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(Investigative Ophthalmology and Visual Science. 2001;42:2380-2385.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Inhibitory Effect of Ischemic Preconditioning on Leukocyte Participation in Retinal Ischemia–Reperfusion Injury

Atsushi Nonaka1, Junichi Kiryu1, Akitaka Tsujikawa1, Kenji Yamashiro1, Kazuaki Nishijima1, Kazuaki Miyamoto1, Hirokazu Nishiwaki1, Yoshihito Honda1 and Yuichiro Ogura2

1 From the Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Japan; and the 2 Department of Ophthalmology, Nagoya City University Medical School, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. Recent reports have shown that ischemic preconditioning induces strong protection against retinal damage by subsequent prolonged ischemia and that this protection is mediated by mechanisms involving the adenosine A1 receptor. This study was designed to evaluate quantitatively the effects of ischemic preconditioning on leukocyte-mediated reperfusion injury after transient retinal ischemia and to define the role of the adenosine A1 receptor in these effects.

METHODS. Transient retinal ischemia was induced in male rats by temporary ligation of the optic nerve. Ischemic preconditioning (5 minutes of ischemia) was induced 24 hours before 60 minutes of ischemia. The adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was administered intramuscularly immediately after ischemic preconditioning. Leukocyte behavior in the retina after 60 minutes of ischemia was evaluated in vivo with acridine orange digital fluorography.

RESULTS. Ischemic preconditioning inhibited leukocyte rolling. The maximum number of rolling leukocytes was reduced to 3.0% at 12 hours after reperfusion (P < 0.01). Subsequent leukocyte accumulation was also decreased with ischemic preconditioning. The maximum number of accumulated leukocytes was reduced to 22.6% at 24 hours after reperfusion (P < 0.01). These inhibitory effects were suppressed by administration of DPCPX (P < 0.0001). The numbers of rolling leukocytes at 12 hours after reperfusion and accumulated leukocytes at 24 hours after reperfusion were 102.7% (NS) and 83.4% (P < 0.01), respectively, compared with the number without ischemic preconditioning.

CONCLUSIONS. The present study demonstrates the inhibitory effects of ischemic preconditioning on leukocyte rolling and subsequent leukocyte accumulation during retinal ischemia–reperfusion injury. Furthermore, the adenosine A1 receptor may play an important role in these inhibitory effects.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Recent intense investigations have revealed that ischemic preconditioning, a brief sublethal ischemic insult, makes tissues resistant to the deleterious effects of subsequent prolonged ischemia and reperfusion.1 2 3 Since first demonstrated in canine myocardium by Murry et al.,4 this phenomenon has attracted the increasing attention of researchers into the cellular mechanisms of this effect, because ischemic preconditioning harnesses the intrinsic and strong protective potentials of a tissue.5 The role of adenosine has been examined as a possible mediator in the mechanisms of ischemic preconditioning,5 6 7 but its precise mechanism is not fully understood.

Because leukocytes are thought to play a central role in ischemia–reperfusion injury,8 9 10 investigation of leukocyte dynamics in the postischemic retina would be valuable for the evaluation of postischemic retinal injury. Recent studies have demonstrated that inhibition of inflammatory leukocyte–endothelial cell interactions after transient ischemia is an important mechanism in inducing tolerance of ischemia by preconditioning and, moreover, have demonstrated a pivotal role of adenosine in these effects.11 12 13 So far, however, no reports describe the effects of ischemic preconditioning on leukocyte-mediated ischemia–reperfusion injury in the central nervous system, including retina.

We have developed a method of acridine orange digital fluorography that allows us to visualize leukocytes and to evaluate quantitatively leukocyte dynamics in the retinal microcirculation in vivo.14 15 16 17 Using this technique, we previously evaluated leukocyte dynamics in rat retina during ischemia–reperfusion injury,18 which was useful to investigate the effects of various treatments.19 20 21 The purpose of the present study was to evaluate quantitatively the inhibitory effect of ischemic preconditioning on leukocyte behavior during retinal ischemia–reperfusion injury in vivo using acridine orange digital fluorography. Specific adenosine receptor antagonists and agonists were studied to elucidate the role of adenosine in this inhibition.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animal Model
All procedures conformed with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Male pigmented Long-Evans rats, weighing 200 to 250 g (n = 104), were anesthetized with a mixture (1:1) of xylazine hydrochloride (4 mg/kg) and ketamine hydrochloride (10 mg/kg). The pupils were dilated with 0.5% tropicamide and 2.5% phenylephrine hydrochloride.

