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(Stroke. 1995;26:318-323.)
© 1995 American Heart Association, Inc.

Articles

Transient Increase of Cytokine-Induced Neutrophil Chemoattractant, a Member of the Interleukin-8 Family, in Ischemic Brain Areas After Focal Ischemia in Rats

Yasundo Yamasaki, PhD; Yoshiyuki Matsuo, BSc; Naosuke Matsuura, PhD; Hiroshi Onodera, MD; Yasuto Itoyama, MD Kyuya Kogure, MD

From the Department of Neurology, Institute of Brain Disease, Tohoku University School of Medicine, Sendai, Miyagi (Y.Y., Y.M., H.O., Y.I.); Hanno Research Center, Taiho Pharmaceutical Co Ltd, Hanno, Saitama (N.M.); and Institute of Neuropathology, Kanto Neurosurgical Hospital, Kumagaya, Saitama (K.K.), Japan.

	Abstract

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Background and Purpose We have indicated that neutrophils play an important role in cerebral ischemia-reperfusion injury. Neutrophils are also known to adhere to the endothelial wall through adhesion molecules and to infiltrate into the tissue, and this neutrophilic invasion correlates with the concentration gradient of chemotactic factors. The aim of the present study was to evaluate the role of cytokine-induced neutrophil chemoattractant (CINC) on brain damage in rats from transient ischemia.

Methods The brain water content was measured to evaluate postischemic brain injury in rats with 60 minutes of middle cerebral artery occlusion with reperfusion. An enzyme-linked immunosorbent assay was used to evaluate the blood and brain concentrations of CINC, and enzymatic and histological techniques were used to measure the neutrophilic infiltration into the brain.

Results The increase of water content was first observed at 6 hours after reperfusion, after which this increase was gradual, with brain edema peaking from 24 to 48 hours after reperfusion. Neutrophilic infiltration into the parenchyma and myeloperoxidase activity were first noted 12 hours after reperfusion, after which a marked increase occurred from 24 to 48 hours after reperfusion. In the ischemic brain areas, CINC was first detected at 3 hours after reperfusion. The CINC level peaked at 12 hours after reperfusion (9.15±0.45 ng/g wet wt, n=5) and then gradually reduced from 24 to 48 hours after reperfusion (5.35±0.95 ng/g wet wt, n=5, and 1.25±0.10 ng/g wet wt, n=5, respectively). Interestingly, the serum CINC concentration was transiently elevated from 3 to 6 hours after reperfusion. No CINC production was detected in the brain of rats subjected to 60 minutes of ischemia without reperfusion.

Conclusions A marked increase in CINC concentration was detected in brain and serum during early reperfusion. This suggests that the time course of CINC production precedes brain edema formation and neutrophilic infiltration. It thus appears that CINC may play an important role in neutrophilic infiltration in ischemic lesion and in brain edema formation after ischemia-reperfusion injury.

Key Words: brain edema • cerebral ischemia, focal • interleukins • rats

	Introduction

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It has been reported that an inflammatory reaction was observed in an ischemia-reperfusion injury of the brain, and the aggregation of neutrophils and the adhesion of these neutrophils to the endothelium may contribute to delayed hypoperfusion after reperfusion in an ischemia-reperfusion injury.^{1 2} It also has been speculated that the development of edema induced by ischemia-reperfusion may be alleviated by depleting neutrophils by means of an anti-neutrophil antibody³ and by inhibiting neutrophilic adhesion by means of an anti-adhesion molecule antibody (anti-CD18).⁴ These findings appear to indicate that neutrophils, after adhering to the endothelial cells through adhesion molecules, infiltrate under a concentration gradient of chemotactic factor(s).

As one of the possible participating chemotactic factors, we reported on the contribution of interleukin-1 (IL-1) in the pathogenesis of postischemic brain damage (Reference 5 and Y. Yamasaki et al, unpublished data). Interleukin-8 (IL-8) belongs to a family of chemotactic cytokines and has been described as being a neutrophil-activating protein, a neutrophilic chemotactic factor, or a T cell chemotactic factor.^{6 7} The structure of IL-8 varies, depending on its cellular source. [Ala-IL-8]⁷⁷ is secreted in vitro by activated human endothelial cells,⁸ and [Ser-IL-8]⁷² is the predominant form of IL-8 produced by activated blood monocytes.⁹ Furthermore, it has been suggested that the gradient of IL-8 concentration at the vascular wall interface may influence neutrophil migration. Recently Sekido et al¹⁰ reported that reperfusion in ischemic lung caused neutrophil infiltration and the destruction of lung tissue as well as local production of IL-8. This report appears to indicate that IL-8 produced in response to an ischemia-reperfusion injury is a major neutrophilic chemotactic and activating factor. It was reported that IL-1–treated rat glomerular epithelial cells and rat kidney epithelial cell line NRK-52E predominantly produced an IL-8–like neutrophil chemoattractant, cytokine-induced neutrophil chemoattractant (CINC).¹¹ From the biological activity and peptide sequences, it is likely that CINC in rats was related to IL-8 in humans and was a member of the IL-8 family.

