(Circulation. 2000;101:1019.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Crucial Role of Endogenous Interleukin-10 Production in Myocardial Ischemia/Reperfusion Injury
From the Children’s Hospital Medical Center (Z.Y., B.Z., C.S.), Division of Critical Care, Cincinnati, Ohio; and Inotek Corporation (C.S.), Beverly, Mass.
Correspondence to Csaba Szabó, MD, PhD, Inotek Corporation, Suite 419 E, 100 Cummings Center, Beverly, MA 01915. E-mail szabocsaba{at}aol.com
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Abstract |
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Background—The anti-inflammatory cytokine interleukin-10 (IL-10) has been detected in the plasma of patients with myocardial ischemia/reperfusion. The aim of our study was to investigate the role of endogenously produced IL-10 in myocardial ischemia/reperfusion.
Methods and Results—In the present study, we used wild-type
and IL-10–deficient mice subjected to myocardial
ischemia/reperfusion. Significant levels of IL-10 were produced
in wild-type mice at 2 to 6 hours after myocardial reperfusion. The
genetic deletion of IL-10 enhanced neutrophil infiltration into the
reperfused tissues at 6 hours after reperfusion and increased infarct
size and myocardial necrosis. Furthermore, in the absence of IL-10, an
enhancement of the inflammatory response was seen, as demonstrated by
increased plasma levels of tumor necrosis factor-
, nitrite/nitrate
(breakdown products of NO), and increased tissue expression of
intercellular adhesion molecule-1. Reperfusion for 24 hours was
associated with a 75% mortality rate in IL-10–deficient mice, whereas
no deaths occurred in the wild-type animals.
Conclusions—The present findings provide the first direct
evidence that endogenous IL-10 inhibits the
production of tumor necrosis factor- and NO and serves to
protect the ischemic and reperfused myocardium
through the suppression of neutrophil recruitment.
Key Words: reperfusion • interleukins • nitric oxide • cell adhesion molecules
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The prominent anti-inflammatory cytokine interleukin-10 (IL-10) is released into the plasma of patients with myocardial ischemia/reperfusion.1 2 3 4 The production of IL-10 in many forms of shock and inflammation serves to limit the burst of proinflammatory mediators.5 6 7 8 9 With the use of IL-10–deficient mice, here we defined the role of endogenous IL-10 in the modulation of myocardial ischemia/reperfusion injury.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Myocardial Ischemia/Reperfusion
The present investigation conforms with the "Guide for the Care and Use of Laboratory Animals" published by National Institutes of Health and was performed with the approval of the Institutional Animal Care and Use Committee. Male C57BL/6 IL-10 wild-type (IL-10 WT) and C57BL/6 IL-10 knockout mice (4 weeks old) were obtained from Jackson Laboratories. These mice were originally generated by Kuhn and colleagues,10 as previously described. The mice used in the present study have been back-crossed for 10 generations to C57/BL6 mice for 10 generations at Jackson Laboratories. By definition, these mice are considered congenic, with >99.8% of the genome belonging to BL6 strain, and the only genetic region derived from the other strain is the region immediately surrounding the IL-10 gene; therefore, the difference between the two experimental groups is due to the presence or absence of the functional IL-10 gene and not to other factors. Animals received food and water on an ad libitum basis, and lighting was maintained on a 12-hour cycle.
