In
solution, MeO-Suc-
Ala-Ala-Pro-D,L-boro-Val
pinacol ester (
Boroval) is a highly effective but reversible inhibitor of both porcine
pancreatic elastase and human
neutrophil elastase (HNE) (50% inhibition with a 1.5 M ratio of
Boroval to
elastase).
Boroval has been shown to prevent porcine-
pancreatic-elastase-induced
emphysema in hamsters. But with HNE-induced
emphysema in hamsters, pretreatment with as much as a 170-fold M excess of
Boroval, given intratracheally 1 h before 0.3 mg HNE, did not prevent
emphysema. Indeed, lung volumes were larger after
Boroval pretreatment than after HNE alone.
Emphysema was also induced by instilling HNE that had been mixed with and inactivated by a 41-fold M excess of
Boroval (a molar ratio of 42). When 0.25 or 0.5 mg of HNE were given mixed with a 41-fold M excess of
Boroval, the
emphysema was much more severe with the 0.5 mg dose. Two hours after instillation of 0.3 mg HNE inactivated with a 34-fold M excess of
Boroval, bronchoalveolar lavage contained elastolytic activity but no evidence of
hemorrhage. In contrast,
hemorrhage was severe in hamsters that had been instilled with 0.3 mg HNE alone. We conclude that
Boroval can enhance HNE-induced
emphysema. We postulate that
Boroval suppresses HNE-induced
hemorrhage and the resultant influx of plasma
protease inhibitors; the HNE-
Boroval complex is transported into the alveolar interstitium, followed by dissociation of the inhibitor from the active site of HNE. Because of its small size, free
Boroval is rapidly cleared, and the reactivated HNE attacks elastic fibers, giving rise to
emphysema.