AN INHIBITOR OF LEUKOCYTE ELASTASE PREVENTS IMMUNE COMPLEX-MEDIATED HEMORRHAGE IN THE RAT LUNG

The typical reverse passive Arthus reaction (RPA) was attained in rats by the instillation of a rabbit antiovalbumin serum into the lungs an d intravenous injection of ovalbumin, Instillation of antiserum alone caused accumulation of polymorphonuclear leukocytes (PMN) and increase d vascular permeability, but did not cause hemorrhage. However, when a n intravenous injection of ovalbumin was also given, the vascular perm eability of the lungs increased dramatically and PMN, as well as hemog lobin, were measurable in the lung lavage fluids by 4 hr after initiat ion of the reaction. Various proteinase inhibitors were instilled into the lungs after the initial stages of the RPA had developed, specific ally 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-dependen t inhibitor of human and rat PMN elastase, effectively prevented the l ung hemorrhage associated with the RPA reaction (ED(50) = 2 x 55 mu g doses/animal when instilled at 1.5 and 2.5 hr after initiating the RPA ), The PMN elastase inhibitor, yl-alanyl-alanyl-prolyl-valine-chlorome thylketone, also inhibited hemorrhage in this model, Compounds of the same chemical class as these elastase inhibitors, but having no activi ty against PMN elastase in vitro, did not affect the hemorrhage associ ated with the RPA, Several specific inhibitors of proteinases other th an PMN elastase (e.g., pepstatin and yl-prolyl-glycyl-alanyl-lysine-ch loromethylketone) were found to have little effect on the hemorrhage a ssociated with the RPA reaction, These results implicate PMN elastase as a major contributor to the tissue damage that results in hemorrhage during the RPA reaction in the rat lung and, together with previous r eports on the role of PMN proteinases in inflammatory reactions, sugge st that elastase inhibitors may be useful therapeutic agents for PMN-m ediated diseases.