Relative adrenal insufficiency is a risk factor and an endotype of sepsis - A proof of concept study to support a precision medicine approach for glucocorticoid sepsis therapy

BioRxiv : the Preprint Server for Biology
C.-H. WuXiang-An Li


Rational: 25-60% of septic patients experience relative adrenal insufficiency (RAI) and glucocorticoid (GC) is frequently used in septic patients. However, the efficacy of GC therapy and whether the GC therapy should be based on the status of RAI are highly controversial. Critical barriers include technical limitations in properly identifying RAI in septic patients and a lack of RAI animal model. Objectives: We established a new RAI animal model to test our hypothesis that precision medicine approach should be used for GC sepsis therapy - only applying GC to a subgroup of septic mice with RAI. Methods: We generated SF1CreSR-BIfl/fl conditional knockout mice. The mice exhibited specific depletion of SR-BI expression in adrenal gland, resulting in a lack of production of inducible GC in response to ACTH stimulation or sepsis, but the mice had normal basal GC levels. Mice were treated with cecal ligation and puncture to develop sepsis. Mice were also supplemented with or without GC to study the effect of GC in sepsis therapy. Plasma and organs were collected for biochemical assays. BODIPY FL-conjugated Escherichia coli was used for phagocytosis assay. Macrophages were used to study effects of GC on inflammatory responses. Measurem...Continue Reading

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