Azat ALINAK, TAMER DEMİR, Burak TURGUT, Nusret AKPOLAT, Orhan AYDEMİR, NESRİN DEMİR

Retinal iskemi-reperfüzyon modelinde rekombinant İL-11'in retinal dokuya etkisi

Amaç: Bu çalışma guinea pig modelinde retinal iskemi-reperfüzyon (İ-R) hasarında retina üzerine Rekombinant İL-11 (rhİL-11)'in koruyucu etkisinin araştırılması amacıyla yapılmıştır. Gereç ve Yöntem: Çalışmada 15 adet kobay randomize olarak her biri beş guinea pig içeren üç gruba ayrıldı: plasebo, sham ve tedavi (rhİL-11) grubu. Plasebo grubundaki kobaylara sadece günlük 0,1 cc salin solüsyonu intraperitoneal verildi. Her bir göze 90 dakika basınçla indüklenen iskemi peryodundan 1 saat önce ve 2 günlük reperfüzyon süreci boyunca sham grubundaki kobaylara günlük 0,1 cc salin solüsyonu ve tedavi grubundaki kobaylara ise günlük 5μg/kg rhİL-11 intraperitoneal olarak verildi. İkinci günün sonunda kobaylar sakrifiye edilerek tüm gruplardaki hayvanların her iki gözleri enüklee edilip retinaları histopatolojik olarak incelendi. Bulgular: Histopatolojik olarak incelenen retina kesitlerinde iç pleksiform tabakanın kalınlığı, rhİL-11 grubunda hem plasebo hem de sham grubuna göre anlamlı olarak farklı bulunmamıştır (sırasıyla p=1.000, p= 0.095). Ancak sham grubunda plasebo grubuna göre anlamlı olarak daha kalın ölçülmüştür (p=0.032). Retinanın iç tabakalarındaki (internal limitan membran ve iç pleksiform tabaka) polimorfonükleerlokosit (PMNL) infiltrasyonu, sham grubunda plasebo grubuna (p=0.012) ve rhİL-11 grubuna göre anlamlı artmış bulunurken (p=0.032), rhİL-11 grubunda plasebo grubuna göre anlamlı fark bulunamadı (p=0.189). Sonuç: Çalışmamızda retinal İ-R hasarında retinal dokuyu koruyucu etki gösteren rhİL-11, retinal İ-R hasarının engellenmesinde potansiyel alternatif bir ajan olabilir.

The effect of recombinant Il-11 on retina in experimental ischemia/reperfusion model

Objective: This experimental study was performed to investigate the protective effect of Recombinant IL-11 (rhIL-11) on retina tissue in the ischemia/reperfusion (I/R) injury in a guinea pig model. Materials and Methods: In this study, fifteen guinea pigs were randomly divided to three groups that each one has five guinea pigs: placebo, sham and the treatment (rhIL-11) groups. The guinea pigs in the placebo group were only given 0,1 cc saline solution intraperitoneally. Pressure induced 90 minutes of retinal ischemia and 48 hours of reperfusion were established in the sham and treatment groups. Saline for the sham group and 5μg/kg of rhIL-11 for the treatment group were administered intraperitoneally daily. At the end of the reperfusion period eyes of the animals of all groups were sacrificed and were enucleated. Retinal tissues were evaluated histopathologically. Results: The thickness of inner plexiform layer of retina in the treatment group was not shown significantly difference than placebo and sham (p=1.000, p= 0.095 respectively). However, in the sham group it was measured as significantly thicker than that of placebo group (p=0.032). The infiltration of the polymorphonuclear cells in the internal limiting membrane and inner plexiform layer of the sham group was significantly higher than those of the placebo (p=0.012) and treatment group (p=0.032). However, it was observed that there is no significant difference between treatment and placebo groups (p=0.189). Conclusion: rhIL-11 that shows a protective effect in retinal I/R injury kept retinal tissue in our study, this may make it a potential alternative agent for the prevention of retinal I/R injury.

