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Effects of the hepatic glucocorticoid receptor in the setting of sepsis, infection, and inflammation
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Summer 2023
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2023-08
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Each year hundreds of thousands of people develop life-threatening sepsis, defined by a combination of infection and organ dysfunction. Although many affected biological pathways are typically regulated by the glucocorticoid receptor (GR), during sepsis this is deficient and supplementation with exogenous glucocorticoids is often ineffective in reducing mortality. The GR has different effects in different organs. In liver many effects are beneficial, whereas in immune or muscular systems many effects are deleterious. A sampling of this literature is reviewed in chapter 1. With the hypothesis that liver-specific glucocorticoid therapy will be more clinically beneficial than systemic therapy, we studied liver-specific GR effects in infection, inflammation, or sepsis. Chapter 2 describes in-vitro chemokine alterations from GR activation in primary human hepatocytes, with inflammation or infection modeled by TNFα and/or lipopolysaccharide. Comparisons were made in primary human hepatocytes, the human hepatoma cell line HEPG2, and the non-liver cell line HEK293t. Chapter 3 outlines outcomes of liver-specific GR deficiency using mice with inducible liver-specific GR knockout, modeling sepsis with cecal ligation and puncture. Results of these two models show mRNA and/or protein changes induced by GR in chemokines; transcription factors; genes related to protein degradation, metabolism, metal management, inflammation, liver regeneration, and hemodynamic stability. Results of these 2 models demonstrate a significant role of the hepatic GR in many pathways dysregulated during sepsis. Therefore, targeting GR therapy to the liver instead of systemic treatment may prove more clinically beneficial to reducing the morbidity and mortality of sepsis.