Toxic effects of human eosinophil products on isolated rat heart cells in vitro.
Rat heart cells and mitochondria were incubated with supernatants from eosinophils or neutrophils that had been stimulated with zymosan-C3b. Supernatants from eosinophils, but not neutrophils, were toxic to rat heart cells in a dose-dependent manner. This was associated with an increased O2 uptake, which was blocked by either 1 mM-cyanide or 100 microM-ouabain. Supernatants from eosinophils, but not neutrophils, caused a decrease in O2 uptake by rat heart mitochondria utilizing pyruvate (+ malate) but not other substrates. The activity of pyruvate dehydrogenase (EC 1.2.4.1) from rat heart was inhibited by Ca2+-free eosinophil supernatants. The activity of oxoglutarate dehydrogenase (EC 1.2.4.2) was also inhibited but not that of lipoamide dehydrogenase (EC 1.6.4.3). Prior incubation with heparin prevented these effects of eosinophil supernatants on heart cells, suggesting that they were caused by eosinophil cationic proteins. Other cationic proteins, including poly-L-lysine and poly-L-arginine were also toxic to rat heart cells, but these reduced O2 uptake. It was concluded that granulocyte secretion products containing eosinophil cationic proteins are toxic to isolated rat heart cells in vitro. This may be due to an initial increase in membrane permeability, which may lead to activation of (Na+ + K+)-dependent ATPase and increased O2 uptake. A second step may involve inhibition of pyruvate dehydrogenase by the same products, leading to a decreased O2 uptake. It is suggested that these mechanisms could contribute to the development of cardiac injury and myocardial disease in clinical situations where many degranulated eosinophils are present.
D000818:Animals; D001798:Blood Proteins / Q000494:pharmacology; D002474:Cell-Free System; D047091:Eosinophil Granule Proteins; D004804:Eosinophils / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007655:Ketoglutarate Dehydrogenase Complex / Q000037:antagonists & inhibitors; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D012260:Ribonucleases
D001798:Blood Proteins; D047091:Eosinophil Granule Proteins; D011768:Pyruvate Dehydrogenase Complex; D007655:Ketoglutarate Dehydrogenase Complex; D012260:Ribonucleases