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Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia e
*
Dipartimento di Discipline Chirurgiche, Rianimatorie e dei Trapianti, University of Bologna, 40138 Bologna, Italy and
Dipartimento di Medicina Interna e Pubblica University of Bari, 70124 Bari, Italy
2To whom correspondence should be addressed. E-mail: caraceni{at}med.unibo.it.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • food deprivation • mitochondria • ischemia-reperfusion injury • oxidative stress • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Mitochondria play a central role in the cellular metabolism; they are
responsible for cellular respiration coupled to the generation of ATP
from ADP and inorganic phosphate. Maintenance of this capacity is
essential for recovering cell function during postischemic
reperfusion (1
,2)
. However, mitochondria are also a target
of ischemia-reperfusion injury, and their dysfunction, in turn,
becomes an important pathogenic factor (3)
.
Many studies indicate that mitochondria are a main intracellular source
of reactive oxygen species
(ROS)3
(4
,5)
. Under physiologic conditions, 
1–4% of oxygen
reacting with the mitochondrial respiratory chain is incompletely
reduced to superoxide anion and, consequently, hydrogen peroxide
(5)
. Mitochondrial ROS generation dramatically increases
during reperfusion because the electrons released by the respiratory
chain can be donated directly to the newly supplied oxygen
(4
,6)
. Due to their location and activity, mitochondrial
structures are exposed to the attack by ROS generated both outside and
within the mitochondria. Oxidative damage includes lipid peroxidation,
protein oxidation, mutation of mitochondrial DNA, and can induce the
mitochondrial transition permeability, which ultimately results in the
loss of mitochondrial integrity and function (4)
.
To counteract the deleterious effects of ROS, mitochondria contain a
small number of antioxidant systems, represented mainly by reduced
glutathione (GSH) (7
8
9)
. Thus, conditions that lower the
mitochondrial content of GSH may increase the oxidative injury
associated with ischemia-reperfusion. Food deprivation is
associated with a striking depletion of antioxidant systems in the
whole liver tissue. Starvation reduces GSH concentration up to 50% in
liver tissue of adult rodents due to the utilization of the hepatic and
intestinal GSH stores as cysteine reservoirs during food deprivation
(10
11
12)
. By using the perfused rat liver model,
(13)
recently showed that food deprivation augments lipid
peroxidation in the whole tissue during postischemic reperfusion.
However, the relationship between starvation and mitochondrial
oxidative balance has not been investigated.
Thus, the aim of this study was to determine the oxidative damage to lipids and proteins and the alteration of the GSH content that occur during normothermic ischemia-reperfusion in mitochondria isolated from livers of fed and food-deprived rats.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Male Wistar rats (Charles-River, Calco, LC, Italy) were allowed to
acclimate to the animal quarters and were given free access to a
nonpurified diet (Laboratorio Dott. Piccioni, Milano, Italy) and water
for 1 wk. The diet composition is shown in Table 1
. Before killing, the rat weights ranged from 230 to 260 g. All
procedures involving rats were conducted according to the guidelines
for the care and use of laboratory animals approved by our Institution.
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The day before the experiment, the rats were divided into groups as follows: rats with free access to food and water until the time of surgery (fed group); rats with access only to water for the 18 h before surgery (18-h food-deprived group); and rats with access only to water for the 36 h before surgery (36-h food-deprived group).
Lobar liver ischemia-reperfusion followed by a partial hepatectomy
of the noninvolved liver was performed in all rats using a modification
of the technique described by Kawano et al. (14)
. Briefly,
in rats under light enflurane anesthesia, the abdomen was opened
through a midline incision and the left hepatic artery and portal vein
were occluded with a nontraumatic microvascular clip inducing ischemia
of the left lateral and median lobes (70% of the total liver
volume). After 1 h, the microvascular clip was removed and the
hepatectomy of the nonischemic right lateral and caudate lobes was
performed. The abdomen was closed and the rats allowed to recover. This
model of partial hepatic ischemia-reperfusion injury avoids
splanchnic congestion and thus any confounding effects resulting from
bowel ischemia and hemodynamic disturbances. Moreover, resection of the
noninvolved portion forces the animal to survive only on the liver
lobes subjected to the ischemia-reperfusion insult as occurs in the
case of liver transplantation (15)
.
