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(Investigative Ophthalmology and Visual Science. 2008;49:3605-3610.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-0817
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Deleterious Role of TNF-{alpha} in Retinal Ischemia–Reperfusion Injury

Samuel Berger,1,2 Sean I. Savitz,2,3 Sheetal Nijhawan,1 Manjeet Singh,1 Joel David,1 Pearl S. Rosenbaum,4,5 and Daniel M. Rosenbaum1

1From the Department of Neurology, SUNY Downstate Medical Center, Brooklyn, New York; 3Department of Neurology, University of Texas Houston Medical School, Houston, Texas; 4Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York; and 5Department of Ophthalmology, Bronx-Lebanon Hospital Center, Albert Einstein College of Medicine, Bronx, New York.

PURPOSE. Tumor necrosis factor (TNF)-{alpha} is a mediator of neuronal cell death and survival in ischemia–reperfusion injury. This study was conducted to further elucidate the role of TNF-{alpha} and its receptor in an in vivo model of retinal ischemia–reperfusion injury by investigating its effects on retinal histopathology and function.

METHODS. Retinal ischemia–reperfusion injury was performed on p55 and p75 knockout (KO) mice and Sprague–Dawley rats using the high intraocular pressure method. The temporal expression of TNF-{alpha} was ascertained with immunohistochemical staining. Separate rats received intravitreal recombinant TNF-{alpha} or neutralizing antibody before or after ischemia. TUNEL labeling was performed to assess for cell death, and electroretinography was performed to assess function.

RESULTS. TNF-{alpha} expression peaked at 12 to 24 hours after ischemia–reperfusion injury. TUNEL staining was diminished after intravitreal TNF-{alpha} antibody. Both transgenic KOs demonstrated significantly less functional impairment. Rats receiving recombinant TNF-{alpha} 48 hours after ischemia showed exaggerated functional impairment. Animals treated with TNF-{alpha} antibody before ischemia displayed significant functional improvement.

CONCLUSIONS. TNF-{alpha} plays a largely deleterious role in ischemia–reperfusion injury in an in vivo model of retinal injury. Direct neutralization of this cytokine partially preserves retinal function. The diverse characteristics of TNF-{alpha} are attributed in part to the timing of its expression after injury. TNF-{alpha} receptor expression and function, along with combination treatments targeting death receptor–mediated apoptosis, should be further explored to develop neuroprotective therapeutic strategies for acute retinal ischemic disorders.






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