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-dependent bilateral renal injury is induced by
unilateral renal ischemia-reperfusion
Department of Urology, Johns Hopkins University, Baltimore, Maryland 21287; and Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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While tumor necrosis factor
(TNF)-
is an important mediator of renal
ischemia-reperfusion (I/R) injury, its role in contralateral renal injury after isolated renal ischemia remains unknown. We therefore investigated the effect of isolated left renal
ischemia on the nonischemic contralateral kidney.
To study this, male Sprague-Dawley rats were anesthetized and exposed
to varying degrees of left renal I/R injury. Both kidneys were
subsequently harvested, serum samples were obtained, and TNF-
protein expression (ELISA), TNF- mRNA content (RT-PCR), TNF-
immunolocalization, and neutrophil infiltration (myeloperoxidase assay)
were determined. The effect of TNF- on neutrophil infiltration was
assessed by neutralizing TNF- with TNF binding protein (TNF-BP)
before left renal I/R injury. TNF- protein expression, TNF- mRNA
induction, and neutrophil infiltration increased significantly in both
kidneys after unilateral renal I/R injury. Furthermore, the
administration of TNF-BP before unilateral renal I/R substantially
reduced the degree of neutrophil infiltration bilaterally. These
results constitute the initial demonstration that unilateral renal I/R
induces bilateral TNF- production and neutrophil infiltration
through a TNF--dependent mechanism.
tumor necrosis factor binding protein; myeloperoxidase; neutrophil; cytokine; inflammation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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ISCHEMIA-REPERFUSION
(I/R) is a complex insult involving multiple pathophysiological
mechanisms. Calcium dyshomeostasis, oxygen free radical formation,
mitochondrial dysfunction, cytokine generation, and neutrophil
sequestration/activation have all been identified as mediators of I/R
injury (18, 19, 23, 24, 29, 33, 37). While these mediators
are clearly involved in local tissue damage after I/R, their role in
remote organ injury has been less well defined. Increasing evidence
suggests that tumor necrosis factor (TNF)-, a proinflammatory
cytokine, causes remote organ injury after localized tissue
ischemia (7, 32, 38). Hindlimb ischemia
stimulates the release of TNF- from both local and remote organ
sites (lung) and is an important mediator of neutrophil-dependent tissue damage in both the limb and the lung (32, 38).
Furthermore, TNF- production has been linked to multisystem organ
failure (MOF) after noxious stimuli such as endotoxemia and acid
aspiration pneumonia (15, 25, 36). TNF- causes diverse
physiological alterations including hypotension, myocardial depression,
hemoconcentration, metabolic acidosis, pulmonary infiltrates, acute
tubular necrosis, and death (5, 25, 35). The mechanisms by
which TNF- exerts such diffuse organ injury are multiple. TNF-
stimulates the release of other inflammatory mediators including
interleukin-1, platelet-activating factor, oxygen radicals, nitric
oxide, and prostaglandins (3, 4, 8, 21, 30). In addition,
TNF- stimulates the global activation and sequestration of
neutrophils (6, 11, 13, 28, 34).
Recently, TNF- has been established as an important mediator of
renal I/R injury (2, 10). In contrast to other organs, renal ischemia/infarction is usually managed nonoperatively,
because the only reported sequela of such management is renin-mediated hypertension (1, 9, 16). The aforementioned studies
suggest, however, that single organ ischemia can generate
remote organ injury. Furthermore, ectopic generation of TNF- may
complicate use of the contralateral kidney as a negative control after
unilateral renal ischemia (39). We therefore
evaluated the effect of unilateral renal ischemia on the
nonischemic contralateral kidney by determining both
ischemic and contralateral kidney 1) TNF- mRNA
and protein production, 2) TNF- immunolocalization,
3) neutrophil accumulation, and 4) the effect of
TNF- neutralization on neutrophil accumulation in both kidneys.
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MATERIALS AND METHODS |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Male Sprague-Dawley rats weighing 250-300 g were acclimated and maintained on a standard pellet diet for 1 wk before the initiation of experiments. Animals were anesthetized intraperitoneally with pentobarbital sodium (30 mg/kg). The animal protocol was reviewed and approved by the Animal Care and Research Committee of the University of Colorado Health Sciences Center. All animals received humane care in compliance with the National Institutes of Health's (NIH) Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, Revised 1985).
