 g · kg1 · day1 (27% of
total calories) and was increased 1 g/kg every 2 days until the end of
the first week and then 1 g/kg every 4 days until the end of the
experiment (final alcohol delivered = 28 g · kg1 · day1; 40% of
total calories). Animals had free access to water and cellulose pellets
as a source of fiber.
Clinical chemistry.
Ethanol concentrations in urine, which are representative of blood
alcohol levels (3), were measured daily. Mice were housed in metabolic cages that separated urine from feces, and urine was
collected over 24 h in bottles containing mineral oil to prevent evaporation. Each day at 9:00 AM, urine collection bottles were changed
and a 1-ml sample was stored at 
20°C in a microtube for later
ethanol analysis. Ethanol concentration was determined by measuring
absorbance at 366 nm resulting from the reduction of NAD+
to NADH by alcohol dehydrogenase (4).
20°C in a microtube until it was
assayed for alanine aminotransferase (ALT) by standard enzymatic
procedures (4).
Pathological evaluation. After 4 wk of ethanol treatment, livers were formalin fixed, embedded in paraffin, and stained with hematoxylin and eosin to assess steatosis, inflammation, and necrosis. Liver pathology was scored as described by Nanji et al. (20) as follows: steatosis (percentage of liver cells containing fat): <25% = 1+; <50% = 2+; <75% = 3+; 75% = 4+; inflammation and necrosis: 1 focus per low-power field = 1+; 2 or more foci = 2+. For the evaluation of infiltrating leukocytes, liver tissues were stained with Giemsa stain. Polymorphonuclear neutrophils (PMNs) and lymphocytes transmigrating into parenchyma were identified by morphology and were counted respectively in eight high-power fields. The number of hepatocytes was also counted in each field, and the number of leukocytes was expressed per 400 hepatocytes. Pathology was scored in a blinded manner by one of the authors and by an expert in rodent liver pathology.
Myeloperoxidase assay. Liver tissues were assayed for myeloperoxidase (MPO) activity as an index of neutrophil infiltration into the liver. The reaction mixture contained 16 mmol/l 3,3',5,5'-tetramethylbenzidine dissolved in N,N-dimethylformamide in 0.22 mol/l phosphate buffer. The reaction was initiated by the addition of 3 mmol/l hydrogen peroxide. MPO activity was assessed at 37°C by monitoring the change in absorbance at 655 nm over a 3-min period.
RNase protection assay for TNF- mRNA.
Total RNA was isolated from liver tissue using RNA STAT 60 (Tel-Test),
and RNase protection assays were performed using the RiboQuant
multiprobe assay system (Pharmingen). Briefly, with the multiprobe
template set rCK-1, [32P]RNA probes were transcribed with
T7 polymerase. RNA (10 µg) was hybridized with 4 × 105 cpm of probe overnight at 56°C. Samples were then
digested with RNase followed by proteinase K treatment,
phenol-chloroform extraction, and ethanol precipitation. Samples were
resolved on a 5% acrylamide-bisacrylamide (19:1) urea gel and
visualized by autoradiography after drying.
Statistics. ANOVA or Student's t-test was used for determination of statistical significance as appropriate. For comparison of pathological scores, the Mann-Whitney rank-sum test was used. A P value <0.05 was selected before the study as the level of significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Body weight gain and liver weight-to-body weight ratio.
Diets were initiated 1 wk after surgery to allow for complete recovery,
and all mice were healthy during the enteral feeding period. Steady
weight gains were observed during 4 wk of continuous enteral feeding of
liquid diets with or without ethanol, indicating adequate nutrition
(Table 1). Liver weight-to-body weight
ratios in wild-type mice fed ethanol (8.2 ± 0.3%) were
significantly greater than in wild-type mice fed the high-fat control
diet (4.9 ± 0.2%; Table 1). However, the ratios in the ICAM-1
knockout mice fed ethanol (6.3 ± 0.3%) were not different from
those fed the high-fat control diet (4.8 ± 0.2%) and
significantly less than in wild-type mice fed ethanol.
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Ethanol concentrations in urine.
Representative plots of daily urine alcohol concentrations in mice
given ethanol are depicted in Fig. 1. As
reported previously from this laboratory (11, 25) with the
Tsukamoto-French enteral protocol in mice, urine alcohol levels also
fluctuated in a cyclic pattern from 0 to >500 mg/dl in this study,
even though ethanol was infused continuously. Similar patterns were
observed here in wild-type and ICAM-1 knockout mice. Mean urine alcohol
concentrations over 4 wk were 228 ± 19 mg/dl in wild-type and
229 ± 24 mg/dl in ICAM-1 knockout mice (Table 1). There were no
significant differences in mean urine alcohol concentrations between
the groups studied. Furthermore, there were no differences in the
behavioral score between wild-type and ICAM-1 knockout mice fed
ethanol.
