# Relative adrenal insufficiency as a risk factor and an endotype for sepsis

> **NIH NIH R35** · UNIVERSITY OF KENTUCKY · 2022 · $382,500

## Abstract

Summary
Sepsis is a major health issue with a mortality rate of 30%. Sepsis induces huge stress
responses, including a 5-10 fold induction in glucocorticoid (GC) production in adrenal
gland, 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, a 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, we
demonstrated that mice with relative adrenal insufficiency are susceptible to 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. Our findings demonstrate that relative adrenal insufficiency is a risk factor
and an endotype of sepsis. Our findings also provide a “proof of concept” to support a
precision medicine approach to guide the use of GC for sepsis therapy, specifically,
selectively using GC therapy for a subgroup of septic patients with relative adrenal
insufficiency. In this R35/MIRA application, we propose to use our newly developed
adrenal-specific SR-BI null mice as a unique relative adrenal insufficiency animal model
to understand why relative adrenal insufficiency is a risk factor for sepsis and why GC
therapy benefits mice with relative adrenal insufficiency, but harms those without. The
translation of this study will improve the overall efficacy of sepsis therapy and save
lives.

## Key facts

- **NIH application ID:** 10400083
- **Project number:** 5R35GM141478-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** XIANG-AN LI
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400083

## Citation

> US National Institutes of Health, RePORTER application 10400083, Relative adrenal insufficiency as a risk factor and an endotype for sepsis (5R35GM141478-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10400083. Licensed CC0.

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