Release of neutrophil elastase and its role in tissue injury in acute inflammation: effect of the elastase inhibitor, FR134043

Abstract

Neutrophil elastase degrades extracellular matrix components and is involved in tissue destruction in several inflammatory states. We examined the inhibition of the elastase activity derived from activated neutrophils in vitro and in vivo by FR134043, disodium( Z,1 S,15 S,18 S,24 S,27 R,29 S,34 S,37 R)-29-benzyl-21-ethylidene-27-hydroxy-15-isobutyrylamino-34-isopropyl-31,37-dimethyl-10,16,19,22,30,32,35,38-octaoxo-36-oxa-9,11,17,20,23,28,31,33-octaazatetracyclo[16.13.6.1 24,28.0 3,8]octatriconta-3,5,7-trien-5,6-diyl disulfate, an elastase inhibitor with broad specificity, and elucidated the role of neutrophil elastase in pathogenesis of acute inflammation. In a culture of human neutrophils, phorbol myristate acetate (PMA) and calcium ionophore increased elastase activity in the supernatants, which was amplified by co-existing mononuclear leukocytes. Formyl–Met–Leu–Phe stimulated elastase release in the presence of, not without, mononuclear leukocytes. Intratracheal injection of lipopolysaccharide elevated the elastase activity in bronchoalveolar lavage fluid of rats. These elastase activities were significantly inhibited by FR134043. Intratracheal treatment with FR134043 in rats also inhibited the enzyme induced by lipopolysaccharide, though the maximum inhibition was 52%. Ear edema elicited by topical application of PMA in mice was significantly suppressed by pretreatment with FR134043 (38% inhibition at 1 mg/ear). In carrageenan-induced joint injury in rats, plasma extravasation into the synovial cavity was partially and significantly inhibited by FR134043 at 1 mg/knee, while an elastase-specific inhibitor showed no effect. These results suggest that neutrophil elastase is partially involved in tissue damage in acute inflammation provoked by irritants, but not in carrageenan-induced hyperpermeability.