Transient retinal ischemia was induced by a method that has been described previously,22 with slight modification.18 23 After a lateral conjunctival peritomy, the lateral rectus muscle was disinserted, and the optic nerve of the right eye was exposed by careful blunt dissection. A ligature of 6-0 nylon was then placed around the optic sheath and tightened until blood flow in the retinal vessels stopped, as determined by funduscopic examination with an operating microscope. After we confirmed the absence of perfusion, the suture was removed. In this study, we used only eyes in which complete reperfusion within 5 minutes of ligature removal was confirmed through the operating microscope.

Ischemic preconditioning (5 minutes of ischemia) was induced at 24 hours before 60 minutes of ischemia. To examine the role of adenosine in ischemic preconditioning, the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 4.5 mg/kg) was administered intramuscularly immediately after ischemic preconditioning preceding to ischemia for 60 minutes (n = 8). In addition, the adenosine A1 receptor agonist (R)-N6-phenylisopropyladenosine (R-PIA, 0.2 mg/kg) was administered intramuscularly 60 minutes before 60 minutes of ischemia without ischemic preconditioning (n = 8). Rats without DPCPX or R-PIA treatment received an intramuscular injection of the same volume of saline (n = 8).

Experimental Design
At 6, 12, 24, and 48 hours after reperfusion, subsequent to 60 minutes of ischemia, leukocyte behavior in the retina was evaluated in vivo with acridine orange digital fluorography. Acridine orange digital fluorography has been described in detail elsewhere.14 15 16 Eight eyes of eight different rats were examined at each time point. Eight nonischemic rats were evaluated as control subjects.

Immediately before acridine orange digital fluorography, rats were anesthetized with the same agent used before ischemia induction, and the pupils were dilated. A contact lens was placed on the cornea to maintain transparency throughout the experiments. Acridine orange (0.1% solution in saline) was injected continuously through the catheter inserted into the tail vein for 1 minute at a rate of 1 ml/min. The fundus was observed with the scanning laser ophthalmoscope in the 40° field for 5 minutes. After the laser ophthalmoscopic images were obtained, the rat was killed with an overdose of anesthesia. The eye was then enucleated to determine a calibration factor with which to convert values measured on a computer monitor (in pixels) into real values (in micrometers).

Image Analysis
The video recordings were analyzed with an image analysis system, as described in detail elsewhere.14 15 16 In brief, the system consisted of a computer equipped with a video digitizer (Radius, San Jose, CA) that digitizes the video image in real time to 640 horizontal and 480 vertical pixels with an intensity resolution of 256 steps. Using this system, we evaluated the flux of rolling leukocytes along the major retinal veins and the number of leukocytes that accumulated in the retinal microcirculation.17 18 19 20 21

Rolling leukocytes were defined as leukocytes that moved at a velocity slower than that of free-flowing leukocytes. The number of rolling leukocytes was calculated from the number of cells crossing a fixed area of the vessel per minute at a distance of 1 disc diameter from the optic disc center. The flux of rolling leukocytes was defined as the total number of rolling leukocytes along all major veins.

The number of leukocytes that accumulated in the retinal microcirculation was evaluated 30 minutes after acridine orange injection. The number of fluorescent dots in the retina within 8 to 10 areas of 100 pixels square at a distance of 1 disc diameter from the edge of the optic disc was counted. The average of the numbers of dots in the areas studied was used as the number of leukocytes accumulated in the retinal microcirculation for each rat.

Statistical Analysis
Data are expressed as mean values ± SEM. The data were analyzed using an analysis of variance, with post hoc comparisons tested by the Fisher protected least-significant difference test. Differences were considered statistically significant when the probability was <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Rolling Leukocytes
Immediately after acridine orange was infused intravenously, leukocytes were stained selectively among circulating blood cells. In rats with transient ischemia for 60 minutes and reperfusion, among many free-flowing leukocytes, some were observed to be slowly rolling along major retinal veins but not along any major retinal arteries throughout the experiments (Fig. 1) .



