Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.726390
Title: Liver death and regeneration : indirect mechanisms of paracetamol toxicity
Author: McGregor, Angus H.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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Abstract:
Background: Paracetamol overdose (POD) remains a pressing clinical problem as despite the availability of a safe and effective antidote, patients continue to die or require a liver transplant. Recent evidence suggests that toxicity after POD may be more than a simple direct toxic effect as has previously been accepted and that Kupffer cells and cytokine4s such as TNF-a are involved in the pathogenesis of liver injury. Paracetamol and Hepatocyte Apoptosis Examination of liver in patients after POD revealed hepatocyte apoptosis occurring alongside striking regenerative activity. Apoptosis is important for several reasons. First, at this time paracetamol is undetectable in serum and paracetamol metabolites should be cleared from the liver, so apoptosis is not directly induced by paracetamol. Second, the rate of apoptosis represents a significant rate of cell loss from the liver. Third, the apoptosis occurs despite the background of regeneration. Paracetamol and TNF-a: Some, but not all, studies support a role for TNF-a in inducing liver injury after paracetamol overdose. In a murine model, TNF-a was elevated in serum after POD but inhibition of TNF-a action did not alter survival or liver injury. However, TNF-a augmented paracetamol toxicity in vitro by increasing rates of both apoptosis and necrosis; TNF-a also lowered the threshold for toxicity. Paradoxically, while TNF-a had no apparent effect on hepatocytes in the absence of paracetamol, pretreatment with TNF-a protected against subsequent paracetamol toxicity. Paracetamol and Kupffer Cells: Kupffer cells modulate toxic hepatic injury induced by several agents including paracetamol. Co-culture experiments comparing hepatocytes alone or in culture with Kupffer cells showed no differences in toxicity. However, production of TNF-a by macrophages was augmented by paracetamol and was further significantly elevated in co-culture with hepatocytes. The levels of TNF-a in these experiments was similar to the concentration of recombinant TNF-a which augmented paracetamol toxicity in hepatocytes alone in previous studies but in this model no difference in toxicity was noted. This finding suggests that Kupffer cells produce TNF-a in response to high doses of paracetamol, that hepatocytes behave differently in coculture than when grown alone and that the differences in response may relate to soluble factors produced by Kupffer cells. Conclusions: These studies offer new insights into mechanisms of hepatocyte death by apoptosis and regeneration in the context of drug-induced liver injury. A model is presented whereby toxin-induced activation of Kupffer cells with resulting production of cytokines modulates hepatocyte responses and alters the course of disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.726390  DOI: Not available
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