It has recently been shown that CINC mRNA was detected in permanent occlusion of the middle cerebral artery (MCA) of rats.¹² However, the role of CINC production in an ischemia-reperfusion injury of the brain has yet to be clarified. The present study investigated the changes in CINC concentration and neutrophil infiltration in the rat brain after transient occlusion of the MCA.

	Materials and Methods

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Adult male Wistar rats (weight, 270 to 320 g) were anesthetized with a gas mixture of N₂O/O₂ (70:30) containing 2% halothane. Then, using a modification of the method of Longa et al,¹³ after a median incision of the neck skin we carefully dissected the right external carotid artery and inserted an 18-mm-long 4-0 nylon thread (coated with silicon) from the external carotid artery to the right internal carotid artery to occlude the origin of the right MCA. Next, after 60 minutes of MCA occlusion, the thread was removed to allow complete reperfusion of the ischemic area via the right common carotid artery. Neurological deficits that are characterized by severe left-sided hemiparesis and right Horner's syndrome were used as the criteria for evaluating the ischemic insults, and in this model ischemic insults can be induced without the occurrence of seizure activity.

To assess the content of the brain water, immediately (without reperfusion) and at 6, 12, 24, and 48 hours after reperfusion, brain was dissected into the cerebral cortex perfused by MCA (MCA area) and the caudate putamen perfused by MCA (CP) in a humidified glove box. The brain samples were dried in an oven at 110°C for 24 hours, and the water content of these samples was then measured by the wet and dry weight method¹⁴ as follows:

For the histopathological study, the rats were anesthetized with sodium pentobarbital and then perfused transcardially with phosphate-buffered saline, followed by 4% buffered paraformaldehyde. Next the brain of each rat was removed, postfixed, and embedded in paraffin. Then 5-µm-thick brain sections were stained with hematoxylin and eosin. In this way, the profiles and degree of neutrophilic infiltration into infarcted and uninfarcted areas were determined and photographed.

The method to quantify myeloperoxidase (MPO) activity in ischemic areas was performed according to the method described by Barone et al.^{15 16} Briefly, frozen tissue specimens were quickly weighed and homogenized (Polytron, three times for 5-second bursts) in 20 times the volume of 5 mmol/L phosphate buffer (pH 6.0) at 4°C, followed by centrifugation at 30 000g for 30 minutes at 4°C. The supernatant was discarded, and the pellets were extracted by suspension in 10 times the volume of 0.5% hexadecyltrimethylammonium bromide (Sigma) in 50 mmol/L phosphate buffer (pH 6.0) at 25°C. These samples then were frozen on dry ice, with three freeze/thaw cycles, and sonicated for 10 seconds at 25°C. After sonication, the samples were incubated for 20 minutes at 4°C and centrifuged at 12 500g for 15 minutes at 4°C. MPO activity in the supernatant was assayed as described by Bradley et al.¹⁷ The rate of a colored product, formed during the MPO-dependent reaction in 50 mmol/L phosphate buffer (pH 6.0) containing o-dianisidine hydrochloride (Sigma) and hydrogen peroxide, was then measured. Changes in absorbance over 100 seconds at 460 nm were recorded at 20-second intervals by means of a spectrophotometer, and the MPO activity was calculated by use of a standardized solution (WAKO).

To measure the CINC concentration in the brain, right jugular venous blood was collected, after which the rats were decapitated under ether anesthesia and the brains dissected into the MCA and the CP areas according to the following time schedule: immediately (without reperfusion) and at 3, 6, 12, 24, and 48 hours after reperfusion. We then homogenized samples of the brain with 5 volumes of phosphate-buffered saline containing 0.5% bovine serum albumin and 0.05% Tween 20, using a polytetrafluoroethylene homogenizer (100 mg wet wt/0.5 mL). Next, each homogenate was centrifuged (3000 rpm, 4°C, 15 minutes), and the resultant supernatant was collected and stored at -80°C until assayed. A rat CINC enzyme-linked immunosorbent assay (ELISA) kit (Amersham) was used according to the maker's recommendations to determine CINC concentration in the brain and serum. This ELISA system does not react significantly with human IL-8 or rat Gro-ß (data not shown). However, we could measure CINC-like immunoreactivity in this system because of the possible cross-reactivity between other chemokines.

