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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online January 30, 2002 as doi:10.1096/fj.01-0707fje. |
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suppression1
,
,2
,
* Retina Research Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA;
Department of Vitreoretinal Surgery, Center for Ophthalmology, University of Cologne, 50931 Köln, Germany;
Center for Molecular Medicine (ZMMK), University of Cologne, 50931 Köln, Germany; and
Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
3Correspondence: Retina Research Laboratory, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 324 Cambridge St., Boston, MA 02115, USA. E-mail: tony_adamis@meei.harvard.edu or joussena{at}aol.com
SPECIFIC AIMS
Diabetic retinopathy remains a leading cause of blindness. The disease has an underlying inflammatory component, manifesting leukocyte recruitment and adhesion to the retinal vasculature and up-regulation of inflammatory genes. Earlier reports have shown that high doses of aspirin are associated with decreased severity of diabetic retinopathy in patients with concurrent rheumatoid arthritis. However, clinical trials of low and intermediate doses of aspirin failed to show a beneficial effect. The aim of the current study was to explore the mechanisms underlying this clinical dichotomy. The involvement of nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2, and tumor necrosis factor 
(TNF-) in the pathogenesis of diabetic retinopathy was investigated in a rat model of diabetic retinopathy.
PRINCIPAL FINDINGS
Aspirin, meloxicam, and eternacept reduce leukocyte adhesion in the diabetic retina
Leukocyte adhesion in diabetic retinas is elevated twofold more than levels in nondiabetic animals. High-dose aspirin (50 mg/kg) has been shown to significantly reduce leukocyte adhesion in retinal arterioles (61%, n=10, P<0.0001), venules (52%, n=10, P<0.0001), and capillaries (41%, n=10, P<0.0001) of the treated animals compared with control untreated diabetic animals. Low-dose aspirin (1 mg/kg) did not affect leukocyte adhesion. At 0.2 mg/kg per day, the COX-2 inhibitor meloxicam inhibited leukocyte adhesion in retinal arterioles (P<0.05) but not in venules and capillaries. When increased to 2 mg/kg/day, leukocyte adhesion in the retinal arterioles (54%, n=7, P<0.0001), venules (54%, n=7, P<0.0001), and capillaries (36%, n=7, P<0.005) was significantly reduced in treated vs. control untreated diabetic animals. The soluble TNF- receptor eternacept (0.3 mg/kg) reduced leukocyte adhesion in retinal arterioles (37.6%, n=8, P<0.005), venules (38%, n=8, P<0.005), and capillaries (39%, n=8, P<0.001) of treated animals vs. diabetic controls.
Aspirin, but not meloxicam or eternacept, reduces LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) expression on diabetic neutrophils
Integrins LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) bind to the endothelial counter-receptor ICAM-1. CD18 blockade inhibits diabetic retinal leukocyte adhesion in vivo. We analyzed surface expression of CD11a, CD11b, and CD18 in leukocytes from diabetic rats treated with aspirin, meloxicam, and eternacept. In agreement with published results, neutrophil CD11a, CD11b, and CD18 levels were 3.3-fold (n=3, P<0.0001), 3.6-fold (n=3, P<0.0001), and 5.5-fold (n=3, P<0.0001) greater in leukocytes from 1 wk diabetic animals vs. nondiabetic controls. Treatment with either high-dose meloxicam or the TNF- inhibitor eternacept did not significantly alter neutrophil surface integrin levels (P>0.05 for all; data not shown). In contrast, high-dose aspirin reduced surface expression of CD18, CD11a, and CD11b to levels in nondiabetic animals (P<0.0001, n=3).
Aspirin, meloxicam, and eternacept reduce ICAM-1 protein levels in the diabetic retina
We previously demonstrated a significant increase of ICAM-1 mRNA expression in the retina 1 wk after induction of diabetes. Diabetic animals showed a threefold increase in ICAM-1 protein levels (P<0.0001, n=8) compared with nondiabetic control animals. Treatment with high-dose aspirin resulted in a reduction to half of the values in diabetic animals (P<0.0005, n=8). Similarly, treatment with eternacept reduced ICAM-1 protein levels by 57% (P<0.0001, n=8). High-dose meloxicam inhibited ICAM-1 less efficiently, by 35% (P<0.01, n=8).