Chemicals and reagents. Recombinant human TNF binding protein (TNF-BP) was kindly supplied by Dr. Carl Edwards (Amgen; Boulder, CO). TNF-BP is expressed in Escherichia coli as the four extracellular domains of the p55 TNF receptor linked together at the Fc portion of IgG. TNF-BP was diluted in normal saline containing 0.25% human serum albumin. Negative control rats received vehicle (0.25% human serum albumin) pretreatment before I/R. Unless specifically mentioned, all other chemicals were obtained from Sigma (St. Louis, MO).
Experimental groups and operative technique.
The entire left renal pedicle (artery and vein) was isolated and
occluded with an atraumatic snare, and the abdomen was subsequently closed. Sham animals underwent identical surgical treatment, including isolation of the renal pedicle; however, occlusion of the pedicle was
not performed. In the reperfusion treatment groups, the renal pedicle
snare was removed externally without the need for abdominal reentry.
The animals were able to breathe spontaneously and were maintained
under a heat lamp throughout the duration of the experiment. After
abdominal closure, the animals were allowed to awaken spontaneously. Mean arterial pressure (MAP), oxygenation (pulse oximetry), and temperature were monitored and recorded in each animal. Upon completion of the experiment, the animals were reanesthetized, both kidneys were
removed and frozen in liquid nitrogen, serum samples were taken, and
the animals were subsequently euthanized. The samples were stored at
70°C until further testing could be performed. The animals were
divided into the following experimental groups: 1) 1-h sham
operation (negative control, n = 4); 2) 2-h
sham operation (negative control, n = 4); 3)
3-h sham operation (negative control, n = 4);
4) 5-h sham operation (negative control, n = 4); 5) 15 min of ischemia alone (n = 3); 6) 30 min of ischemia alone (n = 3); 7) 45 min of ischemia alone (n = 3); 8) 1 h of ischemia alone (n = 6); 9) 1 h of ischemia followed by 1 h
of reperfusion (n = 6); 10) 1 h of
ischemia followed by 2 h of reperfusion (n = 6); and 11) 1 h of ischemia followed by
4 h of reperfusion (n = 6). To determine the
effect of TNF- expression on neutrophil accumulation in both
kidneys, TNF- was neutralized (TNF-BP) before the animals were
exposed to 1 h of left renal ischemia and 4 h of
reperfusion (n = 6). TNF-BP (160 mg) suspended in 0.5 ml PBS was administered intravenously 30 min before injury. This dose was based on previous experiments demonstrating prevention of I/R-induced renal neutrophil accumulation and injury (10).
Tissue homogenization.
A portion of each kidney was homogenized for the TNF- ELISA assay.
Homogenization was performed after the samples had been diluted in 4 volumes of homogenate buffer [10 mM HEPES (pH 7.9), 10 mM KCl, 0.1 mM
EGTA, 1 mM dithiothreitol, and Complete Protease Inhibitor tabs
(Boehringer-Mannheim; Indianapolis, IN)] using a vertishear tissue
homogenizer. Renal homogenates were centrifuged at 3,000 g
for 15 min, supernatant total protein concentration was quantified
using the Lowry assay, and supernatants were stored at 70°C until
the TNF- ELISA assay could be performed.
TNF- protein expression.
Renal homogenate and serum TNF- protein content were determined
using ELISA. ELISA was performed by adding 100 µl of each sample to
wells in a 96-well plate of a commercially available ELISA kit (R&D
Systems). The samples were tested in duplicate. According to the
manufacturer, this ELISA is highly specific for TNF-, with a
detection limit of 15 pg/ml. TNF- ELISA was performed according to
the manufacturer's instructions. Final results were expressed as
picograms of TNF- per milligram of protein (tissue) or per
milliliter (serum).
RT-PCR.
