Document Type : Original Article

Authors

1 Poostchi Ophthalmology Research Center, Department of Ophthalmology, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Clinical Sciences, Faculty of Veterinary Medicine, Shiraz University, Shiraz, Iran

3 Department of Clinical Sciences, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran

Abstract

The objective of the present study was to investigate the clinical and histopathological effects of intravitreal injection of pentoxifylline (PTX) the management of an experimental model of uveitis. Fifty-two rabbits were divided randomly into six intravitreal treated groups as below: 1) Balanced salt solution (BSS), 2) Salmonella typhimurium lipopolysaccharide endotoxin (LPS) + BSS, 3) LPS + PTX 100 μg, 4) LPS + PTX 500 μg, 5) BSS + PTX 100 μg and 6) BSS + PTX 500 μg. Inflammation was evaluated by clinical examinations using slit lamp on days 1, 3, 5 and 7 post injections and histopathological examinations were also performed at the end of the study. Clinical examinations demonstrated a statistically significant difference between group 1 and group 2 on day 5 and day 7. Moreover, the comparison of clinical severity scores of group 1 with groups 3, 4, 5 and 6, on third, fifth and seventh post-injection days showed statistically significant differences. The mean histopathological inflammation intensity score in groups 5 and 6 was significantly higher than group 1. The mean histopathological inflammation intensity score in groups 3, 4, 5 and 6 was significantly higher than group 2. Intravitreal injection of PTX in an experimental model of uveitis in rabbits not only does not reduce inflammation but also leads to inflammation when used alone or in combination with LPS.