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Serum transaminase levels and pathological evaluation. Serum ALT levels were ~30 IU/l in wild-type mice fed a high-fat control diet for 4 wk; however, values were increased significantly about fourfold by enteral ethanol (Table 1). In contrast, values were blunted significantly by ~50% in ICAM-1 knockout mice fed ethanol.
Figure 2 shows representative photomicrographs of livers from wild-type and ICAM-1 knockout mice. After 4 wk of high-fat control diet, no pathological changes were observed in livers from both wild-type (Fig. 2A) and ICAM-1 knockout (Fig. 2B) mice. However, wild-type mice fed enteral ethanol for 4 wk developed severe steatosis in the pericentral to midzonal regions as well as focal inflammation and necrosis (Fig. 2C) with total pathology scores of 4.6 ± 0.6 (Table 2). In contrast, these pathological changes were significantly less in ICAM-1 knockout mice fed ethanol (Fig. 2D; total pathology score 1.9 ± 0.4). The predominant pathological change observed in this study was steatosis. Furthermore, infiltrating inflammatory cells, sinusoidal congestion (Fig. 2E), and focal necrosis (Fig. 2F) were observed in wild-type mice fed ethanol. In contrast, these pathological changes were not observed in ICAM-1 knockout mice fed ethanol (Fig. 2, G and H). A macro- or microvesicular pattern of fat accumulation was observed mainly in the pericentral to midzonal regions, except for one to three layers of hepatocytes around central veins as observed in other studies with enteral alcohol in mice (11, 25).
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Number of infiltrating neutrophils and MPO activity in liver.
After 4 wk of control diet, the number of infiltrating leukocytes
in the liver was minimal and there were no differences between wild-type and ICAM-1 knockout mice. Four weeks of enteral ethanol treatment had a tendency to increase the number of lymphocytes and
mononuclear cells in hepatic sinusoids (data not shown) and significantly increased the numbers of sinusoidal PMNs (14 + 1.1 vs. 3.8 + 0.9; P < 0.05). This increase of
infiltrating PMNs in hepatic sinusoids was blunted significantly in
ICAM-1 knockout mice fed ethanol (7.5 + 1.3; P < 0.05). Furthermore, significant increases in both lymphocytes and PMNs
transmigrating into the parenchyma were observed in wild-type mice fed
ethanol. These increases were blunted significantly in ICAM-1
knockout mice (Fig.3B). In
wild-type mice fed ethanol, these extravasated leukocytes were clustered around necrotic hepatocytes. These clusters were composed mostly of lymphocytes and included a few PMNs (Figs. 2E and
3A).
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TNF- mRNA expression in liver.
TNF- mRNA expression was increased in the liver by enteral
ethanol feeding in wild-type mice; however, this elevation was prevented in ICAM-1 knockout mice fed ethanol (Fig.
5).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Studies with knockout mice in mechanism of alcohol-induced liver
injury.
Long-term intragastric enteral feeding in the rat has recently been
adapted to the mouse (11, 25). With this protocol, it was
demonstrated that TNF- was involved in early alcohol-induced liver
injury via tumor necrosis factor receptor 1 (TNFR-1) (25). Furthermore, in studies using CYP2E1 knockout mice and
p47phox knockout (NADPH oxidase deficient) mice
(13), NADPH oxidase in the Kupffer cells, but not CYP2E1
in the parenchymal cell, was identified as the predominant source of
oxidants in the early alcohol-induced liver injury (see Fig.
6). Thus the intragastric enteral feeding
model with the knockout mouse provides a powerful new tool to study the
mechanism of alcohol-induced liver injury. However, this model is not
without its difficulties. For example, during continuous intragastric
feeding, careful observation for intoxication and nursing care were
required for maximal success, because mice did not recover from severe
alcohol intoxication as well as rats. Accordingly, animals given
ethanol were observed frequently for signs of severe alcohol
intoxication. With care, however, continuous intragastric feeding has
been successful for up to 4 mo.
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Role of TNF- and ICAM-1 in early alcohol-induced liver injury.
