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Rôle de la MAP kinase p38α au cours d'une agression aiguë du foie

Abstract : To prevent acute liver injuries induced by viral hepatitis, toxins or drug overload, liver activates different interconnected processes such as proliferation, inflammation or cell death. Interestingly, one protein is at the crossroad of these pathways: the MAP (Mitogen Activated Protein) kinase p38 alpha. Several studies showed a dual role for the p38a mitogen-activated protein kinase pathway in liver. Even if its role as a negative regulator of hepatocyte proliferation has been largely described, p38a may also harbor an oncogenic role involving cancer related-processes and notably inflammation. However, its function during an acute injury, in adult liver, remains uncharacterized. My thesis aim was to characterize p38 alpha MAP Kinase role during an acute liver injury thanks to a mouse model with a conditional hepatocyte specific deletion of p38a (KO model). To that end, we used an experimental hepatopathy system classically used to reproduce hepatocyte division in inflammatory context: the carbon tetrachloride model (CCl4). An injection of this hepatotoxic in mice induces hepatocyte cytolysis in centrilobular zone rapidly followed by immune cell infiltration and compensatory healthy hepatocyte proliferation to repair hepatic tissue. Control (CT) and KO mice were sacrificed at different timings after injection to establish a post-CCl4 kinetic, during which blood and liver tissue were collected. Liver injuries, inflammation, apoptosis and proliferation processes were then assayed. First, absence of p38a decreases hepatocyte number into cell cycle S phase (BrdU labelling, CyclinA2 levels) during regenerative process post-CCl4. Interestingly, we showed that p38a deficiency confers a protective effect against hepatic injuries induced by CCl4. Indeed, cytolysis areas and alanine transaminase levels (hepatocyte death reflection) were significantly decreased (40H to 60H post-CCl4) in KO mice. To explain this phenotype, we investigated apoptosis pathway during regenerative kinetic, but our results did not show any significant differences between CT and KO mice. On the other hand, antioxidant response is increased in KO livers and could therefore be involved in the hepatic tissue protection. Finally, immunohistochemistry analysis showed a massive inflammatory cell recruitment to cytolysis areas correlated with a significant increase of cytokines (as TNFa) and pro-inflammatory chemokines (as CCL2 and CCL5). These data strongly suggest that p38a deficiencies mediate a specific immune response to favor hepatic tissue clearance and repair. In conclusion, my thesis work shows that the absence of p38a MAP Kinase is hepatoprotective during an acute liver injury enhancing "proliferation - inflammatory response" balance, therefore promoting early tissue repair and maintaining liver homeostasis.
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Manon Fortier. Rôle de la MAP kinase p38α au cours d'une agression aiguë du foie. Médecine humaine et pathologie. Université Sorbonne Paris Cité, 2018. Français. ⟨NNT : 2018USPCB100⟩. ⟨tel-02513338⟩



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