Year of Publication

2014

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Nutritional Sciences

First Advisor

Dr. Xiang-An Li

Abstract

Sepsis claims over 215,000 lives in the US annually. Inducible glucocorticoids (iGC) is produced during sepsis. However, the precise effects of iGC in sepsis remain unclear due to a lack of appropriate animal models. Glucocorticoid (GC) insufficiency is associated with a marked increase in mortality and occurs in 60% of severe septic patients. Yet the conclusion of GC therapy on septic patients is still controversial.


Scavenger receptor class B type I (SR-BI) in the adrenal mediates the selective uptake of cholesteryl ester from lipoproteins for GC synthesis. SR-BI-/- mice completely lack iGC during sepsis and are highly susceptible to septic death, which presents SR-BI-/- mice as a GC insufficient model. However, SR-BI-/- mice display multiple defects contributing to septic death, making it difficult to study iGC by using these mice. Therefore, we utilized adrenal-specific SR-BI-/- mice (ADR-T SR-BI-/-) generated by adrenal transplantation. As expected, the ADR-T SR-BI-/- mice failed to generate iGC under cecal ligation and puncture (CLP)-induced sepsis and showed a significantly higher mortality than the control mice, demonstrating that iGC is essential for preventing septic death. High blood urea nitrogen (BUN) was observed in the ADR-T SR-BI-/- mice but not in the control mice in CLP, indicating that iGC protects kidney injury in sepsis. Plasma IL-6 was remarkably higher in the ADR-T SR-BI-/- mice than the control mice, demonstrating an anti-inflammatory effect of iGC in sepsis. The ADR-T SR-BI-/- mice also displayed significantly lower phagocytic activity of monocytes and neutrophils in the blood and lower activation of T cells in the spleen compared to the control mice in CLP, suggesting that iGC is immunomodulatory in sepsis. Low-dose GC supplementation significantly improved the survival of SR-BI-/- mice in CLP, but did not increase the survival rate of SR-BI+/+ mice in CLP, indicating that GC supplementation improves the survival specifically in mice with adrenal insufficiency.


Overall, we revealed that iGC is essential for sepsis survival. iGC prevents kidney damage, modulates inflammatory responses and exerts immunomodulatory functions in sepsis. GC supplementation specifically improves survival of individuals with adrenal insufficiency in sepsis.

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