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    1. Siddique SS, Shah R, Suelves AM, et al. Road to remission: A comprehensive review of therapy in uveitis. Expert Opin Investig Drugs 2011; 20(11): 1497-1515.
    2. Durrani O, Tehrani N, Marr J, et al. Degree, duration, and causes of visual loss in uveitis. BrJ Ophthalmol 2004; 88(9): 1159-1162.
    3. Franks WA, Limb GA, Stanford MR, et al. Cytokines in human intraocular inflammation. Curr Eye Res 1992; 11: 187-191.
    4. de Boer JH, Van Haren MAC, de Vries-Knoppert W, et al. Analysis of IL-6 levels in human vitreous fluid obtained from uveitis patients, patients with proliferative intraocular disorders and eye bank eyes. Curr Eye Res 1992; 11: 181-186.
    5. Hofman FM, Hinton DR. Tumor necrosis factor-alpha in the retina in acquired immune deficiency syndrome. Investig Ophthalmol Vis Sci 1992; 33(6): 1829-1835.
    6. De Vos AF, Hoekzema R, Kijlstra A. Cytokines and uveitis, a review. Curr Eye Res 1992; 11(6): 581-597
    7. Demir T, Gödekmerdan A, Balbaba M, et al. The effect of infliximab, cyclosporine A and recombinant IL-10 on vitreous cytokine levels in experimental autoimmune uveitis. Indian J Ophthalmol 2006; 54(4): 241-245.
    8. Lindstedt EW, Baarsma GS, Kuijpers RW, et al. Anti-TNF-α therapy for sight threatening uveitis. Br J Ophthalmol 2005; 89(5): 533-536.
    9. Yoshida M, Yoshimura N, Hangai M, et al. Interleukin-1 alpha, interleukin-1 beta, and tumor necrosis factor gene expression in endotoxin-induced uveitis. Invest Ophthalmol Vis Sci 1994; 35 (3): 1107-1113.
    10. Salhiyyah K, Senanayake E, Abdel‐Hadi M, et al. Pentoxifylline for intermittent claudication. Cochrane Database Syst Rev 2012; 18:1:CD005262. doi: 10.1002/14651858.CD005262.pub2.
    11. George J, Abel PW. Pentoxifylline. In: xPharm: The comprehensive pharmacology reference. New York, USA: Elsevier 2011; 1-18.
    12. Salyer JL, Bohnsack J, Knape WA, et al. Mechanisms of tumor necrosis factor-alpha alteration of PMN adhesion and migration. Am J Pathol 1990; 136(4): 831-841.
    13. Bessler H, Gilgal R, Djaldetti M, et al. Effect of pentoxifylline on the phagocytic activity, cAMP levels, and superoxide anion production by monocytes and polymorphonuclear cells. J Leukoc Biol 1986; 40(6): 747-754.
    14. Leimenstoll G, Zabel P, Schroeder P, et al. Suppression of OKT3-induced tumor necrosis factor alpha formation by pentoxifylline in renal transplant recipients. Transplant Proc 1993; 25(1): 561-563.
    15. Fong Y, Tracey KJ, Moldawer L, et al. Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia. J Exp Med 1989; 170: 1627-1633.
    16. Moreira A, Sampaio EP, Zmuidzinas A, et al. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 1993; 177: 1675-1680.
    17. Neuner P, Klosner G, Schauer E, et al. Pentoxifylline in vivo down-regulates the release of IL-1 beta, IL-6, IL-8 and tumour necrosis factor-alpha by human peripheral blood mononuclear cells. Immunology 1994; 83(2): 262-267.
    18. Appenzeller S, Hazel E. Pentoxifylline for the treatment of anterior uveitis in Behcet’s disease: Possible alternative for TNF blockers. Rheumatol Int 2011; 31(11): 1511-1513.
    19. Yasui K, Ohta K, Kobayashi M, et al. Successful treatment of Behçet disease with pentoxifylline. Ann Intern Med 1996; 124(10): 891-893.
    20. Avunduk AM, Avunduk MC, Oztekin E, et al. Characterization of T lymphocyte subtypes in endotoxin-induced uveitis and effect of pentoxifylline treatment. Curr Eye Res 2002; 24(2): 92-98.
    21. Erşanli D, Karadayi K, Toyran S, et al. The efficacy of hyperbaric oxygen for the treatment of experimental uveitis induced in rabbits. Ocul Immunol Inflamm 2005; 13(5): 383-388.
    22. Verma MJ, Mukaida N, Vollmer-Conna U, et al. Endotoxin-induced uveitis is partially inhibited by anti–IL-8 antibody treatment. Invest Ophthalmol Vis Sci 1999; 40: 2465-2470.
    23. Kanai K, Ito Y, Nagai N, et al. Effects of instillation of eye drops containing disulfiram and hydroxypropyl-β-cyclodextrin inclusion complex on endotoxin-induced uveitis in rats. Curr Eye Res 2012; 37: 124-131.
    24. Koizumi K, Poulaki V, Doehmen S, et al. Contribution of TNF-α to leukocyte adhesion, vascular leakage, and apoptotic cell death in endotoxin-induced uveitis in vivo. Invest Ophthalmol Vis Sci 2003; 44(5): 2184-2191.
    25. Santos Lacomba M, Marcos Martin C, Gallardo Galera J, et al. Aqueous humor and serum tumor necrosis factor-α in clinical uveitis. Ophthalmic Res 2001; 33(5): 251-255.
    26. De Vos AF, Van Haren MAC, Verhagen C, et al. Systemic anti-tumor necrosis factor antibody treatment exacerbates endotoxin-induced uveitis in the rat. Exp Eye Res 1995; 61(6): 667-675.
    27. Van Furth A, Verhard‐Seijmonsbergen E, Van Furth R, et al. Effect of lisofylline and pentoxifylline on the bacterial‐stimulated production of TNF‐α, IL‐1β and IL‐10 by human leucocytes. Immunology 1997; 91(2): 193-196.
    28. Chou PI, Chang JS, Chen JT, et al. The short-term effect of pentoxifylline on rabbit choroidal blood flow. J Ocul Pharmacol Ther 2000; 16(5): 455-462.
    29. Schmetterer L, Kemmler D, Breiteneder H, et al. A randomized, placebo-controlled, double-blind cross-over study of the effect of pentoxifylline on ocular fundus pulsations. Am J Ophthalmol 1996; 121(2): 169-176.
    30. Yasukawa T, Ogura Y, Sakurai E, et al. Intraocular sustained drug delivery using implantable polymeric devices. Adv Drug Deliv Rev 2005; 57(14): 2033-2046.
    31. Sen HA, Campochiaro PA. Stimulation of cyclic adenosine monophosphate accumulation causes breakdown of the blood-retinal barrier. Invest Ophthalmol Vis Sci 1991; 32(7): 2006-2010.
    32. Krause PJ, Kristie J, Wang W, et al. Pentoxifylline enhancement of defective neutrophil function and host defense in neonatal mice. Am J Pathol 1987; 129(2): 217-222.
    33. London NJS, Garg SJ, Moorthy RS, et al. Drug-induced uveitis. J Ophthalmic Inflamm Infect 2013; 3: 43. doi.org/10.1186/1869-5760-3-43.
    34. Cunningham Jr ET, Pasadhika S, Suhler EB, et al. Drug-induced inflammation in patients on TNFα inhibitors. Ocul Immunol Inflamm 2012; 20(1): 2-5.
    35. Viguier M, Richette P, Bachelez H, et al. Paradoxical adverse effects of anti-TNF-alpha treatment: Onset or exacerbation of cutaneous disorders. Expert Rev Clin Immunol 2009; 5(4): 421-431.