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  		Figure 1. (A) Fundus image with acridine orange digital fluorography at 12 hours after reperfusion. Leukocytes were stained selectively among circulating blood cells. Among the many free-flowing leukocytes, some were observed to roll slowly along major retinal veins (arrowheads) but not along any major retinal arteries. It was difficult to distinguish rolling leukocytes from free-flowing ones on a still image. (B) Arrowheads: a rolling leukocyte along a major retinal vein; arrows: a free-flowing leukocyte. The times in each frame represent the time the images were obtained subsequent to the image in the first frame (top). It was not difficult to discriminate rolling leukocytes from free-flowing leukocytes on a video monitor, because the velocities of rolling and free-flowing leukocytes were markedly different.

 
In rats without preceding ischemic preconditioning, a small number of leukocytes was observed rolling along the venous walls at 6 hours after reperfusion. The flux of rolling leukocytes substantially increased and peaked at 12 hours after reperfusion (146.8 ± 56.3 cells/min). In preconditioned rats, leukocyte rolling was significantly inhibited (P < 0.0001; Fig. 2 ). The flux of rolling leukocytes was 4.3 ± 3.2 cells/min at 12 hours after reperfusion. The numbers of rolling leukocytes were reduced by 94.9% (P < 0.01), 97.0% (P < 0.01), and 97.6% (P < 0.01) at 6, 12, and 24 hours after reperfusion, respectively, as a result of ischemic preconditioning (n = 8 at each time point, total n = 72).



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  		Figure 2. Time course of flux of rolling leukocytes along major retinal veins after reperfusion in rats, with and without ischemic preconditioning (n = 8 at each time point). Values are mean ± SEM. *P < 0.05 compared with rats without ischemic preconditioning.

 
Figure 3 shows the effects of DPCPX administration on ischemic preconditioning, with estimates of leukocyte rolling at 12 and 24 hours after reperfusion. In rats administered DPCPX immediately after ischemic preconditioning, leukocyte rolling was significantly increased (150.8 ± 55.5 cells/min at 12 hours and 55.5 ± 13.2 cells/min at 24 hours after reperfusion) compared with vehicle-treated rats (4.3 ± 3.2 cells/min at 12 hours and 1.7 ± 0.8 cells/min at 24 hours after reperfusion, P < 0.05; n = 8 in each group). In addition, we examined whether stimulation of adenosine A1 receptor with R-PIA mimics the effects of ischemic preconditioning on leukocyte behavior after reperfusion. As shown in Figure 3 , administration of R-PIA without preconditioning significantly reduced leukocyte rolling after transient ischemia for 60 minutes (1.5 ± 1.0 cells/mm2 at 12 hours and 2.0 ± 0.7 cells/mm2 at 24 hours after reperfusion, P < 0.05).



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  		Figure 3. Effects of administration of DPCPX and R-PIA on flux of rolling leukocytes. Values are mean ± SEM. *, {dagger}: P < 0.05 compared with vehicle-treated rats after 60 minutes of ischemia and reperfusion with and without ischemic preconditioning, respectively (n = 8 at each time point).

 
Leukocyte Accumulation in Postischemic Retina
After acridine orange was injected, leukocytes that accumulated in the retina remained fluorescent for approximately 2 hours. At 30 minutes after acridine orange injection, accumulated leukocytes could be identified as distinct fluorescent dots with the highest contrast (Fig. 4) . The fluorescence of circulating leukocytes decreased gradually after acridine orange injection due to washout effects and was faint at this time.



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  		Figure 4. Leukocytes that accumulated in the retina were observed as fluorescent dots 30 minutes after acridine orange injection. A small number of leukocytes were found in control rats (A). The number of leukocytes that accumulated at 12 (B) and 24 (C) hours after ischemia–reperfusion was reduced in rats that had undergone ischemic preconditioning (D, E, respectively). Administration of DPCPX inhibited the ability of ischemic preconditioning to reduce leukocyte accumulation at 12 (F) and 24 (G) hours after reperfusion.