After premedication with 0.04 mg/kg atropine sulfate IM, animals were anesthetized with 100 mg/kg sodium pentobarbital IP. The animals were placed in a supine position with their paws and tails taped to the operating table. The head was retracted with a thin rubber band fasten to the upper incisors. The upper portion of the trachea was exposed through a middle incision in the neck, and the pretracheal muscles were bluntly dissected. A black-tipped endotracheal tube, made with PE-60 tubing, was inserted by way of the mouth into the trachea with the black tip placed 5 to 8 mm below the thyroid cartilage.11 Artificial respiration was maintained through the use of a respirator with an FIO2 of 0.80, a frequency of 100 strokes/min, and a tidal volume of 0.8 to 1.2 mL to maintain normal arterial PaO2, PaCO2, and pH. The middle skin incision in the neck was extended down to the xiphoid. The left pectoris major muscle and the muscle beneath it were dissected longitudinally, without cutting these muscles, to expose the left 3rd and 4th ribs. A parasternal incision was made to open the chest by cutting the left 3rd and 4th ribs and intercostal muscles with a cautery pen (General Medical Corporation). The animal was slightly rotated to the right through the release of the left upper paw to fully expose the left ventricle. Coronary artery ligation was achieved with a balloon occluder fixed onto the left anterior descending coronary artery (LAD) with a 7-0 silk suture passed with a tapered needle underneath the LAD and 2 to 3 mm inferior to the left auricle. Coronary artery occlusion and reperfusion were induced through inflation and deflation of the balloon. Significant ECG changes, including widening of the QRS complex (monitored with a Maclab ETH-255 Bridge/Bio Amplifier; CB Science Inc) and elevation of ST segment, and color changes of the area at risk were considered indicative of successful coronary occlusion and reperfusion. Once the reperfusion started, the chest was closed in layers. The respirator was weaned, and the endotracheal tube was removed when the animal recovered spontaneous breathing and began to move. Five percent dextrose and whole blood from animals with the same genotype were administered intraperitoneally or intravenously to replace the fluid and blood loss that occurred during surgery. Five percent dextrose (0.5 to 1.0 mL IP) was injected after the animal was ventilated. Blood was transfused through the left external jugular vein immediately after the chest was entered and after the chest was closed, with a total volume of 0.4 to 0.8 mL. Rectal temperature was monitored with a rectal probe and was maintained within 36.5° and 37.5°C. Mean arterial blood pressure (monitored with the Maclab ETH-255 Bridge/Bio Amplifier) was measured for hemodynamic study through cannulation of the right common carotid artery.
Experimental Groups
Animals were assigned to various groups. For the sham groups, in
wild-type control (IL-10+/+) animals and
IL-10–deficient (IL-10-/-) mice, the chest was
opened for 35 minutes and the suture was placed around LAD but not
ligated. The animals were sacrificed 2, 4, or 6 hours later. For the
myocardial ischemia/reperfusion groups, wild-type control
(IL-10+/+) animals and IL-10–deficient
(IL-10-/-) mice were subjected to 30-minute LAD
occlusion and 2-, 4-, or 6-hour reperfusion.
Before the hearts were harvested, the animals were
reanesthetized, and the blood was drawn via cardiac puncture.
The excised hearts were either stained with tetrazolium for measurement
of myocardial infarction size or maintained at -70°C for the
preparation of frozen sections for immunohistochemical determination of
ICAM-1 or for tissue myeloperoxidase (MPO) activity measurements
(Table 1
). In
subsequent experiments, 24-hour reperfusion was also performed;
in these experiments, 6 of 8 IL-10-/-
animals died within 12 hours of reperfusion, whereas all 8
IL-10+/+ wild-type animals that were tested
survived for 24 hours.
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Analysis of Myocardial Infarction
After excision, the hearts were cannulated through the ascending
aorta with a 23-gauge needle and perfused with 2 to 3 mL of 37°C
0.9% sodium chloride solution and then with 3 to 4 mL of 37°C 1.0%
tetrazolium red in phosphate buffer (pH 7.4). After tetrazolium
staining, the LAD was reoccluded. Then, the hearts were perfused with 2
mL of 2% Evans blue to delineate the nonischemic tissue. The
hearts were then frozen, and the right ventricle and atria were trimmed
off. The left ventricle was cut into 5 to 7 transverse slices, which
were fixed in 10% neutral buffered formalin solution. Each slice was
weighed and photographed under a dissecting microscope. The pictures of
both sides of each slice were traced along the borders of infarction
area, the ischemic area (area at risk), and the
nonischemic area. The corresponding areas were calculated as
previously described12 through scanning of the images,
followed by the determination of the respective areas with the use of
Adobe Photoshop. The sizes in weight of nonischemic area, area
at risk, and infarction area of each slice were then calculated as a
percentage of corresponding area multiplied by the weight of the
slice.12
MPO Activity
The left ventricles, which were harvested 2, 4, or 6 hours after
reperfusion, were homogenized in a solution containing
0.5% hexadecyltrimethylammonium bromide dissolved in 10 mmol/L
potassium phosphate buffer (pH 7) and centrifuged for 30
minutes at 20 000g at 4°C. An aliquot of the supernatant
was allowed to react with a solution of tetramethylbenzidine (1.6
mmol/L) and 0.1 mmol/L
H2O2. The rate of change in
absorbance was measured with spectrophotometry at 650
nm.13
Serum Creatine Phosphokinase Activity
Serum levels of creatine phosphokinase (CPK) and its
myocardium-specific isoform (CK-MB) were measured with the
use of commercial kits (Sigma Chemical Co).13
Immunohistochemical Staining for ICAM-1
ICAM-1 expression was evaluated in cardiac sections through
immunohistochemistry.13 Frozen sections (5 µm
thick) were fixed in 4% paraformaldehyde and incubated
in 2% hamster serum for 2 hours to minimize nonspecific adsorption.
