Effect of inhibition of inflammatory mediators on trauma-induced stromal edema.
OBJECTIVE
To determine the specific biochemical pathways involved in the initial-phase inflammatory response that causes stromal edema after epithelial debridement of the rabbit cornea.


METHODS
Adult New Zealand White rabbit corneas were treated with 2 mM synthetic inhibitor of metalloproteinase (SIMP)-1, 1 mM DFU (a specific cyclooxygenase [COX]-2 inhibitor) in 50/50 dimethyl sulfoxide (DMSO)/Ringer's solution, 300 KIU aprotinin (a serine protease inhibitor), 0.05% or 0.10% IL-1 receptor type II solution, 1 mM gliotoxin (a Ras farnesyltransferase inhibitor), or vehicle alone (the control). These were applied topically in vivo in five doses over a 3-hour period except IL-1 receptor type II, which was applied in vitro. After rabbits were killed, the corneas were mounted in perfusion chambers with the endothelium bathed in a modified Ringer's solution and the epithelium bathed with silicone oil. Corneal thickness was measured with an automatic specular microscope. The corneal thickness typically stabilized 1 hour after mounting. After stabilization, the corneal epithelium was removed with a rotating bristle brush and stromal thickness monitored for 1 hour. Paired control corneas were treated similarly. RESULTS. Stromal swelling after epithelial debridement was significantly less in most treated corneas, compared with untreated controls: 18.4 +/- 5.3 microm vs. 28.6 +/- 7.7 microm (n = 6, P = 0.004); SIMP-1, 18.7 +/- 10.2 microm vs. 34.3 +/- 10.2 microm (n = 7, P = 0.02); DFU, 19.3 +/- 10.2 microm vs. 23.5 +/- 8.4 microm (n = 6, P = 0.01); and IL-1 receptor type II (0.05%), 26.2 +/- 5.6 microm vs. 30.4 +/- 5.6 microm (n = 5, P = 0.03) and (0.10%), 26.6 +/- 5.6 microm vs. 32.1 +/- 7.4 microm (n = 8, P = 0.03). Gliotoxin was not effective (21.5 +/- 8.0 microm vs. 21.9 +/- 6.2 microm; n = 5, P = 0.94).


CONCLUSIONS
The reduction of stromal edema after topical administration of the inhibitors demonstrates the involvement of the COX-2 enzyme, the matrix metalloproteinase family, plasminogens, and the IL-1 system in the trauma-induced inflammatory response of the rabbit cornea. The inflammatory process in the cornea associated with trauma can proceed along multiple redundant parallel pathways.
Karon
Michael D
MD
Department of Ophthalmology, LSU Health Sciences Center, New Orleans, Louisiana, USA. mkaron@lsuhsc.edu
Klyce
Stephen D
SD
D000287:Administration, Topical; D000818:Animals; D015715:Corneal Edema / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D003319:Corneal Stroma / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2; D003646:Debridement; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019573:Epithelium, Corneal / Q000293:injuries*; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010958:Plasminogen / Q000037:antagonists & inhibitors / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011817:Rabbits
D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D007375:Interleukin-1; D007527:Isoenzymes; D061965:Matrix Metalloproteinase Inhibitors; D010958:Plasminogen; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020782:Matrix Metalloproteinases