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1) Granger DN, Hallwart ME, Parks DA. Ischemia reperfusion injury role of oxygen derived free radicals. Acta Phvsiol Scand 1986; 548 (Suppl.): 47-53.
2) Barry MC, Grace PA. Ischaemia reperfusion injury. Surgery 1997; 15: 68-72.
3) Conger JD, Weil JV. Abnormal vascular function following ischemia-reperfusion injury. J Invest Med 1995; 43: 4311-4342.
4) Cotreau MM, Stonis L, Strahs A, Schwertschlag US. A multiple-dose, safety, tolerability, pharmacokinetics and pharmacodynamic study of oral recombinant human interleukin-11 (oprelvekin). Biopharm Drug Dispos 2004; 25: 291-296.
5) Kwon B, Youn BS, Kwon BS. Functions of newly identified members of the tumor necrosis factor receptor/ligand superfamilies in lymphocytes. Curr Opin Immunol 1999; 11: 340-345.
6) Tezel G, Wax MB. Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. J Neurosci 2000; 20: 8693-8700.
7) Scmidt M, Giessl A, Laufs T, et al. How does the eye breathe? Evidence for neuroglobin-mediated oxygen supply in the mammalian retina. J Biol Chem 2003; 278: 1932-1935.
8) Yoneda S, Tanihara H, Kido N, et al. Interleukin-1beta mediates ischemic injury in the rat retina. Exp eye res 2001; 73: 661-667.
9) Geyer O, Almog J, lupu-meiri M, Lazar M, Oron Y. Nitric oxide synthase inhibitors protect rat retina against ischemic injury. FEBS Lett 1995; 374: 399-402.
10) Sharma HS, Alm P, Westman J. Nitric oxide and carbon monoxide in the brain pathology of heat stres. Prog Brain Res 1998; 115: 297-333.
11) Ahn KS, Sethi G, Aggarwal BB. Simvastatin potentiates TNF-alpha induced apoptosis through the down-regulation of NFkappa B-dependent antiapoptotic gene products: Role of I kapa B alpha kinase and TGF-beta-activated kinase-1. Journal of Immunology 2007; 178: 2507-2516.
12) Kathleen C. Flanders, Maryland James K. Burmester. Medical Applications of Transforming Growth Factor-â. CM&R 2003; 1: 13-20.
13) Furuyoshi N, Furuyoshi M, May CA, et al. Vascular and glial changes in the retrolaminar optic nerve in glaucomatous monkey eyes. Ophthalmologica 2000; 214: 24-32.
14) Yu AL, Fuchshofer R, Bikre M, et al. Hypoxia/reoxygenation and TGF-â increase áB-crystallin expression in human optic nerve head astrocytes. Experimental Eye Research 2007; 84: 694-706.
15) Sanchez RN, Chan CK, Garg S, et al. Interleukin-6 in retinal ischemia reperfusion injury in rats. Invest Ophthalmol Vis Sci 2003; 44: 4006- 4011.
16) Sun Z, Klein AS, Radaeva S, et al. In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats. Gastroenterology 2003; 125: 202- 215.
17) Herrmann O, Tarabin V, Suzuki S, et al. Regulation of body temperature and neuro-protection by endogenous interleukin-6 in cerebral ischemia. J Cereb Blood Flow Metab 2003; 23: 406-415.
18) Hangai, M, Yoshimura, N, Honda, Y. Increased cytokine gene expression in rat retina following transient ischemia. Ophthalmic Res 1996; 28: 248-254.
19) Moreland L, Gugliotti R, King K, et al. Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis. Arthritis Res 2001; 3: 247-252.
20) Peterson RL, Wang L, Albert L, Keith JC Jr, Dorner AJ. Molecular effects of recombinant human interleukin-11 in the HLA-B27 rat model of inflammatory bowel disease. Lab Investig 1998; 78: 1503-1512.
21) Ropeleski MJ, Tang J, Walsh-Reitz MM, Musch MW, Chang EB. Interleukin-11-induced heat shock protein 25 confers intestinal epithelial-specific cytoprotection from oxidant stress. Gastroenterology 2003; 124: 1358-1368.
22) Tsujikawa A, Ogura Y, Hiroshiba N, et al. Retinal ischemia-reperfusion injury attenuated by blocjing of adhesion molecules of vascular endothelium. IOVS 1999; 40: 1183-1190.
23) Trepicchio WL, Bozza M, Pedneault G, Dorner AJ. Recombinant human IL-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production. J Immunol 1996; 157: 3627- 3634.
24) Weber M, Said SM, Hicks D, Dreyfus H, Sahel JA. Monosialoganglioside GM1 reduces ischemia-induced injury in the rat retina. IOVS 1996; 37: 266-273.
25) Hughes WF. Quantitation of ischemic damage in the rat retina. Exp Eye Res 1991; 53: 573-582.
26) Ishihara M, Nakano T, Ohama E, Kawai Y. Postischemic reperfusion in the eyes of young and a ged rats. Jpn J Physiol 2000; 50: 125-132.
27) Ogura Y. In vivo evaluation of leukocyte dynamics in the retinal and choroidal circulation. Jpn J Ophthalmol 2000; 44:322-323.
28) Yoshida S, Yoshida A, Ishibashi T. Induction of DL-8, MCP-1, and bFGF by TNF-alpha in retinal glial cells: implications for retinal neovascularization during post-ischemic inflammation. Graefes Arch Clin Exp Ophthalmol 2004; 242: 409-413.