Sections were then incubated overnight at 4°C with monoclonal
biotinylated antibodies directed at ICAM-1 (hamster anti-mouse CD54) at
a dilution of 1:500. Control preparations included buffer alone or
nonspecific purified IgG. Antibody-binding sites were visualized with
an avidin-biotin peroxidase complex immunoperoxidase technique (Vector
Laboratories) with the use of diaminobenzidine. A grading system was
used in which 0 indicates no staining, 1 indicates constitutive
presence of staining along the endothelial wall, 2 and
3 indicate increasing degrees of intermediate staining along the
endothelial wall, and 4 indicates increased staining
along the endothelial wall and the presence of staining
on myocytes. In each group, 5 or 6 sections were evaluated by 2
independent observers who were blinded to the experimental
protocol.
Measurement of Serum Levels of Tumor Necrosis Factor-, IL-10,
and Nitrite/Nitrate
Immunoreactive murine IL-10 and tumor necrosis factor-
(TNF-) were quantified with the use of ELISA according to the
manufacturer’s protocol.14 Serum concentrations of
nitrite/nitrate, stable breakdown products of NO, were measured
according to the modified Griess reaction.14 First,
nitrate in 50 µL serum was reduced to nitrite through incubation with
25 µL nitrate reductase (670 mU/mL) and 25 µL NADPH (160
mmol/L) at room temperature for 3 hours. Then, 100 µL Griess reagent
(0.1% naphthalethylenediamine dihydrochloride in
H2O and 1% sulfanilamide in 5% concentrated
H3PO4; vol 1:1) was added.
The absorbance at 550 nm was then measured.
Materials
Primary monoclonal ICAM-1 (CD54) antibody for
immunohistochemistry was purchased from PharMingen. Reagents and
secondary and nonspecific IgG antibodies for immunohistochemical
analysis were obtained from Vector Laboratories. Plasma levels
of IL-10 and TNF- were measured with the use of ELISA kits purchased
from Genzyme Co. All other chemicals were obtained from
Sigma/Aldrich.
Data Analysis
All values in the figures and text are expressed as mean±SEM.
The results were examined with the use of ANOVA, followed by the
Bonferroni correction post hoc t test. Differences in
survival rates were analyzed with a 
2
test. A value of P<0.05 was considered statistically
significant.
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Results |
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Hemodynamic Parameters
Hemodynamic measurements were recorded under baseline conditions, during ischemia, and up to 15 minutes after reperfusion. There were no significant baseline differences in hemodynamics between wild-type and IL-10–deficient animals, as assessed with measurements of mean arterial pressure (MAP) and heart rates. Cardiac function was depressed in both IL-10+/+ and IL-10-/- groups during the period of the occlusion, characterized by a drop in MAP. There was no difference between wild-type and IL-10–deficient animals in the recovery of MAP during the early reperfusion period (Table 2
).
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Endogenous IL-10 Regulates Myocardial Infarct Size and
Neutrophil Infiltration After Coronary Occlusion and
Reperfusion
In wild-type mice, 1-hour occlusion of the left coronary
artery followed by 6-hour reperfusion resulted in a marked myocardial
injury. On histological examination of the reperfused
hearts, a marked necrosis of the tissue with the development of
contraction bands was observed, with an infarct size of 49±4% of the
ischemic area (Figure 1). Serum
CPK level, an index of myocyte injury, increased compared with baseline
level at 2, 4, and 6 hours after the start of reperfusion
(P<0.01; Figure 2). There was
a significant degree of neutrophil infiltration, as measured by an
increase in tissue MPO activity over baseline at 2, 4, and 6 hours
after the start of reperfusion (P<0.01; Figure 3).
