Effect of FTY720 on retinal leukocytes adhesion and vascular permeability in diabetic rats_Chinese Journal of Ocular Fundus Diseases

Authors：

FanLingling ,  YanHua

Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin 300052, China;

Corresponding author：

YanHua, Email: phuayan2000@163.com

Keywords：

Diabetic retinopathy/therapy; Diabetic retinopathy/physiopathology; Immunologic factors/therapeutic use; Animal experimentation

DOI：

10.3760/cma.j.issn.1005-1015.2016.02.012

Video：

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Objective Methods Ninety male Wister rats were randomly divided into normal control group, diabetic group and FTY720 group, thirty rats in each group. Diabetes was induced by giving a single intraperitoneal injection of streptozocin. FTY720 group was administered with FTY720 at a dose of 0.3 mg/kg by oral gavage daily for 3 months after establishment of diabetes. All rats were used for experiments following intervention for 3 months in FTY720 group. Immunohistochemical staining was used to observe the expression and distribution of intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1), and the positive cells were counted. Real-time reverse transcription PCR was used to measure mRNA expression of ICAM-1 and VCAM-1. Fluorescein isothiocyanate-Concanavalin A perfusion was used to detect retinal leukocytes adhesion. Evans blue (EB) perfusion was used to analyze retinal vascular permeability. Immunofluorescence staining was used to detect retinal inflammatory cells infiltration. Results In diabetic group, both ICAM-1(t=12.81) and VCAM-1 (t=11.75) positive cells as well as their mRNA expression (t=16.14, 9.59) were increased compared with normal control group, with statistical significance (P < 0.05). In FTY720 group, both ICAM-1(t=-9.93) and VCAM-1 (t=-6.61) positive cells as well as their mRNA expression (t=-15.28, -6.10) were decreased compared with diabetic group, with statistical significance (P < 0.05). Retinal leukocytes adhesion (t=16.32) and EB permeability (t=17.83) were increased in diabetic group compared with normal control group, while they were decreased in FTY720 group compared with diabetic group(t=-9.93, -11.82),with statistical significance (P < 0.05). There were many CD45 positive leukocytes infiltration in retina of diabetic group, including CD11b positive macrophage/activated microglia, while both of them were little in FTY720 group. Conclusions FTY720 can decrease retinal leukocytes adhesion, reduce retinal vascular permeability and inflammatory cells infiltration, which is associated with down-regulation of ICAM-1 and VCAM-1.

Citation： FanLingling, YanHua. Effect of FTY720 on retinal leukocytes adhesion and vascular permeability in diabetic rats. Chinese Journal of Ocular Fundus Diseases, 2016, 32(2): 163-168. doi: 10.3760/cma.j.issn.1005-1015.2016.02.012 Copy

