Anti-pneumolysin activity of commercially available alpha 1-antitrypsin is due to cholesterol impurities.
Pneumolysin (PLY), the principal cytolytic toxin of Streptococcus pneumoniae, may be important in the pathogenesis of acute lung injury during pneumococcal pneumonia. However, the local host defenses that limit PLY injury to lung tissues have not been characterized. We investigated the ability of a commercial preparation of alpha 1-antitrypsin (alpha 1-AT), a major plasma anti-proteinase, to inhibit PLY. At normal plasma concentrations, the alpha 1-AT preparation prevented PLY injury to bovine pulmonary artery endothelial cells, rat alveolar epithelial cells, and human erythrocytes. The alpha 1-AT preparation selectively inhibited thiol-activated bacterial toxins; it was inactive against snake venom hemolysins, mastoparan, and oxygen-stable bacterial toxins. Biochemical characterization of the alpha 1-AT preparation and comparison with other available alpha 1-AT preparations revealed that this inhibitory activity was due to contamination with nanomolar concentrations of cholesterol. Characterization of non-immune human plasma anti-pneumolysin activity showed that beta-lipoprotein fractions contain the major inhibitory activity. We caution other investigators that the inhibition of bacterial virulence by these alpha 1-AT preparations may indicate toxin-mediated, rather than protease-mediated, mechanisms.
Rubins
J B
JB
Department of Medicine, Veterans Affairs Medical Center, Minneapolis, MN.
Freiberg
M R
MR
D000818:Animals; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors; D002417:Cattle; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology*; D004340:Drug Contamination; D004847:Epithelial Cells; D006460:Hemolysin Proteins / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D011650:Pulmonary Alveoli / Q000166:cytology; D051381:Rats; D013301:Streptolysins / Q000037:antagonists & inhibitors*; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D013301:Streptolysins; D000515:alpha 1-Antitrypsin; C032290:plY protein, Streptococcus pneumoniae; D002784:Cholesterol; D010196:Pancreatic Elastase