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J. C. Morrison, W. O. Cepurna, T. A. Doser, J. A. Dyck, E. C. Johnson; A Short Interval of Controlled Elevation of IOP (CEI) Reproduces Early Chronic Glaucoma Model Optic Nerve Head (ONH) Gene Expression Responses. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5216.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies using our chronic rat glaucoma model identified the upregulation of Il6-type cytokine signaling, cell proliferation and extracellular matrix (ECM) genes as dominant early ONH expression responses to elevated intraocular pressure (IOP). Although these responses may play a role in initial axonal injury, they may also indicate protective or recovery processes, or be secondary to axon loss. Currently it is not possible to differentiate these possibilities in a chronic model, because the exact level and duration of IOP elevation cannot be accurately measured or controlled. The purpose of this study was to show that an 8 hour interval of CEI can reproduce these responses in the rat ONH and provide insights into their interrelationships.
IOP was elevated in anesthetized rats by anterior chamber cannulation with a 30 gauge needle connected to a reservoir suspended above the eye. IOP was determined by a calibrated pressure transducer and adjusted by reservoir height. IOP was elevated to 60 mm Hg for 8 hours, with retinal perfusion confirmed by direct ophthalmoscopy. Groups of 8 ONH from control and CEI eyes were collected at 0 h, 12 h, 3 days and 10 days following exposure.ONH mRNA was prepared for qPCR to determine levels of selected messages known to be altered in our chronic model. ANOVA was used to test for significant changes relative to control values.
Significant upregulation of the cytokines IL6 and Lif, Socs3 (a direct feedback inhibitor of the Jak/Stat pathway) and downregulation of the Lif receptor (Lifr) were all evident immediately after pressure exposure. By 12 hours post-exposure, mRNA levels for ECM proteins Postn, Tnc and Fbln2 reached their maximum values. Significant upregulation of cell proliferation, indicated by Top2a and Prc1, did not occur until 3 days post-exposure.
An interval of CEI dramatically alters regulation of ONH genes indicative of cytokine signaling, ECM alteration and cell proliferation, reproducing early changes found in our chronic model. In addition, this CEI model reveals a possible sequence to these initial events.
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