1.	Tang J, Kern TS. Inflammation in diabetic retinopathy [J]. Prog Retin Eye Res, 2011, 30(5): 343-358. DOI: 10.1016/j.preteyeres.2011.05.002.
2.	Miyamoto K, Oqura Y. Pathogenetic potential of leukocytes in diabetic retinopathy [J]. Semin Ophthalmol, 1999, 14(4): 233-239.
3.	Miyamoto K, Khosrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition [J]. Proc Natl Acad Sci USA, 1999, 96(19): 10836-10841.
4.	Imeri F, Blanchard O, Jenni A, et al. FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P and phosphoinositide 3-kinase [J]. Naunyn Schmiedebergs Arch Pharmacol, 2015, 388(12):1283-1292. DOI: 10.1007/s00210-015-1159-5.
5.	段惠惠, 黄建梅, 于素云, 等. STZ糖尿病大鼠视网膜病变模型的再评价 [J]. 中国比较医学杂志, 2013, 23(5): 12-18.Duan HH, Huang JM, Yu SY, et al. Revaluation of experimental animal model of diabetic retinoapthy induced by STZ rats [J]. Chin J Compar Med, 2013, 23(5): 12-18.
6.	杨宏伟, 陈晓隆, 卜立敏, 等. 细胞凋亡在STZ诱导糖尿病大鼠早期视网膜病变中的作用机制 [J]. 眼科研究, 2009, 27(6): 472-476.Yang HW, Chen XL, Pu LM, et al. Mechanism of apoptosis in early diabetic retina induced by STZ in rat[J]. Chin Ophthalmic Res, 2009, 27(6): 472-476.
7.	Copland DA, Liu J, Schewitz-Bowers LP, et al. Therapeutic dosing of fingolimod (FTY720) prevents cell infiltration, rapidly suppresses ocular inflammation, and maintains the blood-ocular barrier [J]. Am J Pathol, 2012, 180(2): 672-681. DOI: 10.1016/j.ajpath.2011.10.008.
8.	Miyahara S, Kiryu J, Yamashiro K, et al. Simvastatin inhibits leukocyte accumulation and vascular permeability in the retinas of rats with streptozotocin-induced diabetes [J]. Am J Pathol, 2004, 164(5): 1697-1706.
9.	Xu Q, Qaum T, Adamis AP. Sensitive blood-retinal barrier breakdown quantitation using Evans blue [J]. Invest Ophthalmol Vis Sci, 2001, 42(3): 789-794.
10.	Jorns A, Rath KJ,Terbish T, et al. Diabetes prevention by immunomodulatory FTY720 treatment in the LEW.1AR1-iddm rat despite immune cell activation [J]. Endocrinology, 2010, 151(8): 3555-3565. DOI: 10.1210/en.2010-0202.
11.	Kim JA, Berliner JA, Natarajan RD, et al. Evidence that glucose increases monocyte binding to human aortic endothelial cells [J]. Diabetes, 1994, 43(9): 1103-1107.
12.	Nowak M, Wielkoszynski T, Marek B, et al. Blood serum levels of vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) in diabetic retinopathy [J]. Clin Exp Med, 2008, 8(3): 159-164. DOI: 10.1007/s10238-008-0173-z.
13.	Sharma S, Purohit S, Sharma A, et al. Elevated serum levels of soluble TNF receptors and adhesion molecules are associated with diabetic retinopathy in patients with type-1 diabetes [J/OL]. Mediators Inflamm, 2015, 2015:279393[2015-08-03]. http://dx.doi.org/10.1155/2015/279393. DOI: 10.1155/2015/279393.
14.	Wang L, Sammani S, Moreno-Vinasco L, et al. FTY720 (s)-phosphonate preserves sphingosine 1-phosphate receptor 1 expression and exhibits superior barrier protection to FTY720 in acute lung injury [J]. Crit Care Med, 2014, 42(3): 189-199. DOI: 10.1097/CCM.0000000000000097.
15.	Spampinato SF, Obermeier B, Cotleur A, et al. Sphingosine 1 phosphate at the blood brain barrier: can the modulation of S1P Receptor 1 influence the response of endothelial cells and astrocytes to inflammatory stimuli? [J/OL]. PLoS One, 2015, 10(7): 0133392[2015-07-21]. http://dx.plos.org/10.1371/journal.pone.0133392. DOI: 10.1371/journal.pone.0133392.
16.	Nishihara H, Shimizu F, Sano Y, et al. Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis [J]. PLoS One, 2015, 10(3): 0121488[2015-03-16]. http://dx.plos.org/10.1371/journal.pone.0121488. DOI: 10.1371/journal.pone.0121488.