 
Figure 5 shows the time course of the number of leukocytes accumulating in the retinal microcirculation. Whereas few leukocytes could be recognized in the control rats, in rats without preceding ischemic preconditioning, accumulated leukocytes began to increase with time after ischemia-reperfusion and peaked at 24 hours after reperfusion (655.4 ± 61.9 cells/mm2). In preconditioned rats, leukocyte accumulation was significantly inhibited (P < 0.0001). The number of accumulated leukocytes was 148.0 ± 24.8 cells/mm2 at 24 hours after reperfusion. The numbers of accumulated leukocytes in rats with ischemic preconditioning were reduced significantly, by 51.7% (P < 0.01), 68.6% (P < 0.01), and 77.4% (P < 0.01) at 6, 12, and 24 hours after reperfusion, respectively, compared with rats without ischemic preconditioning (n = 8 at each time point, n = 72 total).



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  		Figure 5. Time course of the number of leukocytes accumulated in the retina after reperfusion in rats, with and without ischemic preconditioning (n = 8 at each time point). Values are mean ± SEM. *P < 0.05 compared with rats without ischemic preconditioning.

 
Figure 6 shows the effects of DPCPX administration on ischemic preconditioning, estimating leukocyte accumulation at 12 and 24 hours after reperfusion. In rats administered DPCPX, leukocyte accumulation was significantly increased (516.7 ± 34.8 cells/mm2 at 12 hours and 546.7 ± 35.9 cells/mm2 at 24 hours after reperfusion), compared with that in vehicle-treated preconditioned rats (200.3 ± 31.4 cells/mm2 at 12 hours and 148.0 ± 24.8 cells/mm2 at 24 hours after reperfusion, P < 0.01; n = 8 in each group). In addition, treatment with R-PIA without preconditioning significantly reduced leukocyte accumulation after transient ischemia (272.0 ± 20.8 cells/mm2 at 12 hours and 352.0 ± 43.2 cells/mm2 at 24 hours after reperfusion, P < 0.01; Fig. 6 ).



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  		Figure 6. Effects of administration of DPCPX and R-PIA on the number of leukocytes accumulated in the retina. Values are mean ± SEM. *, {dagger}: P < 0.05 compared with vehicle-treated rats after 60 minutes of ischemia and reperfusion, with and without ischemic preconditioning, respectively (n = 8 at each time point).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
A large body of evidence suggests that ischemic preconditioning renders various organs remarkably tolerant to ischemic conditions.1 5 Therefore, ischemic preconditioning has attracted a great deal of attention, owing to its neuroprotective property against focal and global cerebral ischemia.24 25 In retina, Roth et al.3 have recently reported the neuroprotective effect of ischemic preconditioning against retinal ischemia by means of histologic and functional analyses. Their findings were supported by previous in vitro evidence that hypoxia increased tolerance of retinal ganglion cells to anoxia.26 In this study, we investigated the effects of ischemic preconditioning on leukocyte behavior during retinal ischemia–reperfusion injury, because accumulating evidence has indicated that leukocytes play a central role in postischemic neural damage.8 9 10 Leukocytes that accumulate in postischemic tissues have been suggested to cause injury by blocking blood flow,10 producing oxygen-free radicals,27 and releasing various types of inflammatory cytokines.28 In the present study, ischemic preconditioning substantially inhibited leukocyte–endothelium interactions in the postischemic retina. The inhibitory effects of ischemic preconditioning on inflammatory leukocyte–endothelium interactions in the postischemic retina would partially contribute to the neuroprotective effect on the ischemic insult.

Recent experiments on leukocyte adhesion to the vascular endothelium have shown that leukocyte recruitment to the area of inflammation takes place through a multistep process mediated by distinct adhesion molecules.29 30 P-selectin–dependent leukocyte rolling is a prerequisite to the establishment of intercellular adhesion molecule (ICAM)-1–dependent adhesive interactions and subsequent leukocyte emigration. We have reported that inhibition of P-selectin or ICAM-1 with the administration of monoclonal antibody substantially attenuates leukocyte–endothelium interactions during retinal ischemia–reperfusion injury.20 Recently, Davis et al.31 have demonstrated the complete prevention of postischemic P-selectin expression in rat jejunum by ischemic preconditioning. In addition, ischemic preconditioning reportedly reduces expression of ICAM-1 in cultured rat aortic endothelial cells after anoxia-reoxygenation.32 Retinal ischemic preconditioning would suppress the expression of these adhesion molecules during retinal ischemia–reperfusion injury, resulting in attenuation of leukocyte rolling and subsequent leukocyte accumulation in the postischemic retina.