For the statistical analysis, Dunnett's multiple test was used, and results were compared with results seen in a control group.

	Results

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Brain Water Content
The brain water content, measured by the wet and dry weight method, for the MCA and the CP areas in the sham-operated rats was 77.8±0.4% and 76.5±0.5%, respectively (mean±SEM). Sixty minutes of ischemia without reperfusion induced a slight increase in the water content (80.5±0.3% and 79.8±0.3%, respectively). The brain water content began to increase from 3 to 6 hours after reperfusion and reached a maximum level from 12 to 48 hours after reperfusion (Table 1). The degree of this increment in brain water content was higher in the CP area than in the MCA area.

View this table: [in this window] [in a new window]   Table 1. Time Course of Brain Edema Formation on Occluded Side 24 Hours After 60 Minutes of Ischemia

MPO Activity and Neutrophilic Infiltration
The MPO activity in the rats of the sham-operated group, the ischemia without reperfusion group, and the ischemia with 6 hours of reperfusion group was below detectable levels. The MPO activity began to increase 12 hours after reperfusion and thereafter gradually elevated. At 24 hours after reperfusion, high levels were detected in both the MCA area and the CP area (Table 2), with MPO activity higher in the MCA area. The temporal profiles of the neutrophilic invasion into the ischemic areas correlated well with the MPO activity. No neutrophilic infiltration was seen in the sham-operated group or in the ischemia without reperfusion group. A neutrophilic infiltration was not observed until 6 hours after reperfusion. Thereafter, a gradual increase in this infiltration was noted at 12 hours after reperfusion, and this increase persisted at 48 hours after reperfusion. (Fig 1).

View this table: [in this window] [in a new window]   Table 2. Time Course of Myeloperoxidase Activity

View larger version (147K): [in this window] [in a new window]   Figure 1. Representative photomicrographs of neutrophilic infiltration on the occluded side after 60 minutes of ischemia. A, Sham-operated rat; B, 3 hours after reperfusion; C, 12 hours after reperfusion; and D, 48 hours after reperfusion. Note the appearance of neutrophils that have attached to the endothelium and the neutrophilic infiltration into the brain parenchyma from 12 to 48 hours after reperfusion (arrows indicate the neutrophils).

CINC Concentration
The control rats had no detectable CINC concentration in either the MCA or CP areas. Also, the CINC concentration in rats that had been killed after 60 minutes of ischemia without reperfusion was below the level of detection. The first detectable level of CINC was found 3 hours after reperfusion, and the peak CINC concentration level occurred 12 hours after reperfusion in the MCA area (9.2±0.5 ng/g tissue wet wt) and in the CP area (7.0±0.9 ng/g tissue wet wt). Thereafter, as shown in Table 3, the brain CINC concentration decreased from 24 to 48 hours after reperfusion.

View this table: [in this window] [in a new window]   Table 3. Time Course of Cytokine-Induced Neutrophil Chemoattractant Concentration in Brain Tissues and Serum

In the nonischemic hemisphere, the CINC concentration in the MCA and the CP areas did not reach a detectable level at any time point studied. In contrast to the temporal profiles of the CINC level in the brain, the CINC concentration in the serum transiently increased after 60 minutes of ischemia without reperfusion and reached a peak at 3 hours after reperfusion that was followed by a decrease from 6 to 48 hours after reperfusion (Table 3).

	Discussion

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These results are the first to show the time courses of CINC concentration in the brain and serum of rats after a reperfusion injury. Inflammatory reactions, such as leukocytosis and elevated body temperature, are often observed in acute stroke patients^{18 19} and in experimental reperfusion injury.^{1 2} Thus, neutrophils are critically involved in an ischemia-reperfusion injury, and it has been suggested that the rolling of neutrophils on the endothelium, the attachment of neutrophils onto endothelium through adhesion molecules, and the migration by chemotactic factors are the essential mechanisms of neutrophilic invasion into areas damaged by ischemia.²⁰ Furthermore, the expression of adhesion molecules is believed to be modulated by a wide spectrum of inflammatory mediators, such as IL-1 and IL-8.^{21 22}

We previously reported on the contribution of IL-1 to ischemic brain damage by showing that IL-1 blocking agents reduce the increase in the brain water content. It also has been established that IL-1 can induce IL-8 production²³ and that the distribution of IL-1 mRNA is almost the same as the distribution of IL-8 mRNA.²⁴ Therefore, it can be speculated that the beneficial effects of an IL-1 blocker may be partially accounted for by the subsequent suppression of IL-8 production.

