Erythropoietin protects the developing retina in an ovine model of endotoxin-induced retinal injury.
OBJECTIVE
Intrauterine infection is a common antecedent of preterm birth. Infants born very preterm are at increased risk for neurologic dysfunction, including visual deficits. With increasing survival of very preterm infants, there is a need for therapies that prevent adverse neurologic outcomes. Using an ovine model, the authors investigated the neuroprotective potential of recombinant human erythropoietin (rhEPO) on retinal injury induced by intrauterine inflammation.


METHODS
At 107 ± 1 days of gestational age (DGA), chronically catheterized fetal sheep received either of the following on 3 consecutive days: intravenous (IV) bolus dose of lipopolysaccharide (LPS; ∼0.9 μg/kg; n = 8); IV bolus dose of LPS, followed at 1 hour by 5000 IU/kg rhEPO (LPS + rhEPO; n = 8); rhEPO alone (n = 5). Untreated fetuses (n = 8) were used for comparison with the three treatment groups. Fetal physiological parameters were monitored. At 116 ± 1 DGA, fetal retinas were assessed quantitatively for morphologic and neurochemical alterations.


RESULTS
Exposure to LPS alone, but not to rhEPO alone, resulted in fetal hypoxemia and hypotension (P < 0.05). Exposure to LPS alone caused retinal changes, including reductions in thickness of the inner nuclear layer (INL), somal areas of INL neurons, process growth in the plexiform layers, and numbers of ganglion and tyrosine hydroxylase immunoreactive (TH-IR) dopaminergic amacrine cells. Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but significantly reduced alterations in retinal layers and ganglion and TH-IR cell numbers.


CONCLUSIONS
rhEPO treatment was beneficial in protecting the developing retina after LPS-induced inflammation. Retinal protection could occur by the antiapoptotic or anti-inflammatory actions of EPO.
Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Victoria, Australia.
Michelle M
MM
Loeliger
Anna
A
Mackintosh
Robert
R
De Matteo
Richard
R
Harding
Sandra M
SM
Rees
D025042:Amacrine Cells / Q000187:drug effects / Q000473:pathology; D000818:Animals; D002452:Cell Count; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D004926:Escherichia coli; D005260:Female; D005311:Fetal Hypoxia / Q000139:chemically induced / Q000188:drug therapy*; D019084:Fluorescent Antibody Technique, Indirect; D005865:Gestational Age; D007124:Immunoenzyme Techniques; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D011247:Pregnancy; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins; D012160:Retina / Q000187:drug effects* / Q000196:embryology; D012164:Retinal Diseases / Q000139:chemically induced / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology; D034561:Sheep, Domestic; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D008070:Lipopolysaccharides; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D014446:Tyrosine 3-Monooxygenase