1. Tang J, Kern TS. Inflammation in diabetic retinopathy [J]. Prog Retin Eye Res, 2011, 30(5): 343-358. DOI: 10.1016/j.preteyeres.2011.05.002.
2. Miyamoto K, Oqura Y. Pathogenetic potential of leukocytes in diabetic retinopathy [J]. Semin Ophthalmol, 1999, 14(4): 233-239.
3. Miyamoto K, Khosrof S, Bursell SE, et al. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition [J]. Proc Natl Acad Sci USA, 1999, 96(19): 10836-10841.
4. Imeri F, Blanchard O, Jenni A, et al. FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P and phosphoinositide 3-kinase [J]. Naunyn Schmiedebergs Arch Pharmacol, 2015, 388(12):1283-1292. DOI: 10.1007/s00210-015-1159-5.
5. 段惠惠, 黄建梅, 于素云, 等. STZ糖尿病大鼠视网膜病变模型的再评价 [J]. 中国比较医学杂志, 2013, 23(5): 12-18.Duan HH, Huang JM, Yu SY, et al. Revaluation of experimental animal model of diabetic retinoapthy induced by STZ rats [J]. Chin J Compar Med, 2013, 23(5): 12-18.
6. 杨宏伟, 陈晓隆, 卜立敏, 等. 细胞凋亡在STZ诱导糖尿病大鼠早期视网膜病变中的作用机制 [J]. 眼科研究, 2009, 27(6): 472-476.Yang HW, Chen XL, Pu LM, et al. Mechanism of apoptosis in early diabetic retina induced by STZ in rat[J]. Chin Ophthalmic Res, 2009, 27(6): 472-476.
7. Copland DA, Liu J, Schewitz-Bowers LP, et al. Therapeutic dosing of fingolimod (FTY720) prevents cell infiltration, rapidly suppresses ocular inflammation, and maintains the blood-ocular barrier [J]. Am J Pathol, 2012, 180(2): 672-681. DOI: 10.1016/j.ajpath.2011.10.008.
8. Miyahara S, Kiryu J, Yamashiro K, et al. Simvastatin inhibits leukocyte accumulation and vascular permeability in the retinas of rats with streptozotocin-induced diabetes [J]. Am J Pathol, 2004, 164(5): 1697-1706.
9. Xu Q, Qaum T, Adamis AP. Sensitive blood-retinal barrier breakdown quantitation using Evans blue [J]. Invest Ophthalmol Vis Sci, 2001, 42(3): 789-794.
10. Jorns A, Rath KJ,Terbish T, et al. Diabetes prevention by immunomodulatory FTY720 treatment in the LEW.1AR1-iddm rat despite immune cell activation [J]. Endocrinology, 2010, 151(8): 3555-3565. DOI: 10.1210/en.2010-0202.
11. Kim JA, Berliner JA, Natarajan RD, et al. Evidence that glucose increases monocyte binding to human aortic endothelial cells [J]. Diabetes, 1994, 43(9): 1103-1107.
12. Nowak M, Wielkoszynski T, Marek B, et al. Blood serum levels of vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1) and endothelial leucocyte adhesion molecule-1 (ELAM-1) in diabetic retinopathy [J]. Clin Exp Med, 2008, 8(3): 159-164. DOI: 10.1007/s10238-008-0173-z.
13. Sharma S, Purohit S, Sharma A, et al. Elevated serum levels of soluble TNF receptors and adhesion molecules are associated with diabetic retinopathy in patients with type-1 diabetes [J/OL]. Mediators Inflamm, 2015, 2015:279393[2015-08-03]. http://dx.doi.org/10.1155/2015/279393. DOI: 10.1155/2015/279393.
14. Wang L, Sammani S, Moreno-Vinasco L, et al. FTY720 (s)-phosphonate preserves sphingosine 1-phosphate receptor 1 expression and exhibits superior barrier protection to FTY720 in acute lung injury [J]. Crit Care Med, 2014, 42(3): 189-199. DOI: 10.1097/CCM.0000000000000097.
15. Spampinato SF, Obermeier B, Cotleur A, et al. Sphingosine 1 phosphate at the blood brain barrier: can the modulation of S1P Receptor 1 influence the response of endothelial cells and astrocytes to inflammatory stimuli? [J/OL]. PLoS One, 2015, 10(7): 0133392[2015-07-21]. http://dx.plos.org/10.1371/journal.pone.0133392. DOI: 10.1371/journal.pone.0133392.
16. Nishihara H, Shimizu F, Sano Y, et al. Fingolimod prevents blood-brain barrier disruption induced by the sera from patients with multiple sclerosis [J]. PLoS One, 2015, 10(3): 0121488[2015-03-16]. http://dx.plos.org/10.1371/journal.pone.0121488. DOI: 10.1371/journal.pone.0121488.

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