Intense examinations of the mechanisms of ischemic preconditioning indicate that adenosine plays a central role in ischemic tolerance produced by preconditioning.6 33 Although the precise mechanism by which adenosine mediates preconditioning phenomenon is uncertain, treatment with adenosine has been suggested to slow the rate of metabolism and delay the accumulation of H+ and Ca+ during ischemia.34 In the present study, blocking of the adenosine A1 receptor by DPCPX resulted in strong suppression of the inhibitory effects of ischemic preconditioning on both leukocyte rolling and accumulation in postischemic retina. Moreover, adenosine A1 receptor stimulation by R-PIA produced partial but significant mimicking of the inhibition of postischemic leukocyte behavior by ischemic preconditioning. Our results show a central role of adenosine in reduced postischemic leukocyte–endothelium cell interactions in preconditioned retinal veins. In addition, adenosine has been known to act as an anti-inflammatory molecule.35 It has been suggested that adenosine inhibits expression of adhesion molecules by activated endothelial cells and, moreover, inhibits leukocyte adherence and extravasation after ischemia-reperfusion.36 It is feasible that anti-inflammatory potential of adenosine would partially contribute to reduced postischemic leukocyte–endothelium interactions in preconditioned vessels.

In the present study, ischemic preconditioning strongly inhibited leukocyte rolling and subsequent accumulation in the postischemic retina. In the postischemic liver, a recent study using intravital microscopy has reported that preconditioning attenuates leukocyte–endothelium interactions in terminal hepatic venules.13 Moreover, Akimitsu et al.11 have reported the inhibitory effects of ischemic preconditioning on postischemic leukocyte adhesion and emigration in skeletal muscle. They also showed that adenosine may mediate the ability of ischemic preconditioning to attenuate postischemic leukocyte–endothelium cell interactions. Indeed, their results in the liver and the skeletal muscle are compatible to our findings. However, Kubes et al.12 have shown that adenosine may play only a minor role in reduced leukocyte–endothelium cell interactions in preconditioned mesenteric venules after ischemia-reperfusion. They have also reported that preconditioning had a minor effect on the flux of rolling neutrophils in mesenteric venules after ischemia-reperfusion.

In the present study, ischemic preconditioning was induced in the retina 24 hours before induction of prolonged ischemic insult. It has been suggested that various organs may demonstrate different natures in the preconditioning phenomenon. Ischemic preconditioning in the heart induces protection in a biphasic pattern.2 5 37 The early preconditioning protective response is seen very early, lasting only hours, and does not need protein synthesis; delayed preconditioning phenomenon needs a day or a few days after ischemic preconditioning and needs protein synthesis.37 A report by Roth et al.3 has shown that preconditioning phenomenon in the retina is not biphasic. Preconditioning before 24 or 72 hours before ischemia completely prevents retinal damage, whereas a short time interval between preconditioning and ischemia causes greater retinal damage. Therefore, some difference in the nature of preconditioning phenomenon between various organs may account for some discrepancy between our findings and those in some previous reports.

In summary, the present study demonstrated the strong inhibitory effects of ischemic preconditioning on leukocyte rolling and after leukocyte accumulation in postischemic retina. In addition, adenosine played an important role in inhibitory effects on leukocyte–endothelium interactions through the A1 receptor. Retinal ischemic preconditioning could partially exert neuroprotective effects against prolonged ischemic insult by inhibition of leukocyte–endothelium cell interactions through the adenosine A1 receptor.


   Footnotes
 
Supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan.

Submitted for publication February 9, 2001; revised April 24, 2001; accepted May 18, 2001.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Junichi Kiryu, Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. kiryu{at}kuhp.kyoto-u.ac.jp


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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