The rats were divided in groups of 5 and killed under general anesthesia before ischemia (baseline), after 60 min of ischemia, and 30 min and 2 h after reperfusion. Liver samples were collected and prepared for mitochondria isolation and ultrastructural analyses.
Serum alanine transaminase (ALT).
Blood (1 mL) was collected in anesthetized rats from the inferior vena cava at the time of killing and the serum stored at -80°C. ALT was assayed spectrophotometrically with a commercially available kit test (Infinity AST and ALT Reagents, Sigma-Aldrich, Milan, Italy).
Mitochondria isolation.
Mitochondria were isolated according to the procedure described by
Hoppel et al. (16)
. Briefly, 5 g of liver were
homogenized in 40 volumes of MSM (mannitol 0.44 mol/L, saccharose 0.07
mol/L, MOPS 5 mmol/L) buffer, pH 7.4, containing 0.1 mol/L
Na2-EDTA. The homogenate was subjected to several
centrifugation steps. Liver homogenate and mitochondrial fractions were
assayed for lactate dehydrogenase. The recovery of lactate
dehydrogenase in the mitochondrial pellet ranged from 0.27 to 0.29%.
Mitochondrial thiobarbituric reactive substances (TBARS).
Mitochondrial TBARS were determined with the thiobarbituric acid
reaction as described previously (18)
. Liver (100 mg)
was homogenized in 5 volumes of 180 mmol/L KCl, 50 mmol/L TrisHCl and
10 mmol/L EDTA (pH 7.4) containing 0.2 g/L BHT. The homogenate was then
precipitated with 10g/L trichloroacetic acid (TCA) and the supernatant
was incubated at 100°C for 45 min with an equal volume of 6.7 g/L
thiobarbituric acid. After cooling, the supernatant was extracted with
1 mL n-butanol and the absorption peak was measured at
532 nm.
Mitochondrial protein carbonyls (PC).
Aliquots of mitochondria (2 mg protein) were incubated for 1 h
at room temperature with 1 mL of 2 g/L dinitrophenylhydrazine (DNPH) in
2 mol/L HCl or 1 mL of 2 mol/L HCl as the control blank. Proteins were
precipitated with 200 µL of 500 g/L TCA and washed
three times with 1:1 (wt/v) ethanol/ethylacetate and three times with
100 g/L TCA. The final precipitate was solved in 6 mol/L guanidine and
the spectrum of the DNPH vs. HCl controls was followed at 350–375 nm
(18)
. The concentration of carbonyl groups was then
calculated using 21.5
(mmol/L)-1 · cm-1
as the extinction coefficient for aliphatic hydrazones.
Mitochondrial GSH.
Mitochondria (1 g protein/L) were suspended in 0.1 mol/L potassium
phosphate buffer (pH 7.4) containing 5 mmol/L EDTA, precipitated with
40g/L sulfosalicylic acid and centrifuged at 700 g for 10
min. The supernatant was analyzed for GSH by the enzymatic
method of Tietze (19)
.
Mitochondrial total proteins.
Total protein concentration in liver mitochondria was determined by the
method of Lowry et al. (20)
. The concentration of protein
in guanidine-solved samples was determined using a Bio-Rad kit
for protein assay (Bio-Rad, Munich, Germany).
Transmission electron microscopy (TEM).
A block of liver tissue, 1 mm thick, was cut from the center of each
lobe and diced into 1-mm cubes. All of the samples for TEM analysis
were fixed initially in 0.25 g/L cacodylate-buffered
glutaraldehyde, then postfixed with 0.1 g/L OsO4,
dehydrated in a graded series of alcohols and embedded in araldite.