Aspirin, eternacept, and (to a lesser extent) meloxicam reduce blood–retinal barrier breakdown in the diabetic retina
Leukocyte adhesion to the retinal vasculature is causal for blood–retinal barrier breakdown in early diabetic retinopathy. The effects of aspirin, meloxicam, and eternacept on blood–retinal barrier breakdown were measured with an Evans blue permeability assay. Blood–retinal barrier breakdown was increased 
threefold in the 1 wk diabetic animals (Fig. 1
). In marked contrast, the diabetes-related blood–retinal barrier breakdown in the high-dose aspirin-treated eyes was suppressed by 63% (1.18±0.18; n=8; P<0.0001). Similarly, treatment with the TNF- inhibitor eternacept resulted in a reduction of diabetic blood–retinal barrier breakdown by 52% (1.87±0.06; n=8; P<0.0005). High-dose treatment with the selective COX-2 inhibitor meloxicam reduced blood–retinal barrier breakdown by 29% (2.26±0.18; n=8; P<0.01).
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Treatment with aspirin, meloxicam, or eternacept does not reduce retinal VEGF levels
VEGF is a major contributor to increased leukocyte adhesion and blood–retinal barrier breakdown in the diabetic retina. To assess whether aspirin, meloxicam, or eternacept reduce leukocyte adhesion through a reduction in VEGF levels, we measured VEGF retinal protein levels via ELISA. Compared with nondiabetic animals, the retinas of diabetic animals demonstrated a 2.3-fold increase in normalized VEGF levels (0.65±0.1pg/mg protein vs. 1.47±0.15 pg/mg; P<0.005, n=6). VEGF levels in diabetic animals treated with either aspirin, meloxicam, or eternacept did not differ significantly from levels in the untreated diabetic animals (n=5–7, P>0.05 for all)
Aspirin and meloxicam reduce retinal TNF- levels
To investigate whether the effect of aspirin and meloxicam on leukocyte adhesion was mediated via a decrease in endogenous retina TNF- levels, we measured retinal TNF- levels with a sandwich ELISA (Fig. 2
). Compared with the retinas of nondiabetic animals, the retinas of diabetic animals demonstrated a 2.0-fold increase in normalized TNF- levels (0.99±0.05pg/mg vs. 2.00±0.18 pg/mg; P<0.0005; n=6). Treatment with high-dose aspirin reduced retinal TNF- in diabetic animals by 43% to levels comparable to those in nondiabetic animals (1.13±0.07 pg/mg protein; P>0.05 compared with nondiabetic animals, n=6). TNF- levels in diabetic animals treated with meloxicam were reduced with increased doses of meloxicam. A reduction of 19% was seen after treatment with 0.2 mg/kg (1.61±0.08 pg/mg, n=7) compared with levels in untreated diabetic animals (P<0.05). This effect was increased with higher doses of the COX-2 inhibitor (2 mg/kg [1.47±0.08 pg/mg, n=6, P<0.01]).
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Aspirin, high doses of meloxicam, and eternacept reduce retinal eNOS levels
Endothelial nitric oxide synthase (eNOS) protein levels and nitric oxide levels are increased early in diabetic retinopathy. The inhibition of nitric oxide reduces diabetic retinal leukocyte adhesion. To investigate the effect of aspirin, meloxicam, and eternacept on retinal eNOS levels, we utilized a commercially available sandwich ELISA. Compared with the retinas of nondiabetic controls, the retinas of diabetic animals demonstrated 2.3-fold higher eNOS levels (0.71±0.07pg/mg vs. 1.67±0.08 pg/mg; P<0.0001, n=6). Treatment with high-dose aspirin or eternacept reduced the retinal eNOS levels by 39% and 46%, respectively (aspirin: 1.01±0.06 pg/mg protein; P>0.05; eternacept: 0.9±0.06 pg/mg retinal weight compared with diabetic controls, n=6). A reduction in eNOS levels was detected after treatment with the selective COX-2 inhibitor meloxicam at 0.2 mg/kg (23%; 1.28±0.05 pg/mg; P<0.005, n=6), and showed a dose response with increasing dose: 2 mg/kg reduced the eNOS levels by 31% (1.14±0.06 pg/mg; P<0.001, n=6).
