Protection of vascular basement membrane and microcirculation from elastase-induced damage with a fluorinated β-lactam derivative

Abstract N -(2-chloromethylphenyl) 3,3-difluoroazetidin-2-one (AA 231-1), a specific suicide-type inhibitor of elastase which is known to suppress the lysis of chromogenic oligopeptides, elastin and elastic fibers, is effective also in preventing the degradation of the vascular basement membrane. The degradation of porcine glomerular basement membrane by purified human leukocyte elastase (HLE), was reduced in proportion of inhibitor dose (8.3 μM for 50% inhibition). It is noteworthy that there was no reduction of the inhibitory effect when the addition of AA 231-1 was delayed for 1 h after the addition of the enzyme to the substrate. In the guinea pig, reduction of the dermal microhemorrhage due to HLE was related to the dose of inhibitor and to its preincubation time with HLE before intradermal injection. The inflammatory hemorrhage associated with the Arthus skin reaction was moderately depressed by AA 231-1 in situ. A part of the vascular permeability induced by HLE also responded to the inhibitor. In spite of the tissular diffusion and the time-dependence parameters which restrict responsiveness of elastase to AA 231-1 in vivo this biochemical compound should be helpful in the study and possibly the cure of vascular injury related to elastase.