Effects of bacterial endotoxin on liver mass and hepatocyte volume

Qian, Dalong (1993) Effects of bacterial endotoxin on liver mass and hepatocyte volume. Masters thesis, Memorial University of Newfoundland.

[English] PDF (Migrated (PDF/A Conversion) from original format: (application/pdf)) - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (21MB) [English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. (Original Version)

Abstract

Hepatomegaly is common in infections. An increase in liver mass, which cannot be accounted for by the net increase of hepatic protein and lipid contents, has been reported to be a common tumour necrosis factor a (TNFα)- mediated host response after such stress stimuli as endotoxemia, sepsis, trauma and chronic inflammation in either fasted or fed rats. The increase of hepatocyte volume has also been associated with, in experiments in vitro, alterations in hepatic metabolic functions such as protein and carbohydrate metabolism. There are, however, no previous studies carried out on alterations in liver mass and hepatocyte volume in vivo as a host response of endotoxic animals which undergo profound metabolic changes in liver. -- In this study, a single intraperitoneal injection of E. coli lipopolysaccharide (LPS, 0127:B8) at a sublethal dose (3 mg/kg, LD₅) was found to introduce a generally time- and dose-dependent increase in hepatic mass and water content of fasted rats compared to corresponding saline-injected controls. Twenty-four hr after LPS treatment, the absolute and relative weight of livers removed by complete hepatectomy remain unaltered in fasted endotoxic rats but they decrease by 20% in the fasted saline-controls, compared to that in the normal rats fed ad libitum. The difference in the mean liver weight between the endotoxin- and saline-treated animals is 2.0-2.5 g, i.e. 20-25% of the total liver mass of 300-350 g rats. The hepatic wet/dry weight ratio is significantly higher in endotoxic livers than that in the other two groups. The hepatic water content increases by almost the same extent (27%) as the increase (26%) in the total liver mass 24 hr after treatment, indicating that the effect of E. coli LPS is mainly on the hepatic water content, rather than on the dry mass components. -- Analyses of hepatic dry mass components and hepatic cellular spaces show that only one third (0.79 g) of the increase (2.18 g) in the total liver mass can be accounted for by the net increase of the dry mass components (0.38 g) plus the blood/plasma and/or interstitial fluid (0.41 ml) in the extrahepatocellular space; and hepatic K⁺ content, the predominant intracellular cation, increases by 25%, 24 hr after LPS injection. These suggest that an expansion of the hepatocellular space is mainly responsible for the increase in the liver mass of endotoxic rats. This hypothesis is also supported by morphometric data from an image analysis system demonstrating that the mean transsectional area and the mean volume is 8% and 12% larger, respectively, in the mononucleate hepatocytes from the endotoxic livers. -- The phenomenon of increases in the hepatic mass, water content and wet/dry weight ratio after LPS treatment can be reproduced by a single intravenous administration of rhTNF-α (25 μg/250 g B.W.) and prevented by the pretreatment of endotoxic rats with an intraperitoneal injection of goat anti-mTNFα serum (20 mg/300 g B.W.). The mean transsectional area and mean volume is 11% and 17% larger, respectively, in mononucleate hepatocytes from the livers of endotoxic rats treated with goat non-immune IgG compared to the anti-mTNFα serum-treated rats. These data suggest that effects of E. coli LPS on the increase in hepatic mass and hepatocyte volume are mediated by cytokine TNF-α. -- Twenty-four hr after E. coli LPS injection, the concentrations of hepatic adenine nucleotides in the endotoxic rats are not significantly different from either the saline-controls or the normal fed rats. There are no significant changes in the activity of SGPT or in the plasma ratio of lactate/pyruvate and β-hydroxybutyrate/acetoacetate during the 24 hr after LPS injection. Those observations argue against "compensatory hyperplasia" resultinq from acute liver damage due to direct endotoxin toxicity or hepatocyte swelling due to tissue hypoxia and impaired energy status in the liver. Metabolic changes mediated by insulin, TNF-α and/or other "hepatotrophic factors" may be responsible for the increase of liver mass after E. coli LPS administration.

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