PURPOSE. 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 farnesyl-transferase 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 μm vs. 28.6 ± 7.7 μm (n = 6, P = 0.004); SIMP-1, 18.7 ± 10.2 μm vs. 34.3 ± 10.2 μm (n = 7, P = 0.02); DFU, 19.3 ± 10.2 μm vs. 23.5 ± 8.4 μm (n = 6, P = 0.01); and IL-1 receptor type II (0.05%), 26.2 ± 5.6 μm vs. 30.4 ± 5.6 μm (n = 5, P = 0.03) and (0.10%), 26.6 ± 5.6 μm vs. 32.1 ± 7.4 μm (n = 8, P = 0.03). Gliotoxin was not effective (21.5 ± 8.0 μm vs. 21.9 ± 6.2 μm; 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.