THE RELATIONSHIP BETWEEN TISSUE DISTRIBUTION AND SELECTED TOXIC EFFECTS OF ENDOTOXIN IN NORMAL AND GALACTOSAMINE SENSITIZED MIC

The relationship between the quantitative localization of endotoxin among host organs and selected toxic effects of endotoxin was studied in normal and galactosamine sensitized mice.;The majority of intravenously (iv) or intraperitoneally (ip) injected endotoxin became associated with the liver and spleen of normal mice by one hour. By contrast, subcutaneously (sc) administered endotoxin was about 50-fold less concentrated in liver while only about 2-fold higher in mean 50% lethal dose when compared to iv or ip injected endotoxin. Although less than 15% of sc injected endotoxin became associated with the deep tissues of the host, sc injected mice exhibited a variety of symptoms typically associated with endotoxin poisoning.;Treatment of mice with galactosamine (ga1N) caused a 1000-fold decrease in the LD(,50) of endotoxin. In addition, mice receiving ga1N and as little as 0.1(mu)g of endotoxin exhibited marked liver damage as evidenced by increased serum ornithine carbamyltransferase (OCT) activity. Galactosamine treatment did not alter the organ distribution of iv injected endotoxin or enhance the uptake of endotoxin by liver parenchymal cells. Furthermore, endotoxin localized in livers of normal mice was primarily associated with Kupffer cells.;Serum from mice that were injected with the LD(,50) of endotoxin caused significant increases in serum OCT activity when transferred to Ga1N-treated mice. The activity of endotoxemic serum was amplified by pretreating donor mice with Corynebacterium parvum before injecting endotoxin. C. parvum/endotoxin serum decreased survival and increased serum OCT levels when injected into ga1N-treated but not normal mice. Serum from mice that received either C. parvum or endotoxin (0.1 LD(,50)) alone was inactive when injected into ga1N-treated mice.;C. parvum-primed mice were sensitized to the lethal effects of endotoxin to about the same extent as ga1N-treated mice. Whereas C. parvum/endotoxin serum was lethal and capable of eliciting elevated serum OCT levels in ga1N-treated mice, neither response occurred following transfer of C. parvum/endotoxin serum to C. parvum-primed mice. Likewise, donor serum obtained from ga1N-treated mice given the same dose of endotoxin (0.1 LD(,50)) was not lethal or capable of elevating serum OCT levels when transferred to C. parvum-primed or ga1N-treated mice, thereby implying different mechanisms of endotoxin sensitization.