THE SENSITIZED LIVER REPRESENTS A RICH SOURCE OF ENDOGENOUS LEUKOTRIENES

The ability of livers to produce endogenous leukotrienes after immunological stimulation was tested with organs from rats and guinea pigs. Passive sensitization of rats in vivo with monoclonal murine antidinitrophenol-IgE before antigen challenge in the isolated perfused liver system elicited a rapid hepatic production and biliary excretion of leukotrienes as judged by radioimmunoassay after separation of individual leukotrienes by high-performance liquid chromatography. Within 10 min after antigen infusion, mainly leukotriene C4, but also leukotriene D4 and N-acetyl-leukotriene E4, appeared in the bile. The biliary excretion rate of antigen-induced cysteinyl leukotrienes rose from < 2 pmol . min-1. (kg body mass)-1 before challenge to about 30 pmol . min-1. (kg body mass)-1 for 20 min before it declined toward prechallenge level. Quantitatively similar hepatic production of cysteinyl leukotrienes was elicited in isolated perfused guinea pig livers challenged with ovalbumin after active sensitization of the animals with ovalbumin plus Al(OH)3. To exclude extrahepatic contributions to the observed leukotriene production, both passive sensitization with anti-dinitrophenol-IgE and subsequent antigen challenge were performed on isolated rat livers perfused with blood-free medium. Such exclusively hepatic sensitization and challenge also resulted in massive production of leukotrienes. The biliary excretion rate of cysteinyl leukotrienes amounted to approximately 20 pmol . min-1. (kg body mass)-1 during the 10 to 20 min period after antigen challenge as compared with < 1 pmol . min-1. (kg body mass)-1 before challenge. These results indicate that during anaphylaxis the liver represents a rich source of leukotrienes, and, among the cellular production sites in question, liver mast cells alone or in cooperation (e.g., with Kupffer cells) are likely candidates for such hepatic leukotriene generation.