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The absence of the IL-10 gene resulted in a significant exacerbation of
reperfusion injury of previously ischemic hearts. This was
demonstrated by a statistically significant increase in infarct size to
64±4% of the ischemic area (P<0.05 compared with
wild-type; Figure 1
). Serum CPK levels showed a marked and
significant increase over the levels seen in the wild-type animals at 6
hours after reperfusion (Figure 2), whereas at 2 and 4 hours, a
tendency toward increase was observed (Figure 2). These
measurements in the changes in total CPK were followed by measurement
of the myocardium-specific isoform (CK-MB). These
measurements confirmed a significant difference between the control and
wild-type animals at 6 hours after the start of reperfusion: in the
wild-type mice, CK-MB levels increased from 43±5 to 412±33 U/L,
whereas in the IL-10–deficient mice, a significantly
(P<0.05) larger increase in CK-MB activity was found: from
51±8 to 687±48 U/L (8 or 9 animals per group). At earlier time points
of reperfusion (2 and 4 hours), similar to the measurements of total
plasma CPK levels, no significant differences in CK-MB plasma levels
were found between wild-type and IL-10–deficient mice (not shown).
There was a more pronounced increase in the MPO levels in the
IL-10–deficient animals at 6 hours compared with the wild-type
response (Figure 3).
Endogenous IL-10 Regulates TNF- Production
and ICAM-1 Expression After Coronary Occlusion and
Reperfusion
Using specific ELISAs, we observed that there was a substantial
increase in IL-10 production in myocardial
ischemia/reperfusion. IL-10 levels peaked at 4 hours and tended
to return toward baseline at 6 hours after the start of the reperfusion
(Figure 4). (In the IL-10–deficient
animals, no IL-10 could be detected in the plasma.) TNF- levels also
increased at 2 to 6 hours after the start of the reperfusion in both
groups of animals (Figure 5). At 6 hours
after reperfusion, TNF- levels were significantly higher in the
IL-10–deficient animals than in the wild-type mice (Figure 5).
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Endogenous IL-10 Regulates ICAM-1 Expression After
Coronary Occlusion and Reperfusion
One of the early endothelial events in the process
of neutrophil recruitment during myocardial ischemia is related
to ICAM-1, which is constitutively expressed at low levels on the
surface of endothelial cells but is upregulated and is
responsible for the firm adhesion of neutrophils.15 16
Stained myocardial tissue sections from sham-operated wild-type mice
with anti–ICAM-1 antibody showed a specific staining along cardiac
vessels that demonstrated ICAM-1 is constitutively expressed in
endothelial cells (Figure 6). After ischemia followed by 6
hours of reperfusion, the staining intensity substantially increased in
the area of early necrosis (Figures 6 and 7). Immunohistochemical staining was
mainly localized in endothelial vascular wall, but a
diffuse staining was also localized in myocytes within the necrotic
lesion (Figures 6 and 7). Sections from IL-10–deficient
mice revealed an increased upregulation of ICAM-1 (the degree of
staining was scored 3.8±0.2 compared with 2.5±0.5 in the wild-type
animals, P<0.05; Figure 7).
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Endogenous IL-10 Regulates NO Production After
Coronary Occlusion and Reperfusion
There are no differences in the baseline serum levels of
nitrite/nitrate (breakdown products of NO) between wild-type and
IL-10–deficient mice (Figure 8). By 6
hours of reperfusion (but not at 2 or 4 hours), serum nitrite/nitrate
significantly increased in both IL-10-/- and
IL-10+/+ mice (P<0.05). The rise was
more evident in IL-10-/- mice than in
IL-10+/+ mice at 6 hours of reperfusion
(P<0.05; Figure 8).