Semiquantitative RT-PCR was used to assess renal TNF- gene
expression. Renal tissue was obtained from sham-operated controls and
both the injured and contralateral kidney after an early time course of
graded left renal ischemia and reperfusion (three samples per
time point). Total RNA was extracted from the tissue by homogenization in TRIzol (GIBCO-BRL; Gaithersburg, MD) and then isolated by
precipitation with chloroform and isopropanol. Two micrograms of the
isolated RNA were subjected to RT-PCR with reverse transcriptase using random hexaoligonucleotides as primers (Promega; Madison, WI). The
samples were incubated for 10 min at 70°C, chilled for 5 min, and,
after the addition of SuperScript II RT (Life Technologies; Gaithersburg, MD), incubated at 37°C for 1 h. PCR was performed by adding 1 µl of RT product to PCR SuperMix containing
Taq DNA polymerase (GIBCO-BRL). For each RT sample, PCR for
TNF- and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; 60 pmol
primer) were performed. Thirty picomoles of each TNF- primer
sequence (sense: 5'-TTC CTC ACT CAC ACC ATC AGC C-3'; antisense: 5'-TGC CCA GAT TCA GCA AAG TCC-3') were used, yielding a 224-bp product. The
samples were loaded in a thermocycler and run for 3 min at 94°C, 34 cycles of 94°C for 1 min, 55°C for 2 min, and then 72°C for 2 min. The samples were run for an additional 7 min at 72°C and held at
4°C until loaded onto the gel. The amplified products were separated
in a 2% agarose gel containing 1× Tris-borate-EDTA; pH 8.3. PCR
amplification products were quantified by staining the gel with
ethidium bromide and determining the density of each band using NIH
Image analysis software (version 1.62). The data are presented as the
ratio of the densitometric units of the TNF- mRNA band to the
densitometric units of the GAPDH mRNA band.
Immunolocalization of TNF-.
Immunolocalization of renal TNF- production was determined using
sections of renal tissue obtained from sham-operated animals and the
ipsilateral and contralateral kidney in animals exposed to 1 h of
left renal ischemia followed by 2 h of reperfusion (time point of maximal TNF- production). Transverse 5-µm cryosections were prepared with a cryostat (2800 Frigocut E. Reichert-Jung) and
collected on poly-L-lysine-coated slides. All sections were fixed for 10 min in 70% acetone-30% methanol at 20°C. Normal goat
serum was applied as a blocking agent, and the slides were washed in
PBS three times for 3 min. Sections were then incubated with diluted
primary antibody (rabbit anti-rat TNF- polyclonal antibody, 1:200
dilution, Genzyme; Cambridge, MA) for 1 h. The sections were
washed with PBS and incubated with Cy-3-conjugated goat anti-rabbit IgG
for 45 min. After a wash with PBS, the nuclei were stained with
bis-benzimide (10 µg/ml in PBS) for 30 s, and the slides were
washed with PBS three times for 2 min. Cell membranes were
counterstained with Oregon green 488-labeled wheat germ agglutinin (1:100 dilution, Molecular Probes) for 30 min and washed with PBS three
times. The slides were mounted with a glycerol-based antiquenching
agent, o-phenylene diamine-d:HCl, and stored at 4°C. The
specificity of the TNF- antibody was assessed by incubating adjacent
sections from each experimental group with goat anti-rat TNF-
antibody before incubation with the secondary antibody and confirming
elimination of the TNF- signal. To test for nonspecific fluorescence, adjacent sections from each experimental group were incubated with nonimmune purified rabbit IgG instead of the primary antibody. Nonspecific fluorescence was digitally subtracted, and the
sections were photographed with a confocal microscope.
Renal tissue myeloperoxidase.
Myeloperoxidase (MPO) is an enzyme specific for neutrophils and is an
accepted index of neutrophil accumulation. Renal samples were obtained
from sham-operated animals and the injured and contralateral kidney in
animals undergoing 1 h of left renal ischemia, followed by
4 h of reperfusion (with or without pretreatment with TNF-BP). The
tissue was homogenized for 30 s in 4 ml of 20 mM potassium phosphate buffer; pH 7.4. The samples were centrifuged for 30 min at
40,000 g at 4°C (Beckman L-80 ultracentrifuge, Beckman Instruments; Palo Alto, CA). The supernatant was discarded, and the
pellet was resuspended in 4 ml of 50 mM potassium phosphate buffer (pH
6.0) with 0.5 g/dl cetrimonium bromide. The samples were then sonicated
for 90 s (ultrasonic homogenizer, Cole-Parmer Instruments;
Chicago, IL) and incubated for 2 h at 60°C. Homogenates were
centrifuged at 14,000 g for 10 min. The supernatant was
decanted, and 25 µl were added to 725 µl of 50 mM phosphate buffer
(pH 6.0) containing 0.167 mg/ml o-dianisidine and 5 × 10
4% hydrogen peroxide. The change in absorbance was
measured spectrophotometrically (Beckman DU7 spectrophotometer, Beckman
Instruments; Irvine, CA) at 460 nm. One unit of MPO activity was
defined as the quantity of enzyme degrading 1 µmol of peroxide per
minute at 25°C.
