EFFECTS OF METALLOPROTEINASE INHIBITORS ON LEUKOTRIENE A(4) HYDROLASEIN HUMAN AIRWAY EPITHELIAL-CELLS

Human neutrophil leukotriene A(4) (LTA(4)) hydrolase is a zinc-contain ing metalloproteinase with aminopeptidase activity and can be inhibite d by some metalloproteinase inhibitors. Human airway epithelial cells also contain an LTA(4) hydrolase enzyme that has some novel properties , suggesting that this enzyme may be functionally and structurally uni que. Thus, we questioned whether the epithelial enzyme could also be i nhibited by metalloproteinase inhibitors. Transformed human airway epi thelial cells were studied either intact or disrupted. Of the metallop roteinase inhibitors examined, only captopril, bestatin, and fosinopri lat had appreciable inhibitory activity for LTA(4) hydrolase in disrup ted epithelial cells. Concentration-inhibition curves to captopril, be statin, and fosinoprilat revealed IC50 values of 430 mu M, 7 mu M, and 1 mM respectively, for disrupted-cell LTA(4) hydrolase activity. In c ontrast to its effects on neutrophils, 1,10-O-phenanthroline had no si gnificant effect on disrupted epithelial cell hydrolase activity and h ad only minimal effects when this activity was partially purified (179 -fold). LTA(4) hydrolase concentration-inhibition curves examined in i ntact cells with captopril, bestatin, and 1,10-O-phenanthroline reveal ed IC50 values of 63, 70, and 920 mu M, respectively. Aminopeptidase a ctivity in disrupted epithelial cells was inhibited by amastatin, best atin, and 1, 10-O-phenanthroline (IC50 values of 500 nM, 1 mu M, and 1 7 mu M, respectively), but not by captopril at the highest concentrati on tested, 10 mM. These findings are in contrast to prior studies in n eutrophils. When neutrophils were stimulated with A23187 after treatme nt with captopril, transcellular synthesis of LTB(4) was inhibited mor e effectively than direct synthesis of leukotriene B-4 (LTB(4)) (43.8 +/- 2.5 vs 18.5 +/- 4.7%; N = 8, P < 0.02). We conclude that LTA(4) hy drolase activity of human airway epithelial cells is inhibited by some metalloproteinase inhibitors, but that the profile of inhibition is d istinct from that for the neutrophil enzyme. These data provide additi onal information that LTA(4) hydrolase in the epithelial cell is a nov el enzyme, distinct from that found in the neutrophil.