Effect of synthetic metalloproteinase inhibitor or citrate on neutrophil chemotaxis and the respiratory burst.

PURPOSE A topical synthetic metalloproteinase inhibitor (SIMP) has been reported to reduce the incidence of corneal ulcerations in the alkali-injured eye by the putative mechanism of collagenase inhibition. The current study was performed to determine whether SIMP has a direct inhibitory effect on the activation of neutrophils and to compare any such effect with that of citrate, a known inhibitor of polymorphonuclear leukocyte (PMNL) activity. METHODS The effect of SIMP or citrate was tested on chemotaxis of PMNL and the respiratory burst in vitro. RESULTS Synthetic metalloproteinase inhibitor (1 mM) or citrate (12 mM) produced significant inhibition of chemotaxis of PMNL and the accompanying behavioral characteristics of motility. Synthetic metalloproteinase inhibitor, but not citrate, generated a dramatic respiratory burst when incubated with resting PMNL. Both SIMP and citrate inhibited the respiratory burst of PMNL in the presence of opsonized zymosan. For a brief, initial period each substance enhanced the respiratory burst generated by the metabolic stimulant from alkali-degraded corneas, followed by a rapid decline in activity that was associated with cell death. CONCLUSIONS Although SIMP has been shown to exhibit powerful collagenase inhibition, its inhibitory effect on chemotaxis of PMNL might be the primary mechanism in reducing the incidence of ulceration in the alkali-injured cornea. Very significant reduction in the accumulation of PMNL in SIMP-treated corneas supports this conviction. Activation by SIMP of the respiratory burst in resting PMNL is of concern, but overall its beneficial effect is favorable, as demonstrated in prior alkali-injured animal models. The dual effect of inhibition of chemotaxis of PMNL and activity of collagenase makes SIMP a potential drug for combating ulceration in the alkali-injured cornea.