Statistical analysis. Data are presented as mean values ± SE. Differences at the 95% confidence level were considered significant. The experimental groups were compared using ANOVA with a post hoc Bonferroni-Dunn test (StatView 4.0).
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RESULTS |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Vital parameters.
The vital parameters collected and recorded during each experiment are
listed in Table 1. In all treatment
groups, MAP remained above 60 mmHg, oxygen saturation remained above
93%, and core temperature remained above 36°C.
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Time course of bilateral renal TNF- production after renal
ischemia and reperfusion.
The time course of bilateral renal TNF- production after varying
lengths of unilateral renal ischemia and reperfusion is shown
in Fig. 1. The values are represented as
picograms of TNF- per milligram of protein. Sham-treated animals
demonstrated low levels of TNF- expression (20.6 ± 1.3, 22.5 ± 0.87, 22.8 ± 1.7, and 18 ± 0.9 pg TNF-/mg
protein for 1-, 2-, 3-, and 5-h shams, respectively). At 1 h of
isolated ischemia, TNF- production increased in both the
ipsilateral and contralateral kidney compared with the 1-h sham
(26.3 ± 1.5 pg TNF-/mg protein, P < 0.05 vs.
sham, and 30.3 ± 3.3 pg TNF-/mg protein, P < 0.05 vs. sham, respectively). TNF- expression increased further in
both kidneys after 1 h of ischemia and 1 h of
reperfusion [33 ± 3.3 pg TNF-/mg protein, P < 0.05 vs. 2-h sham (ipsilateral), and 37 ± 3.6 pg TNF-/mg protein, P < 0.05 vs. 2-h sham (contralateral)], and
TNF- expression peaked in both kidneys after 1 h of
ischemia and 2 h of reperfusion [37 ± 5 pg
TNF-/mg protein, P < 0.05 vs. 3-h sham
(ipsilateral), and 39 ± 3 TNF- pg/mg protein,
P < 0.05 vs. 3-h sham (contralateral)]. After 4 h of reperfusion, TNF- levels decreased toward baseline in both
kidneys [20 ± 2.7 (ipsilateral) and 25 ± 2.0 pg TNF-/mg protein, P < 0.05 vs. 5-h sham (contralateral)].
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Time course of serum TNF- protein expression.
The time course of serum TNF- protein expression after varying
lengths of unilateral renal I/R injury is shown in Fig.
2. The values are represented as
picograms of TNF- per milliliter serum. Sham-treated animals
demonstrated low serum levels of TNF- (2.8 ± 2.8, 0 ± 0, 0 ± 0, and 0 ± 0 pg TNF-/ml serum for 1-, 2-, 3-, and
5-h shams, respectively) as did animals exposed to 1 h of isolated
left renal ischemia (0.2 ± 0.2 pg TNF-/ml serum), 1 h of left renal ischemia followed by 2 h of
reperfusion (0 ± 0 pg TNF-/ml serum), and 1 h of left
renal ischemia followed by 4 h of reperfusion (3.6 ± 3.6 pg TNF-/ml serum). In contrast, serum TNF- levels increased
significantly after 1 h of left renal ischemia and 1 h of reperfusion (56 ± 20 pg TNF-/ml serum, P < 0.05 vs. sham).
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Time course of bilateral renal TNF- mRNA induction after
ipsilateral renal ischemia.
Tissue samples from both kidneys were obtained after an early time
course of graded left renal ischemia. Sham-operated animals did
not demonstrate any TNF- mRNA induction (Fig.
3, A and B). TNF- mRNA increased significantly in both the normal contralateral and injured kidney after 30 min of isolated left renal
ischemia. Densitometric analysis of TNF- mRNA expression as
a percentage of GAPDH mRNA is shown in Fig. 3B. After 15 min
of ischemia, the TNF- mRNA expressed represented 55 ± 27% and 104 ± 42% of GAPDH mRNA in the ipsilateral and
contralateral kidney, respectively. After 30 min of ischemia,
the TNF- mRNA expressed represented 119 ± 12% and 120 ± 30% of GAPDH mRNA in the ipsilateral (P < 0.05 vs.
sham) and contralateral kidney (P < 0.05 vs. sham),
respectively. TNF- mRNA expression was not significantly increased
over the sham in either kidney after 45 min [44 ± 8.6% of GAPDH
mRNA (ipsilateral) and 41 ± 4.1% of GAPDH mRNA (contralateral)]
or 1 h [46 ± 21% of GAPDH mRNA (ipsilateral) and 48 ± 22% of GAPDH mRNA (contralateral)] of ipsilateral
ischemia.
