O2 metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs.
Addition of glucose oxidase (GO) increased H2O2 concentrations and decreased antielastolytic activities of beta-D-glucose containing perfusates of isolated rat lungs. Pretreatment with GO also caused acute edematous injury (increased lung weight gains, increased recovery of Ficoll in lung lavages, and increased pulmonary arterial pressures) in isolated lungs perfused with purified human neutrophil elastase (NE). Acute edematous injury in isolated lungs pretreated with GO and then NE exceeded levels found in lungs following addition of GO or NE alone or NE before GO. Simultaneous addition of catalase (an H2O2 scavenger) or methoxy-succinyl-L-alanyl-L-alanyl-prolyl-L-valine-chloromethyl ketone (an NE inhibitor, but not aminotriazole-inactivated catalase, N-tosyl-L-phenyl-alanine chloromethyl ketone (a chymotrypsin inhibitor) or N-alpha-p-tosyl-L-lysine chloromethyl ketone (a trypsin inhibitor), prevented acute edematous injury in isolated lungs perfused with both GO and NE. This observation indicated that injury was dependent on both H2O2 and NE, especially since the relative inactivating specificities of the inhibitors for H2O2 or NE, respectively, were confirmed under similar conditions in vitro. The synergistic nature of the interaction between H2O2 and NE-mediated injury was further clarified when GO- and NE-induced lung injury was prevented by addition of an oxidant-resistant NE inhibitor (Eglin-C), but not an oxidant-sensitive NE inhibitor (human alpha 1-protease inhibitor, alpha 1PI). Moreover, treatment with H2O2 also decreased the ability of alpha 1PI but not Eglin-C to decrease NE activity in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D004357:Drug Synergism; D004487:Edema; D005949:Glucose Oxidase / Q000633:toxicity*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000633:toxicity*; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008297:Male; D009504:Neutrophils / Q000201:enzymology*; D010100:Oxygen / Q000097:blood; D010196:Pancreatic Elastase / Q000097:blood / Q000302:isolation & purification / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains
D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D010196:Pancreatic Elastase; D010100:Oxygen