Thin sections were obtained with a Reichert Omu 3 ultramicrotome (C
Reichert, Wien, Austria), counterstained with uranyl acetate and lead
citrate and examined using a Philips 400T transmission electron
microscope (Philips, Eindhoven, The Netherlands).
Statistical analysis.
Oxidative variables were normally distributed as assessed by the
Kolmogorov-Smirnov test (21)
. To avoid multiple
comparisons and to obtain significance levels adjusted for the various
factors, two-way ANOVA (22)
with differential contrast
was applied, taking into account the rat’s nutritional status (fed,
18-h and 36-h food-deprived), and the different experimental times
(baseline, the end of ischemia and the time points after reperfusion).
This statistical method allows the estimation of the injury associated
with any interval of the food deprivation. Data are reported as means
± SEM. Statistical analysis was performed by using
the (23)
SPSS for Windows 8.0 package on a personal
computer and a two-tailed P-level equal to 0.05 was
chosen to assign significant difference.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although the serum ALT levels under basal conditions and after ischemia
did not differ between fed and food-deprived rats, significant
differences were observed during reperfusion (Fig. 1
). In fed rats, the ALT level reached a peak value after 30 min and
declined thereafter to 1138 ± 59 U/L at 120 min. In
both the food-deprived groups, the ALT release increased
progressively until the end of reperfusion. At 120 min, serum ALT was
significantly greater in 18-h food-deprived than fed rats (3872
± 400 vs. 1138 ± 59 U/L, P < 0.01). When the time of food deprivation was prolonged to 36 h,
serum ALT reached higher levels than in the other groups (after 120
min: 5438 ± 504 U/L, P < 0.01).
|
Under basal conditions and at the end of ischemia, the TBARS
concentration was significantly greater in mitochondria isolated from
food-deprived than fed rats (Fig. 2
). With reperfusion, TBARS levels increased significantly above the
preischemic values in all groups. However, after 30 min of reperfusion,
food deprivation, regardless of length, was associated with
significantly greater levels of TBARS compared with fed rats. In the
later phase of reperfusion (120 min), a significant difference was
present only between fed and 36-h food-deprived rats.
|
Baseline mitochondrial PC concentration was greater than that of fed
rats (1.40 ± 0.09 nmol/mg protein) only in 36-h food-deprived
rats (1.78 ± 0.07 nmol/mg protein, P < 0.05;
Fig. 3
). Groups did not differ at the end of the ischemic period. After the
restoration of the blood flow, a significant increase in the PC
concentration was observed in all groups, indicating the occurrence of
oxidative damage to the mitochondrial proteins. Again, 36 h of
starvation was associated with a significantly greater PC level than in
controls. After 120 min of reperfusion, the mitochondrial PC
concentration was 3.34 ± 0.11 nmol/mg protein in fed rats, 3.60
± 0.11 nmol/mg protein in 18-h food-deprived rats, and 4.56
± 0.17 nmol/mg protein (P < 0.05) in 36-h
food-deprived rats.
|
Mitochondrial GSH of 18-h food-deprived rats was significantly
lower than that of fed rats under basal conditions (6.54 ± 0.24
vs. 7.64 ± 0.15 nmol/mg protein, P < 0.05), at
the end of ischemia (6.02 ± 0.08 vs. 7.46 ± 0.11 nmol/mg
protein, P < 0.05) and in the early phase of
reperfusion (4.84 ± 0.20 vs. 6.10 ± 0.17 nmol/mg protein,
P < 0.05; Fig. 4
). In rats deprived of food for 36 h, the mitochondrial GSH
concentration was lower than that in 18-h food-deprived rats and
controls (P < 0.05) throughout the experiment.
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The electron microscopic examination of livers from both fed and food-deprived rats in the preischemic conditions showed the regular ultrastructure of the hepatocytes and sinusoidal cells. At the end of ischemia, the majority of hepatocytes had a preserved ultrastructure, whereas others presented swollen and rounded mitochondria and cytoplasmic vacuolization in all groups. The number of hepatocytes presenting ultrastructural alterations were higher in food-deprived rats.
In the fed group, although the restoration of the blood flow enhanced
the ultrastructural changes in few areas, the majority of hepatocytes
maintained a regular ultrastructure (Fig. 5A
). In contrast, in the food-deprived groups, the most prominent
finding was damaged mitochondria, which appeared swollen and rounded,
with a partial loss of the cristae and a normal electron density of the
matrix. Some sinusoids were plugged with thrombi formed by aggregates
of platelets, which appeared to be attached to the subsinusoidal
structures. Although the degree of damage varied within the liver and
areas with preserved cell ultrastructure could be found, the
alterations described above were more diffuse in rats deprived of food
for 36 h (Fig. 5B
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Finally, potential
liver donors staying in intensive care units for prolonged periods may
not have received adequate nutritional support before liver
explantation (25
,26)
.
Nutritional status is an important determinant of the extent of
ischemia-reperfusion injury in the liver. Livers in the
postprandial state are more resistant to the warm ischemic insult
because hepatocytes can use their large glycogen stores to supply
substrates for ATP production by anaerobic glycolysis (3)
.
However, recent evidence indicates that good nutritional status may
also protect against ischemia-reperfusion injury by reducing the
oxidative stress occurring during this type of injury
(27)
.
The novel finding of this experimental study is that exacerbation of the hepatic warm ischemia-reperfusion injury induced by food deprivation is associated with greater mitochondrial oxidative damage. Moreover, the extent of the oxidative stress increases with the prolongation of the period of food deprivation.
An imbalance between the free radical attack and mitochondrial
scavenging capacity was already present under baseline conditions in
food-deprived rats. GSH is considered the principal functional
mitochondrial antioxidant (7)
. Its depletion markedly
enhances the sensitivity to mitochondrial dysfunction caused by
oxidative stress and induces degeneration of the mitochondrial
structure (7
,29)
. This study demonstrated that nutritional
status significantly affects mitochondrial GSH concentration, which
decreased progressively after 18 and 36 h of starvation. This
finding can explain the concomitant rise of the mitochondrial
preischemic level of TBARS, a marker of lipid peroxidation. The
protective role of GSH is clearly demonstrated by the exacerbation of
lipid peroxidation in liver tissue promoted by GSH-depleting
substances (28
29
30)
. In contrast, the
mitochondrial content of PC increased to a significant level only after
36 h of food deprivation, suggesting that the mitochondrial
proteins may be more resistant than lipids to the oxidative stress
related to food deprivation.
We also showed that the ischemia-reperfusion procedure leads to
oxidative injury in mitochondria isolated from both fed and
food-deprived rats. The mitochondrial GSH concentration fell in the
early phase of reperfusion, declining more slowly thereafter in all
groups. However, because the GSH levels of food-deprived rats were
already reduced under baseline conditions, the depletion of this
antioxidant at the end of the experimental procedure was very marked,
especially in rats deprived of food for 36 h. The depletion of
mitochondrial GSH likely reflects consumption by ROS generated during
the reperfusion phase. The newly formed oxidized glutathione (GSSG) can
represent a more specific marker of oxidant stress. However, because
GSSG is very rapidly reduced in mitochondria (31)
, its
concentration may not reflect the exact rate of GSH oxidation in these
organelles and it was not measured in this study. Another mechanism
implicated in the mitochondrial GSH reduction may be its impaired
uptake from the cytosol due to the poor availability of ATP after the
ischemic period (3)
. Indeed, ATP is required for the
function of the system that actively imports GSH from cytosol
(7)
. Thus, the impairment of the ATP metabolism, which is
worsened by starvation (32)
, may contribute to the
lowering of mitochondrial GSH level observed in the early reperfusion
phase.
