Metabolic basis of endotoxicosis.

Whereas as specific immunological responses are elicited only after a delay of some days, alteration in various biochemical parameters is observed within 1-2 h of endotoxin administration in a number of animal species. Generally the level of several hepatic enzymes (tryptophan pyrrolase, phophoenol pyruvate carboxykinase) metabolites (glycogen, NAD) and intermediates in the energetic homeostasis is lowered by the toxin, increased by the glucocorticoid hormones and maintained at the normal level when the toxic effects of endotoxin are annulled by the counter effects of the protective agent (such as cortisone). Antagonism is also noted on the synthesis of cellular RNA, DNA and protein. However, no unitary process has as yet been singled out to possessing a cause and effect relationship between toxicity and survival. In the intact animal, it is not possible to affirm whether the toxin exerts a direct effect on the organ, the cell or the process in question, especially since endotoxin is phagocytized by the cells of the reticuloendothelial system (RES) in the liver and elsewhere and since the biochemical parameters are a property of the organ specific epithelial cells. Experiments with tissue slices suffer from the problem of permeability and uptake in vitro and are not readily reproducible. Isolated cells in culture are theoretically ideal but exhibit loss of functions and undergo neoplastic type of transformation that renders them unsuitable for relevant biochemical studies. Primary explants of the hepatocytes and the RE cells, as well as hybrids between these two cellular types appear more promising. However, at the moment, isolated liver preparations perfused in vitro offer the best solution by exhibiting intact function, morphology and excellent reproducibility. Collectively, it is tempting to speculate that the extent of subsequent immunological response is a reflection of the preceding biochemical processing, that both sorts of events are in some way mediated by the RE cells, and that the latter may most easily be studied in the intact liver in vitro.