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Immunolocalization of renal TNF- production.
Renal samples were obtained from sham-operated animals and the
ipsilateral and contralateral kidney in animals exposed to 1 h of
ipsilateral ischemia followed by 2 h of reperfusion.
Sections of each renal sample were stained for TNF- using
immunohistochemical techniques to determine the cellular localization
of TNF- production in each treatment group. Only trace amounts of
TNF- were detected in samples obtained from sham-operated animals
(Fig. 4A). In contrast, easily visible TNF- (red stain) was present in both the
ipsilateral and contralateral kidney after left renal I/R injury (Fig.
4, B and C). TNF- production localized
primarily to renal tubular cells in the injured kidney after I/R. The
nonischemic contralateral kidney exhibited TNF- staining in
both tubular and glomerular cells.
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Renal tissue neutrophil accumulation.
The MPO assay was performed on renal samples obtained from
sham-operated animals and animals exposed to 1 h of left renal ischemia followed by 4 h of reperfusion. Animals
undergoing renal I/R were treated with either vehicle or TNF-BP 30 min
before injury. MPO levels were elevated in both kidneys (Fig.
5) after left I/R (23 ± 3 U/g in
ipsilateral vs. 4 ± 1.4 U/g in sham, P < 0.05; 17 ± 1.5 U/g in contralateral vs. 3 ± 1 U/g in sham,
P < 0.05). As expected, MPO levels were higher in the
ischemic kidney than the nonischemic contralateral
kidney. Interestingly, pretreatment with TNF-BP decreased
(P < 0.05 vs. sham) the MPO levels in both kidneys
(11 ± 2 U/g in ipsilateral and 9 ± 1.7 U/g in
contralateral) to a similar degree.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study constitutes the initial demonstration that unilateral
renal ischemia induces bilateral renal TNF- production and TNF--dependent neutrophil infiltration. We (10) have
previously shown that TNF- is an important mediator of renal I/R
injury and demonstrated that TNF- induces neutrophil sequestration
and renal dysfunction after I/R. TNF- produced in response to
ischemia causes local cellular injury through a variety of
mechanisms. In addition to recruiting and activating various cells
within the immune system, TNF- is a proinflammatory agent that
stimulates the production of other inflammatory mediators. Furthermore,
TNF- is directly cytotoxic to many cells (3, 4, 6, 8, 11, 13,
21, 28, 30, 34). While TNF- is clearly an important mediator
of local I/R injury, its role in remote organ damage after isolated
ischemia is just beginning to be elucidated. Investigators have
demonstrated TNF- production from remote sites (lung) after I/R and
linked TNF- production to neutrophil-mediated pulmonary injury
(32, 38). Indeed, TNF- production may contribute to the
occasional development of adult respiratory distress syndrome and
multiorgan injury after single organ ischemia and reperfusion.
Clinically, renal ischemia/infarction is managed with
observation. Several studies (1, 9, 17) have demonstrated
that conservative management of this condition is apparently safe
and not associated with life-threatening complications. In
light of mounting evidence implicating TNF- production after single
organ I/R in remote organ damage, we investigated the effect of
unilateral renal ischemia on the nonischemic
contralateral kidney. Our results indicate that 1 h of unilateral
renal ischemia induces TNF- production in both the
ipsilateral (injured) and nonischemic contralateral kidney
after 0, 1, or 2 h of reperfusion. After 4 h of reperfusion, TNF- levels decline toward baseline in both the ipsilateral and contralateral kidney. Serum levels of TNF- reflect tissue levels, with peak serum TNF- expression occurring after 1 h of left
renal ischemia and 1 h of reperfusion. Given these
observations, RT-PCR was performed on renal samples to confirm that the
observed elevation in contralateral kidney TNF- was due to cellular
production of, and not circulating, TNF-. TNF- mRNA induction
occurred in both the normal contralateral and injured kidney after 30 min of isolated left renal ischemia but became undetectable
after 45 min or 1 h of isolated left renal ischemia.
