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Platelet-Activating Factor in Vasoobliteration of Oxygen-Induced Retinopathy

¹ From the Department of Pediatrics, Ophthalmology, and Pharmacology, Research Center of Hôpital Ste-Justine, Montréal, Québec, Canada; the Departments of ² Pharmacology and Therapeutics and ³ Ophthalmology, McGill University, Montréal, Québec, Canada; ⁴ Theratechnologies, Saint-Laurent, Québec, Canada; and the ⁵ Department of Pharmacology, Vanderbilt University, Nashville, Tennessee.

PURPOSE. To test whether platelet-activating factor (PAF) directly causes retinovascular endothelial cell (EC) death.

METHODS. Retinovascular density was calculated in rat pups exposed to 80% O₂ from postnatal days (P)6 to P14 (to produce oxygen-induced retinopathy [OIR]), using the adenosine diphosphatase (ADPase) technique, in animals treated with distinct PAF receptor blockers (PCA-4248, BN52021, or THG315). PAF levels were then measured in the retinas. Viability of ECs from piglets and humans in response to C-PAF (a stable PAF analogue) was determined by the reduction of the tetrazolium salt 3-(4,5-dimethyl thiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) by viable cells, incorporation of propidium iodide (PI), TUNEL assay, and release of lactate dehydrogenase. Release of thromboxane (TX) was measured in the cell media.

RESULTS. PAF levels in retina were markedly increased by exposure of isolated rat retinas to H₂O₂ (1 µM) and of rat pups placed in 80% O₂. Exposure to 80% O₂ induced retinal vasoobliteration, which was equally significantly inhibited (60%) by all PAF receptor blockers tested. C-PAF increased incorporation of PI by isolated rat retinal microvasculature. Also, C-PAF caused time- and concentration-dependent death of cultured retinal ECs, which was prevented by the PAF receptor antagonist CV-3988. This effect of C-PAF was selective on retinal and neurovascular ECs, but not on other ECs. DNA fragmentation (TUNEL) was hardly detected, and inhibition of apoptosis-related processes by nicotinamide, cyclosporin A, and Z-DEVD-FMK and Z-VAD-FMK (caspase inhibitors) barely protected against death in EC, whereas C-PAF increased release of lactate dehydrogenase, implying that necrosis is the nature of EC death. Finally, C-PAF–induced cell death was preceded by an increase in TXB₂ levels and was prevented by TXA₂ synthase inhibition (with CGS12970).

CONCLUSIONS. The data suggest PAF plays a major role in vasoobliteration in OIR by triggering death of neuroretinal microvascular ECs. The cell death seems to be mediated at least in part by TXA₂. These effects of PAF may participate in ischemic retinopathies such as diabetes and retinopathy of prematurity.

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