# Mechanism of adrenal insufficiency as a risk factor for sepsis

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $293,818

## Abstract

Summary
Sepsis is a major health issue with a mortality rate of 30%. During periods of septic
stress, glucocorticoid (GC) production is markedly induced in relation to an increased
demand. However, the function of this inducible GC (iGC) remains poorly understood.
Importantly, 25-60% of septic patients suffer relative adrenal insufficiency – insufficient
iGC production in response to stress. Given the potential complications of adrenal
insufficiency, GC therapy is often used for septic shock patients. However, the true
contribution of adrenal insufficiency to sepsis and the efficacy of GC therapy are highly
controversial. While a number of factors contribute to the debate, the lack of a relative
adrenal insufficiency animal model has limited our capacity to address these issues.
Toward a solution, scavenger receptor BI (SR-BI), a well-established high density
lipoprotein (HDL) receptor, was first identified in our laboratory as a critical protective
factor in sepsis. A number of laboratories including ours recently reported that SR-BI
null mice fail to produce iGC in response to ACTH stimulation, establishing SR-BI null
mice as a relative adrenal insufficiency model. Using this unique model and cecal
ligation and puncture (CLP)-induced sepsis, we demonstrated that mice with relative
adrenal insufficiency are susceptible to CLP-induced septic death, and more
importantly, supplementation of GC rescued mice with relative adrenal insufficiency, but
surprisingly, caused more death in mice without relative adrenal insufficiency. These
findings provide a “proof of concept” that GC therapy may selectively benefits septic
patients with relative adrenal insufficiency. In this application, we propose to use our
newly developed adrenal-specific SR-BI null mice as a unique relative adrenal
insufficiency animal model to elucidate the mechanism of relative adrenal insufficiency
as a risk factor for sepsis and to provide mechanistic support for the selective use of GC
therapy in a subgroup of patients with relative adrenal insufficiency. The translation of
this preclinical study will improve the overall efficacy of sepsis therapy.

## Key facts

- **NIH application ID:** 9999611
- **Project number:** 5R01GM121796-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** XIANG-AN LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $293,818
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999611

## Citation

> US National Institutes of Health, RePORTER application 9999611, Mechanism of adrenal insufficiency as a risk factor for sepsis (5R01GM121796-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9999611. Licensed CC0.

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