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Endogenous IL-10 Is Essential for Survival in
Myocardial Ischemia/Reperfusion
Reperfusion for 6 hours did not result in high mortality rates in
wild-type or IL-10–deficient animals (Table 1). In an
additional set of experiments, we investigated the effect of 30-minute
occlusion of LAD and 24-hour reperfusion on survival in wild-type and
IL-10–deficient mice. Six of 8 IL-10-/- mice
died within 12 hours of reperfusion after 30-minute occlusion of LAD,
whereas all 8 IL-10+/+ mice that were tested
survived the 24-hour reperfusion, yielding a significant difference in
the 24-hour survival rate between the two groups of animals
(P<0.01).
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Discussion |
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IL-10 is a potent anti-inflammatory cytokine. Multiple studies have demonstrated the production of IL-10 during human myocardial ischemia/reperfusion injury and during cardiopulmonary bypass. In one of these settings in humans, an examination of the plasma levels of a large number of cytokines during human cardiopulmonary bypass revealed that IL-10 showed the least interindividual variations, suggesting that this cytokine may provide reliable information regarding modulation of the immune response after bypass and its consequences for patient outcome.10 In the present study, we demonstrated the production of IL-10 in the plasma after myocardial ischemia/reperfusion in the mouse. The production of IL-10 has been previously demonstrated in various animal models of reperfusion injury (eg, in the reperfused liver, brain, kidney, or gut17 18 19 ). However, to our knowledge, our investigations are the first to demonstrate the production of IL-10 in the plasma after myocardial ischemia/reperfusion in an experimental animal. The present study did not identify the mechanism of IL-10 production or the cells responsible for it. In a study of IL-10 production from the reperfused liver, it was found that the inhibition of free radical generation by N-acetylcysteine or allopurinol decreased IL-10 levels in the effluents, as did an inhibitor of transcription factor nuclear factor-
B
mobilization.19 It is conceivable that free
radical–mediated nuclear factor-B activation was responsible for
IL-10 production in the present study. The protective effect of exogenously administered IL-10 in the outcome of myocardial ischemia/reperfusion injury is well established. For example, in a study in anesthetized rats, IL-10 (100 µg/rat) administered 15 minutes before reperfusion significantly attenuated myocardial injury, as indicated by a reduced loss of myocardial creatine kinase from the ischemic/reperfused myocardium.20 Cardiac MPO activity was also significantly attenuated by IL-10. The authors concluded that IL-10 mediates its effects, at least in part, through the inhibition of leukocyte/endothelium interactions.20 Similar conclusions were reached with IL-10 pretreatment in studies in animals of splanchnic artery, pulmonary, or hindlimb ischemia/reperfusion or of stroke.21 22 23
The present study provides the first direct evidence that the
endogenous production of IL-10 during
myocardial ischemia/reperfusion injury plays a key role in
determination of the outcome. The crucial role of IL-10 is demonstrated
by an increased infarct size, massively increased neutrophil
infiltration, or increased plasma TNF- and nitrite/nitrate and
myocardial ICAM-1 levels in the IL-10-/-
animals subjected to myocardial ischemia/reperfusion. There are
a number of recent studies that demonstrate the crucial role of
endogenously produced IL-10 in the modulation of the
cytokine and chemokine response in various forms of systemic
inflammation, induced by bacterial lipopolysaccharide, live
bacteria, or staphylococcal enterotoxin B.7 8 9 10 14
However, to our knowledge, the present report is the first to
demonstrate the crucial role of endogenous IL-10 in
modulation of the course of myocardial reperfusion injury or, in fact,
any form of reperfusion injury. The present findings may be
comparable to those of a recent study by Raisanen-Sokolowski et
al,24 in which the role of IL-10 in late graft outcome was
investigated through the transplantation of BALB/c donor hearts into
immunosuppressed wild-type or IL-10 gene–deficient recipients. In this
study, similar to our findings, there was an increase in the leukocyte
infiltration and parenchymal destruction, with more severe vascular
occlusion in grafts from IL-10-/- recipients
compared with wild-type responses. This was associated with an
enhancement of the inflammatory response in the IL-10–deficient mice,
as demonstrated by an increased expression in interferon-
, Mac-1,
inducible NO synthase (iNOS), and allograft inflammatory
factor-1.24