Chronic alcohol consumption increases gut-derived endotoxin levels in
the portal circulation, which is a key factor in alcoholic liver
disease (9, 14). Gut-derived endotoxin can activate Kupffer cells, which produces reactive oxygen species leading to
activation of redox-sensitive transcriptional factors such as nuclear
factor (NF)-
B. NF-B regulates production of inflammatory cytokines such as TNF-, which is involved in pathogenesis of early
alcohol-induced liver injury (Refs. 10, 14;
see Fig. 6). Indeed, anti-TNF- antibody diminished the number of
infiltrating neutrophils and the amount of necrosis in the liver in the
enteral model in the rat (10). Furthermore, liver injury
observed in wild-type mice was nearly completely prevented in TNFR-1
knockout mouse (25). Moreover, TNF- mRNA expression and
liver injury were blunted nearly completely in a NADPH
oxidase-deficient mouse fed alcohol (13). One important
effect of TNF- is stimulation of endothelial cells to synthesize
adhesion molecules such as ICAM-1. ICAM-1 and other adhesion molecules
expressed constitutively on the surface of endothelial cells facilitate
adhesion to CD11/CD18 integrins expressed on the surface of leukocytes,
leading to recruitment and adhesion of leukocytes into the liver
(5, 6). Thus ICAM-1 could be involved in pathogenesis of
alcoholic liver disease. Indeed, ethanol increases ICAM-1 expression on
the sinusoidal endothelial cell in the Tsukamoto-French model (9,
10). Furthermore, pathological changes observed in the liver
from wild-type mice fed enteral ethanol were prevented in ICAM-1
knockout mice (Fig. 2). Subsequently, the number of infiltrating
leukocytes and amount of the marker enzyme MPO were increased in the
liver after 4 wk of enteral alcohol feeding in wild-type mice. These
increases were blunted significantly in ICAM-1 knockout mice, as
expected (Figs. 3 and 4). Interestingly, the increase of TNF- mRNA
expression in wild-type mice caused by ethanol was blunted in ICAM-1
knockout mice (Fig. 5). The mechanism underlying this suppression of
TNF- is inexplicable without the role of infiltrating leukocytes.
One possibility is that TNF- was produced mainly by infiltrating leukocytes. Alternatively, it is also possible that chemoattractant molecules released by infiltrating leukocytes activate Kupffer cells
and endothelial cells to produce TNF-.
. It is known that TNF-
stimulates lipid synthesis in the liver (8) and causes
peripheral lipolysis that increases circulating levels of free fatty
acids (7). In this experiment, TNF- production was
blunted in ICAM-1 knockout mice fed ethanol, consistent with the
hypothesis that reduced hepatic steatosis is the result of a decrease
in production of TNF-. Furthermore, it was previously shown that
chronic enteral ethanol treatment caused hypoxia in liver tissue in
vivo (2) and it is also known that blocking ICAM-1
expression improves microcirculatory blood flow and oxygenation (23). In this study, sinusoidal congestion observed in
wild-type mice fed ethanol was undetectable in ICAM-1 knockout mice.
Thus it is also possible that improved microcirculation and oxygenation may increase fat metabolism, leading to a reduction of fat accumulation.
Conclusion.
It was clear from previous studies that Kupffer cells play an important
role in initiation of early alcohol-induced liver injury (1,
25). On the basis of recent evidence from studies using knockout
mice, it is concluded that free radicals from NADPH oxidase in the
Kupffer cell cause NF-B activation, which induces ICAM-1 expression
on the sinusoidal endothelial cell via TNF- (see Fig. 6).
Furthermore, the data presented here support the hypothesis that ICAM-1
and infiltrating leukocytes are also involved in the pathogenesis of
alcohol-induced liver injury in addition to a role for the Kupffer
cell. Thus alcohol-induced liver injury involves several organs (gut,
liver, adipose tissue) as well as several critical cell types in the
liver (Kupffer cells, endothelial cells, infiltrating leukocytes, and
the ultimate target, parenchymal cells). Obviously, progress can be
made best by studies using in vivo models in which these elements are
all present.
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ACKNOWLEDGEMENTS |
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This work was supported, in part, by grants from the National Institute on Alcohol Abuse and Alcoholism.
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. Uesugi, Laboratory of Hepatobiology and Toxicology, Dept. of Pharmacology, Univ. of North Carolina, CB#7365, 1124 Mary Ellen Jones Bldg., Chapel Hill, NC 27599-7365.
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 14 August 2000; accepted in final form 16 January 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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1, transforming growth factor-