Alkali-induced corneal stromal melting prevention by a novel platelet-activating factor receptor antagonist.
OBJECTIVE
To evaluate the effect of LAU0901 (2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester), a novel platelet-activating factor (PAF) receptor antagonist, on a rabbit model of severe corneal alkali injury.


METHODS
Adult New Zealand albino rabbits were anesthetized and the right eyes were injured with 2N sodium hydroxide for 60 seconds using a 12-mm plastic well, then rinsed. After the injury, 10 rabbits were treated topically with LAU0901 every 2 hours 4 times per day and received a subconjunctival injection of 200 microL of LAU0901 once per week and 10 rabbits were treated with vehicle the same way. Over the course of 4 weeks, the corneas were examined daily by slitlamp microscopy and corneal ulcers were graded with a clinical scoring system. Ten additional rabbits were treated as described but 1 rabbit from each group was killed at 1, 3, 7, 14, or 21 days after injury. The corneas were processed for histopathologic and immunofluorescence examination.


RESULTS
Persistent epithelial defects were present in both groups from day 5 postinjury, but from day 9 through day 25, the average clinical scores of both epithelial defects and stromal ulcerations in the vehicle-treated eyes were significantly higher than those in the LAU0901-treated eyes (P<.01). By day 28, 90% of the eyes in the vehicle-treated group perforated, while only 20% of the eyes in the LAU0901-treated group developed deep ulceration and none were perforated. Histologic examination showed that the corneas treated with LAU0901 for 4 weeks were completely reepithelialized, with fewer inflammatory polymorphonuclear leukocytes and more repair fibroblasts (myofibroblasts) in the stroma as compared with those treated with vehicle.


CONCLUSIONS
LAU0901 inhibits corneal ulceration and perforation in a severe alkali-burn model in the rabbit. In the cornea, PAF is a strong inflammatory mediator, a chemotactic to inflammatory polymorphonuclear leukocytes, and an inducer of several proteases that degrade the extracellular matrix. Clinical Relevance The inhibition of PAF action by LAU0901 could be important in the immediate and intermediate treatment of chemical injuries to preserve the integrity of the cornea.
He
Jiucheng
J
Department of Ophthalmology and Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, LA 70112, USA.
Bazan
Nicolas G
NG
Bazan
Haydee E P
HE
D000818:Animals; D017209:Apoptosis; D002057:Burns, Chemical / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D003319:Corneal Stroma / Q000187:drug effects* / Q000473:pathology; D003320:Corneal Ulcer / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004095:Dihydropyridines / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005126:Eye Burns / Q000139:chemically induced* / Q000188:drug therapy; D005260:Female; D020287:In Situ Nick-End Labeling; D008297:Male; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011817:Rabbits; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D012422:Rupture, Spontaneous; D012972:Sodium Hydroxide / Q000633:toxicity
D004095:Dihydropyridines; C487837:LAU 0901; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D012972:Sodium Hydroxide