Aspirin, high-dose meloxicam and eternacept inhibit the activation of NF-
B in the retina
The transcription factor NF-B (nuclear factor B) is a key component for the inducible expression of adhesion molecules such as ICAM-1 and cytokines such as TNF-. TNF- is also a potent activator of NF-B, whereas aspirin inhibits the degradation of its inhibitor, IB. We therefore investigated the effect of aspirin, meloxicam, and eternacept on NF-B activation with a modified binding assay. Measurement in the retina showed 2.8-fold higher NF-B activity in diabetic than in nondiabetic animals (2.52±0.05 pg/mg vs. 0.89±0.05 pg/mg; P<0.0001, n=7). Treatment with aspirin and eternacept reduced retinal NF-B activity by 55 and 67%, respectively (aspirin: 1.11±0.01 pg/mg protein; P>0.05; eternacept: 0.8±0.08 pg/mg protein compared with diabetic controls, n=6). The reduction in NF-B activation was less prominent after treatment with low-dose meloxicam (32%; 1.72±0.04 pg/mg; P<0.005, n=7). Increasing the dose to 2 mg/kg reduced NF-B activation by 54% (1.15±0.03 pg/mg; P<0.001, n=6).
Aspirin down-regulates Erk kinase activity in neutrophils
It was recently found that aspirin down-regulates CD11a/CD18 and CD11b/CD18 via the inhibition of Erk kinase. Given the down-regulation of surface expression of CD11a/CD18 and CD11b/CD18 observed in leukocytes from aspirin-treated rats, we investigated the effect of aspirin on Erk kinase activation in our model. Erk kinase activity increased threefold in diabetic neutrophils compared with the nondiabetic controls (0.13±0.01pg/mg vs. 0.4±0.01 pg/mg; P<0.0001, n=6). Treatment with high-dose aspirin resulted in a 55% reduction compared with diabetic control animals (0.18±0.01pg/mg; P<0.0001, n=6).
CONCLUSIONS
Adhesion of leukocytes to the retinal vasculature is one of the earliest events in experimental diabetes and results in blood–retinal breakdown, endothelial cell damage, and capillary nonperfusion. We earlier showed that ICAM-1 and the leukocyte integrin CD18 are up-regulated during diabetic retinopathy and that proinflammatory cytokines such as VEGF drive the up-regulation of retinal ICAM-1, most likely via NO- and NF-B-dependent pathways. Given the inflammatory nature of early diabetic retinopathy, we hypothesized that NSAIDs may prove therapeutic in diabetic retinopathy. In the current study, we found that high doses of aspirin and intermediate doses of COX-2 inhibitors reduced leukocyte adhesion and blood–retinal barrier breakdown in part through the inhibition of NF-B activation and TNF- production. Aspirin as well as the inhibition of COX-2 and TNF- prevented the up-regulation of eNOS and ICAM-1 early in the course of diabetic retinopathy. Among the three drug classes tested, only aspirin was able to down-regulate Erk kinase activation and leukocyte CD11a, CD11b, and CD18 surface protein levels. Biological agents that neutralize TNF- have been approved by the U.S. Food and Drug Administration as safe and efficient for treatment of rheumatoid arthritis. NSAIDs like meloxicam and aspirin are used for a variety of inflammatory diseases. Our study demonstrates that these pharmacological agents have a beneficial effect in early experimental diabetic retinopathy and hold promise for clinical efficacy in patients.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0707fje; to cite this article, use FASEB J. (January 30, 2002) 10.1096/fj.01-0707fje 
2 These authors contributed equally to this work.
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S. Chen, Z. A. Khan, M. Cukiernik, and S. Chakrabarti Differential activation of NF-kappa B and AP-1 in increased fibronectin synthesis in target organs of diabetic complications Am J Physiol Endocrinol Metab, June 1, 2003; 284(6): E1089 - E1097. [Abstract] [Full Text] [PDF]
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K. Koizumi, V. Poulaki, S. Doehmen, G. Welsandt, S. Radetzky, A. Lappas, N. Kociok, B. Kirchhof, and A. M. Joussen Contribution of TNF-{alpha} to Leukocyte Adhesion, Vascular Leakage, and Apoptotic Cell Death in Endotoxin-Induced Uveitis In Vivo Invest. Ophthalmol. Vis. Sci., May 1, 2003; 44(5): 2184 - 2191. [Abstract] [Full Text] [PDF]
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 N. Vartiainen, G. Goldsteins, V. Keksa-Goldsteine, P. H. Chan, and J. Koistinaho Aspirin Inhibits p44/42 Mitogen-Activated Protein Kinase and Is Protective Against Hypoxia/Reoxygenation Neuronal Damage Stroke, March 1, 2003; 34(3): 752 - 757. [Abstract] [Full Text] [PDF]
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