Interestingly, contralateral TNF- mRNA induction occurred before
reperfusion of the ischemic ipsilateral kidney. This pattern of
mRNA induction supports the observed time course of TNF- protein
expression and suggests that contralateral renal TNF- production
during isolated ipsilateral renal ischemia may represent, in
part, a "stress" phenomenon.
To provide further evidence of TNF- production and to localize the
intrarenal source of TNF- in the contralateral kidney, immunohistochemistry was performed. Indeed, we detected intracellular TNF- in both the ipsilateral and contralateral kidney.
Interestingly, the pattern of TNF- production differed between the
two kidneys. In the nonischemic kidney, TNF- production was
more uniformly distributed between glomerular and tubular cells. In
contrast, the ischemic kidney exhibited a predominance of
tubular cell TNF- production. The increased glomerular cell
production of TNF- in the contralateral kidney may indicate that
circulating factors are an important source of remote cellular injury.
In contrast, the predominance of tubular cell TNF- production in the
ipsilateral kidney may reflect the well-recognized sensitivity of these
cells to ischemic injury (14, 20, 31). The
pathophysiology and clinical implications of these findings are not
entirely clear. It has been well established that reperfusion of
ischemic tissue leads to the production of reactive oxygen
species and cytokines, such as TNF-. These factors may circulate to
remote sites, including the contralateral kidney, and induce further
cytokine production and inflammation. Interestingly, our results
demonstrate that the contralateral kidney is affected before
reperfusion of the ischemic kidney, suggesting that some other
mechanism of injury (i.e., stress) is also involved.
The MPO assay was used to assess the neutrophil response of both
kidneys to unilateral renal I/R. An increase in neutrophil accumulation
was detected in both kidneys after 1 h of ischemia and
4 h of reperfusion. While the measured inflammatory response was
somewhat less in the nonischemic contralateral kidney than in
the injured kidney, the observed increase in neutrophil infiltration demonstrates that the contralateral kidney suffers a biologically significant injury after ipsilateral renal I/R. Furthermore, deletion of the TNF- signal by administration of TNF-BP diminished the inflammatory response in both kidneys to a similar degree. While the
observed inhibition of neutrophil accumulation may be partially related
to indirect effects of TNF-BP, our data demonstrate that the reduction
in neutrophil accumulation is a direct result of specific TNF-
bioactivity inhibition by TNF-BP (10). This finding supports our previous observations (10) and suggests that
TNF- is an important mediator of neutrophil-induced remote organ
injury after unilateral renal I/R.
These results also support much of the current investigative work in MOF. Recently, a "two hit" model of inflammatory injury has been proposed in the pathophysiology of MOF (22, 27). This paradigm is based on observations that neutrophils become "primed" after an initial noxious stimulus (i.e., trauma, ischemia, or sepsis) such that their response to a subsequent insult is altered (12, 19, 26, 27). In this manner, neutrophils may become sequestered and primed in remote organs after unilateral renal ischemia; however, they are not activated (releasing oxygen radicals and proteases and causing tissue damage) until they have received a second, sometimes seemingly insignificant, insult.
The current literature implies that unilateral renal ischemia/infarction is a benign condition, which may safely be ignored therapeutically. We have demonstrated, however, that ipsilateral renal I/R causes inflammatory injury to the contralateral kidney and possibly to other remote organs. The degree of injury to the contralateral kidney may be insufficient to cause detectable functional impairment; nevertheless, it may make the contralateral kidney susceptible to further injury during states of additional physiological stress.
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ACKNOWLEDGEMENTS |
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The authors thank Alex Poole and Leonid Reznikov for technical instruction and to Dr. Carl Edwards for providing the TNF-BP.
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FOOTNOTES |
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This research was supported in part by National Institute of General Medical Sciences Grants GM-08135 and GM-49222 (to A. H. Harken).
Address for reprint requests and other correspondence: K. K. Meldrum, Johns Hopkins Hosp., Marburg Bldg., Rm. 414, 600 N. Wolfe St., Baltimore, MD 21287 (E-mail: kkmeldrum{at}earthlink.net).
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/ajpheart.00072.2001
Received 6 February 2001; accepted in final form 11 October 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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