Inhibitory effect of a complementary peptide on ulceration in the alkali-injured rabbit cornea

PURPOSE. Two tripeptide chemoattractants, acetyl-proline-glycine-proline (A c-PGP) and methyl-proline-glycine-proline (Me-PGP), are the primary trigger s for early neutrophil invasion into the alkali-injured cornea. In the pres ent study the effectiveness of a complementary peptide designed to inhibit the PGP chemoattractants (arginine-threonine-arginine [RTR] tetrameric pept ide) and an apo A-1 mimicking peptide (5F) was investigated in the alkali-i njured rabbit eve. METHODS. (L)-RTR tetramer, (D)-RTR tetramer, and 5F were tested in vitro fo r their effects on neutrophil polarization. Synthetic 5F was also tested in vitro for its effect on the neutrophil respiratory burst. In the alkali-in jured rabbit eye model, the right corneas of 48 rabbits were exposed to 1 N NaOH for 35 seconds. Sixteen animals were randomly assigned to each of thr ee groups: phosphate-buffered saline (PBS) control; 800 muM RTR (dextrorota tory) tetramer in PBS alternating each hour with 1.5 mM RTR (levorotatory) tetramer in PBS; and 12 muM 5F in PBS. One topical drop of each substance w as administered hourly (14 times per day) for 33 days. The experiment was c ontinued until day 42 with no additional drops administered. RESULTS. (L)-RTR tetramer and (D)-RTR tetramer inhibited neutrophil polariz ation activated by the PGP chemoattractants in vitro. Synthetic 5F did not inhibit neutrophil polarization in the presence of Ac-PGP or the respirator y burst of neutrophils in the presence of a metabolic stimulant derived fro m alkali-degraded corneas. During the entire animal experiment, statistical ly fewer ulcers occurred in the RTR tetramer group than in the PBS control group (43.8% vs. 87.5%, P = 0.0046). The frequency of ulceration in the 5F group (68.8%) was not significantly different from the PBS control group. CONCLUSIONS. The reduction in the frequency of corneal ulceration by the RT R tetramer possibly resulted from its complementary binding to Ac-PGP and M e-PGP in the cornea shortly after alkali injury, leading to a reduction in the early and late infiltration of neutrophils, RTR tetramer appears to hol d enough promise to warrant additional study as a therapeutic drug for the alkali-injured eye.