IL-8 is a large peptide secreted by mononuclear phagocytes, neutrophils, endothelial cells, fibroblasts, and the synovial cells in response to inflammatory stimuli.^{25 26} IL-8 also has been found to stimulate the binding activity of CD11b/CD18 on human neutrophils²⁷ and thus plays a critical role in the neutrophilic invasion into the damaged tissue. Furthermore, Licinio and coworkers²⁸ reported that IL-8 mRNA has been detected in the brain in the paraventricular nucleus and the hippocampus. It also has been reported that an intracerebroventricular injection of recombinant IL-8 significantly increased oxygen consumption and body temperature.²⁹ Thus, given these findings, it may be that IL-8 plays a part in the stress-related neuroendocrine-neuroimmune system. Recently it has been reported that reperfusion of an ischemic lung caused a neutrophilic infiltration and the local production of IL-8 in the lung.^{10 30} Furthermore, an intravenous injection of IL-8 caused a neutrophilic infiltration into a reperfusion injury of the rabbit heart.³¹ These reports would seem to indicate that IL-8 is a strong neutrophilic, chemotactic, and activating factor produced in response to an ischemia-reperfusion injury.

Although IL-8 is the major chemotactic cytokine in humans, IL-8 in rats is not identified and CINC in rats may be responsible for neutrophil recruitment as a major chemoattractant. CINC in rats is believed to be structurally and functionally related to IL-8 in humans and to be a member of the IL-8 family.

In this study CINC production in the ischemic areas was detected 3 hours after reperfusion and peaked 12 hours after reperfusion (Fig 2). Then, from 24 to 48 hours after reperfusion, the CINC level decreased drastically. Furthermore, it was also found that ischemia without reperfusion did not induce CINC production, although the brain water content slightly increased. It also is of interest to note that a significant level of CINC was detected in the serum after ischemia and that this CINC serum level peaked at 3 hours after ischemia, before the CINC level peaked in the brain tissue (Fig 2). Thereafter, the serum CINC level returned to normal, whereas the brain CINC level still remained high 24 hours after ischemia.

View larger version (15K): [in this window] [in a new window]   Figure 2. Schema for correlating the time courses of myeloperoxidase (MPO) activity and cytokine-induced neutrophil chemoattractant (CINC) production in ischemic brain areas and serum. Data were taken from Tables 2 and 3. The curve fitting was applied by use of the interpolation method. The data for CINC (brain) refer to CINC concentration in middle cerebral artery areas, and the data for MPO refer to MPO activity in middle cerebral artery areas.

Recently Sekido and coworkers¹⁰ reported on the pathogenetic contribution of IL-8 in a lung reperfusion injury in the rabbit and found that lung ischemia for 3 hours with reperfusion significantly increased the IL-8 content in the bronchoalveolar lavage fluid and lung tissue, whereas there was no noticeable elevation of plasma IL-8 level. Moreover, they also found that an intravenous administration of anti–IL-8 antibodies inhibited an increase in the neutrophilic infiltration.^{10 30} Therefore, production of the chemokines IL-8 and CINC after ischemia was detected only after reperfusion in both lung and brain ischemia.

In the present study it was also found that the elevation of MPO activity coincided with the neutrophilic adhesion onto the endothelium and the neutrophilic invasion into parenchyma, as has been reported previously.¹⁶ The time courses of the neutrophilic accumulation and MPO activity occurred after the production of CINC in the ischemic brain. Therefore, the possibility that CINC may be a neutrophilic chemoattractant (chemokine) must be considered. However, the source of CINC still remains to be clarified. In this regard, the speculation that CINC molecules from the bloodstream trigger the initial activation and migration of neutrophils in response to an ischemic injury cannot be ruled out (Fig 2). Although the results of this study have shown that an increase in CINC concentration occurred in the brain and circulating blood before neutrophilic infiltration and elevated MPO activity in the brain, further studies are required to confirm whether the inhibition of CINC can reduce this neutrophilic migration into brain and ameliorate ischemic brain damage.

	Footnotes

 
Reprint requests to Y. Yamasaki, PhD, Department of Neurology, Institute of Brain Disease, Tohoku University School of Medicine, Sendai, 980 Miyagi, Japan.

Received May 12, 1994; revision received September 12, 1994; accepted November 16, 1994.

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