Inhibition of elastase-induced acute inflammation and pulmonary emphysema in hamsters by a novel neutrophil elastase inhibitor FR901277

Abstract.

Objective and Design: A neutrophil elastase inhibitor FR901277 was examined for its inhibitory effect on degradation of natural substrate elastin in vitro, and on acute inflammatory states and pulmonary emphysema in vivo.¶Material and Treatment: Elastin-congo red was used as a substrate for elastin degradation assay. Paw edema in male C57BL mice (6 weeks old) and pulmonary hemorrhage in female golden hamsters (5 weeks old) were induced by topical injection of human neutrophil elastase (HNE). Pulmonary emphysema in male golden Syrian hamsters (10 weeks old) was provoked by intratracheal instillation of porcine pancreatic elastase. In all in vivo experiments, FR901277 was administered prior to elastase treatment.¶Methods: Elastin degradation by HNE was monitored spectrophotometrically with elastin-congo red. Foot swelling was measured by calipers. Pulmonary hemorrhage was assessed by hemoglobin concentration in bronchoalveolar lavage fluid. As emphysematous parameters, quasi-static lung compliance and vital capacity were measured.¶Results: FR901277 inhibited HNE-induced elastin degradation. Systemic treatment with FR901277 significantly inhibited paw edema and pulmonary hemorrhage. Intratracheal treatment with FR901277 significantly ameliorated changes in pulmonary function.¶Conclusions: These results suggest that FR901277 inhibits the elastase activity potently both in vitro and in vivo, and that elastase may play a role at least in part in pathogenesis of pulmonary emphysema.