Mechanism responsible for endotoxin-induced lung microsomal dysfunction in rats.

Abstract

This study was designed to investigate the mechanism responsible for the deleterious effect of endotoxin on lung microsomes of Wistar rats. Three experiments were carried out.(1) Mortality Studies. Rats began to die 4 h after the administration of endotoxin and 90% died during the initial period of 24 h. Premedication with either coenzyme Q10 (CoQ10) or chlorpromazine (CPZ) greatly reduced the number of rats that died after endotoxin administration.(2) In Vivo Studies. Lung microsomes were prepared 4 h after the administration of endotoxin to rats. The levels of free fatty acids (FFA) in the microsomes were determined by gas chromatography, and the microsomal electron transport activity was determined by measuring the specific activity of NADPH-cytochromec reductase. The administration of endotoxin significantly increased the levels of FFA, and significantly reduced the specific activity of NADPH-cytochromec reductase. Premedication with either CoQ10 or CPZ largely prevented the increase in FFA and the deleterious effect of endotoxin on microsomal electron transport activity.(3) In Vitro Studies. The in vitro effect of phospholipase A2 (PLase A2) on the levels of FFA in isolated lung microsomes and the specific activity of microsomal NADPH-cytochromec reductase were determined. The addition of PLase A2 significantly increased the levels of FFA and reduced microsomal electron transport activity. The simultaneous addition of either CoQ10 or CPZ protected against these changes caused by PLase A2. These results suggest that the lung microsomal dysfunction caused by endotoxin is a consequence of the degradation of microsomal membranes induced by the activation of PLase A2.