Abortive cell cycle can induce death via apoptosis. In support of this mechanism, LCMV-WE increased the number of cells that simultaneously stained for apoptosis and proliferation. LCMV does not normally infect hepatocytes, and mature hepatocytes did not express the canonical (DAG-1) or novel (AXL-1, TYRO-3, LSECtin) receptors for LCMV. However, stimulating hepatocyte proliferation (via PHx) increased the expression of the novel receptors in liver. Likewise, LCMV-WE induced receptor expression and was only able to infect hepatocytes at timepoints after proliferation was induced. Conclusions.
Taken together, these results shed new mechanistic light on the role of the liver in VHF pathogenesis. Specifically, it is hypothesized that the induction of hepatocyte proliferation by pathogenic
viral strains allows expansion of the infection to parenchymal check details cells. The increase in AST/ALT with VHF is likely explained, at least in part, by abortive cell cycle progression induced by the infection. These results may lead to the development of new therapies to prevent VHF from reaching critical phases. Disclosures: The following people have nothing to disclose: Gavin E. Arteel, Juliane I. Beier, Jenny Jokinen, Patrick S. Whang, Amah M. Martin, Nikole L. Warner, Igor S. Lukashevich Background: Liver hypoxia/ischemia has a strong and irreversible effect on hepatocellular metabolism, morphology and function and causes hepatocyte cell death by both apoptosis and necrosis. One of the hallmarks of cell death is the presence of disruptions MLN0128 in mitochondrial activity leading to disturbance in cellular energy metabolism. We hypothesized that refueling the citric acid cycle by some of its intermediates could revert energy production and levels and therefore protect the liver against hypoxic insult.
In vitro, we have already demonstrated that oxaloacetic acid (OAA) was the most potent citric acid intermediate capable of protecting rat hepatocytes. We here analyze the potential protective effect of this compound in vivo using the left portal vein ligation (LPVL) model of warm liver ischemia. Methods: In vitro, isolated rat hepatocytes were cultured in low glucose medium Tideglusib supplemented with OAA. Hypoxia or anoxia were obtained using a hypoxic chamber (24h/1%O2 or 4h/0%O2). Cell viability was evaluated by MTT assay, cell counting and LDH release in the medium. In vivo, animals subjected to LPVL were treated with OAA through continuous delivery by the portal vein in the ischemic lobes. Results: In vitro, after 4h of anoxia, 40.5±5.3% of untreated hepatocytes were dead; this was limited to 17.1±5.9% (p<0.001) after treatment with OAA, reaching almost the levels observed with normoxic hepatocytes (6.3±3.5%). After 24h of hypoxia, 46.4±2.0% of OAA-treated hepatocytes were dead in comparison to 56.7±3.0% of untreated hepatocytes (p<0.01). These results were confirmed by measuring LDH release in the medium and MTT assay.