Likely due to the greater imbalance between oxidants and antioxidants,
the expected rise of TBARS during reperfusion was significantly greater
in food-deprived than fed rats. Mitochondrial TBARS increased
sharply in food-deprived rats, peaking after 30 min of reperfusion.
Thereafter, contrary to fed rats, the TBARS content declined slightly,
so that the difference between the two groups was less evident.
However, the much greater extent of lipid peroxidation observed in the
early phase of reperfusion likely has important biological consequences
because the rapid recovery of mitochondrial energy metabolism is
essential to sustain cell function and life after the restoration of
the blood flow (2
,28)
. Protein damage from oxidative
stress may occur either directly or as a result of lipid peroxidation
(33)
. This study demonstrated that the sensitivity of
mitochondrial proteins to oxidative stress during postischemic
reperfusion is also affected by the nutritional status, although to a
lesser extent compared with lipids, because the increase in PC groups
after restoration of the blood flow was significantly greater only in
rats deprived of food for 36 h than that in rats with free access
to food.
The mitochondrial swelling and the ultrastructural alterations observed
by electron microscopy in food-deprived rats during postischemic
reperfusion represent indirect evidence of membrane injury and
dysfunction. Whether these alterations are causally related to the
greater oxidative imbalance was not investigated directly in this
study. However, it is reasonable that oxidative stress contributes to
mitochondrial injury. Indeed, GSH depletion induces mitochondrial
dysfunction and structural degeneration (7
,29)
. Lipid
peroxidation can be particularly harmful to mitochondria by altering
the phospholipid bilayer with loss of the normal membrane fluidity and
permeability, which can lead to mitochondrial swelling and uncoupling
(4
,34)
. Lipid hydroperoxides and their breakdown products,
such as aldehydes, are involved in damage to specific mitochondrial
proteins and transport systems either by direct inhibition of enzymes
or by forming covalent adducts with low molecular thiols and protein
sulfydryls (4)
. Moreover, the oxidation of sulfydryl
groups likely contributes to the deactivation and degradation of
mitochondrial enzymes and transport proteins (35
36
37)
.
The release of transaminases after the restoration of blood flow was
significantly greater in food-deprived than fed rats, confirming
the common finding that starvation enhances the liver damage induced by
warm reperfusion injury (38)
. This study suggests a
possible link between mitochondrial oxidative alterations and the
exacerbation of reperfusion injury associated with food deprivation.
Interestingly, the temporal relationship between ROS-mediated
mitochondrial injury and liver damage was closer in food-deprived
than fed rats. Indeed, contrary to fed rats, the peak in serum
transaminases in food-deprived rats followed rather than preceded
the occurrence of significant oxidative injury.
In conclusion, this study indicates that liver mitochondria isolated from food-deprived rats have increased ROS-mediated injury due to warm ischemia-reperfusion compared with mitochondria isolated from fed rats. The severity of the oxidative injury increased with the length of the period of food deprivation. Mitochondrial damage resulting from oxidative stress can contribute to the exacerbation of ischemia-reperfusion injury induced by food deprivation. Finally, these data provide the basis for further studies investigating whether artificial nutritional support, which includes an adequate content of antioxidant substances, can be used effectively to protect the liver in the clinical conditions implying a temporary liver ischemia and reperfusion.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ALT, alanine transaminase;
DNPH, dinitrophenylhydrazine; GSH, reduced glutathione; GSSG,
oxidized glutathione; PC, protein carbonyls; ROS, reactive oxygen
species; TBARS, thiobarbituric reactive substances; TCA,
trichloroacetic acid; TEM, transmission electron microscopy.
Manuscript received April 19, 2000. Initial review completed June 27, 2000. Revision accepted September 27, 2000.
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