Perhaps the most dramatic difference between wild-type and IL-10–deficient mice subjected to myocardial ischemia/reperfusion injury was the amount of neutrophils that infiltrated the reperfused myocardium. Based on the ability of exogenously administered IL-10 to suppress the expression of proinflammatory cytokines and adhesion molecules and the effect of exogenous IL-10 in limiting the neutrophil infiltration in various forms of reperfusion injury (see earlier), we hypothesize that the primary actions of endogenous IL-10 are related to the modulation of the neutrophil activation and their tissue infiltration. These actions may be related to both the suppression by endogenous IL-10 of the activation of neutrophils25 and the expression of endothelial adhesion molecules such as ICAM-1.6 26 27 Interestingly, we observed most of the differences between wild-type and IL-10–deficient mice in terms of inflammatory mediator production, ICAM-1 expression, and myocardial necrosis at 6 hours after the beginning of reperfusion and not at the earlier time points studied. In comparison, plasma IL-10 levels peaked at 2 to 4 hours after the beginning of reperfusion. It is likely that a lag time is required for the endogenously produced IL-10 to exert its anti-inflammatory effects. It is conceivable that in experimental models in which IL-10 is administered exogenously before the beginning of reperfusion, the intervention bypasses this lag time, thereby ameliorating the proinflammatory response and suppressing the tissue recruitment of neutrophils.
With respect to NO production and myocardial ischemia/reperfusion, it is well established that inhibition of the constitutive, endothelial isoform of NO synthase is detrimental in myocardial reperfusion, especially in the early phase.28 29 30 31 32 This is, in a significant part, due to the facts that inhibition of the endothelial NOS causes myocardial ischemia28 and enhances intravascular platelet and neutrophil deposition.30 31 32 On the other hand, expression of the proinflammatory iNOS has been demonstrated in the late phase of reperfusion, as shown in both experimental animals33 34 and humans.35 Selective inhibition of this particular isoform of NO synthase has been shown to have beneficial effects.35 36 37 Based on these data, it is conceivable that by suppressing iNOS expression, endogenous IL-10 serves to maintain the patency of the reperfused hearts.
Taken together, the results of the present study demonstrate that
(1) IL-10 is produced in a murine model of myocardial
ischemia/reperfusion; (2) endogenously produced
IL-10 serves to suppress the production of TNF- and the
expression of iNOS in the reperfusion phase; (3) endogenous
IL-10, produced during myocardial reperfusion, serves to suppress the
tissue infiltration of polymorphonuclear granulocytes; and (4)
endogenous IL-10 is essential for survival during prolonged
periods of myocardial ischemia/reperfusion. In the absence of
endogenous IL-10, marked inflammatory response and
neutrophil infiltration occur, which result in an enhancement of
myocardial infarction, an increase in myocardial necrosis, and a marked
increase in mortality rates. The increased production of
TNF-, NO, and expression of ICAM-1 may be examples of this
inflammatory response. Based on prior studies, it appears likely that
in addition to the above mediators/factors, a host of other
inflammatory mediators (other types of cytokines, chemokines,
adhesion receptors, oxygen-derived free radicals, and so on) are also
upregulated in response to myocardial ischemia/reperfusion in
the IL-10–deficient mice compared with the wild-type animals. As in
many other forms of inflammation or reperfusion injury, it is likely
that the massive injury is due to the synergistic action of many of
these mediators.
There are a number of studies suggesting the potential use of IL-10 in experimental therapy for various forms of reperfusion injury.17 18 19 20 21 22 23 Under systemic or local inflammatory conditions, a number of approaches have recently been identified that are able to boost endogenous IL-10 levels while simultaneously downregulating the production of proinflammatory cytokines and chemokines. Such approaches include, among others, cAMP phosphodiesterase inhibition and ligands of adenosine A3 and other adenosine receptor subtypes.38 Many of these approaches have been previously shown to exert protective effects in various models of myocardial reperfusion.39 40 41 It remains to be determined whether the protection is related to the ability of these approaches to boost endogenous IL-10 levels.
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Acknowledgments |
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This work was supported by a grant from the National Institutes of Health (R01-HL-59266) to Dr Szabó.
Received June 22, 1999; revision received September 7, 1999; accepted September 7, 1999.
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