methyl-o-succinyl-alanyl-alanyl-prolyl-borovaline-pinacol and Lung-Diseases

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.

Topics: Animals; Boronic Acids; Bronchoalveolar Lavage Fluid; Cricetinae; Hemorrhage; Leukocyte Elastase; Lung; Lung Diseases; Lung Volume Measurements; Male; Mesocricetus; Oligopeptides; Pancreatic Elastase; Pulmonary Emphysema

A highly effective, reversible elastase inhibitor, MeOSuc-Ala-Ala-Pro-boroVal-OH, was tested for its ability to prevent emphysema induced by intratracheally administered elastase in hamsters. Anesthetized hamsters were given elastase intratracheally with or without the inhibitor or were given elastase intratracheally and the inhibitor intraperitoneally. Two weeks after administration, lungs were removed, and static air pressure volume curves were performed followed by intratracheal fixation and morphometric determination of mean linear intercepts. The results indicate significant preservation of structure and function whether the inhibitor is given intratracheally or intraperitoneally and suggest that this inhibitor may be useful in controlling diseases arising from aberrant proteolysis by elastolytic enzymes.

Topics: Animals; Boronic Acids; Cricetinae; Drug Evaluation, Preclinical; Lung; Lung Diseases; Male; Mesocricetus; Oligopeptides; Pancreatic Elastase; Peptides; Respiratory Function Tests