Investigator's description): There is a significant need to discover the basic molecular mechanisms responsible for corneal inflammation and ulceration in the alkali-injured eye. This project attacks the afferent limb of the inflammatory reaction by attempting to inhibit the chemoattractants which lure PMNs into the damaged corneal tissue. Previous studies discovered that the alkali-injured eye elaborates two chemoattractants, N-acetyl-pro-gly-pro and N-methyl-pro-gly-pro, which result directly from hydrolysis of protein. Initial efforts will center on the synthesis of other small peptides which might act as receptor antagonists, thereby inhibiting chemotaxis by blocking the receptor site on the PMN membrane. An alternate approach will identify low energy conformations of N-acetyl-pro-gly-pro and N-methyl-pro-gly-pro using NMR and computer modeling. These studies will lead to inhibitors that will bind to both chemoattractants. Suitable inhibitor drugs will be chosen from a library of known compounds. Candidate inhibitors will be screened for toxicity and inhibition of PMNs in the in vitro polarization assay. Successful inhibitor will then be used in a battery of in vivo tests for effectivity. The effect of inhibitors will be tested by intracorneal injections using PMN invasion as a histological yardstick. The inhibitor will be used alone and in conjunction with citrate and ascorbate in the alkali-injured eye.
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