Tissue plasminogen activator (tPA) inhibits human neutrophil superoxide anion production in vitro.
Because neutrophils contribute to reperfusion injury associated with acute myocardial infarction (MI), and because tissue plasminogen activator (tPA) is often used in the management of MI, we evaluated the effect of tPA on superoxide (O2.-) production by human neutrophils in vitro. We found that adding increasing amounts of tPA significantly (r = 0.89, P < 0.025) and progressively reduced O2.- generation by neutrophils treated with phorbol myristate acetate (PMA) in vitro. Furthermore, adding tPA that had been previously treated with the protease inhibitor, D-Phe-Pro-Arg-chloromethyl ketone HCl (PPACK), also decreased neutrophil O2.- generation in vitro (P < 0.05). In contrast, adding L-arginine, a component of the tPA preparation and a precursor of nitric oxide (NO), did not inhibit PMA-induced neutrophil O2.- production. Also, adding increasing concentrations of tPA did not reduce (P > 0.05) the concentrations of O2.- produced by xanthine oxidase (XO) in vitro. Our findings suggest that tPA reduces neutrophil O2.- generation by a mechanism that is not related to L-arginine, is not dependent on tPA proteolytic activity, and is not a function of direct scavenging. This property may account for some of the effectiveness of tPA in the treatment of MI and/or make tPA valuable for treating acute respiratory distress syndrome (ARDS) or other inflammatory disorders involving neutrophil O2.- production.
Stringer
K A
KA
Department of Pharmacy Practice, University of Colorado Health Sciences Center, Denver 80262, USA.
Lindenfeld
J
J
Repine
A J
AJ
Cohen
Z
Z
Repine
J E
JE
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D002469:Cell Separation; D006801:Humans; D006868:Hydrolysis; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000097:blood; D010959:Tissue Plasminogen Activator / Q000097:blood / Q000494:pharmacology*; D014969:Xanthine Oxidase / Q000187:drug effects
D000590:Amino Acid Chloromethyl Ketones; D015842:Serine Proteinase Inhibitors; D013481:Superoxides; D014969:Xanthine Oxidase; D010959:Tissue Plasminogen Activator; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone