The typical reverse passive
Arthus reaction (RPA) was attained in rats by the instillation of a rabbit antiovalbumin serum into the lungs and
intravenous injection of
ovalbumin. Instillation of antiserum alone caused accumulation of polymorphonuclear leukocytes (PMN) and increased vascular permeability, but did not cause
hemorrhage. However, when an
intravenous injection of
ovalbumin was also given, the vascular permeability of the lungs increased dramatically and PMN, as well as
hemoglobin, were measurable in the lung lavage fluids by 4 hr after initiation of the reaction. Various
proteinase inhibitors were instilled into the lungs after the initial stages of the RPA had developed, specifically to investigate their effect on the development of the
hemorrhage, which we chose to monitor as an
indicator of severe vascular damage. A
cephalosporin-based
beta-lactam,
L-658,758, which is a time-dependent inhibitor of human and rat
PMN elastase, effectively prevented the lung
hemorrhage associated with the RPA reaction (ED50 = 2 x 55 micrograms doses/animal when instilled at 1.5 and 2.5 hr after initiating the RPA). The
PMN elastase inhibitor, methoxysuccinyl-
alanyl-alanyl-prolyl-valine-chloromethylketone, also inhibited
hemorrhage in this model. Compounds of the same chemical class as these
elastase inhibitors, but having no activity against
PMN elastase in vitro, did not affect the
hemorrhage associated with the RPA. Several specific inhibitors of
proteinases other than
PMN elastase (e.g.,
pepstatin and methoxysuccinyl-prolyl-glycyl-alanyl-
lysine-chloromethylketone) were found to have little effect on the
hemorrhage associated with the RPA reaction.(ABSTRACT TRUNCATED AT 250 WORDS)