Forbes, Stuart

Boulter, Luke

Livingstone, Eilidh

Medical Research Council (MRC)

2020-04-01T11:32:51Z

2020-04-01T11:32:51Z

2020-06-27

Paracetamol (Acetaminophen, APAP) overdose is responsible for 46% of drug induced liver injury in the Western world, causing 200 deaths in the UK and 500 deaths in the USA per annum. The current treatments for APAP overdose are NAcetyl-Cysteine, which is only effective in the first 12 hours after overdose, or in most serious cases a liver transplantation. Novel therapies are needed outside of this 12 hour window. After a moderate APAP overdose, patients will recover. This process involves macrophages which phagocytose necrotic cells and secrete signals which stimulate hepatocyte proliferation. Understanding and manipulating pathways involved in this endogenous repair process may lead to new therapeutic strategies. Semaphorins are a diverse group of signalling proteins that modulate axon guidance and immune responses. Semaphorin 7a (Sema7a) is a chemoattractant for dendritic cells, monocytes and macrophages. It can also modulate if macrophages secrete pro- or anti- inflammatory cytokines. This thesis investigates the role of Sema7a during APAP injury. 24 hours after a 350 mg/kg APAP overdose, Sema7a was expressed by viable Hnf4α+ peri-necrotic hepatocytes. To further examine the role of Sema7a during APAP injury, mice deficient for Sema7a (Sema7a KO) were compared to wild type (WT) mice, during a time course of APAP injury and recovery. Histological analysis displayed increased injury and necrosis in the Sema7a KO mice, with significantly more neutrophils in the necrotic area at 24 hours post APAP administration. In addition, Sema7a KO mice had increased serum levels of the pro-inflammatory cytokines IL-6 and CXCL1, in comparison to WT mice. These findings demonstrate novel roles of Sema7a reducing injury and inflammation caused by APAP overdose.

https://hdl.handle.net/1842/36926

http://dx.doi.org/10.7488/era/227

en

The University of Edinburgh

paracetamol overdose

liver injury

Semaphorin 7a

Sema7a

macrophages

APAP injury

Investigating the role of Semaphorin7a in paracetamol induced liver injury

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy