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Description
Title
Relative adrenal insufficiency is a risk factor and an endotype for sepsis
Summary
Sepsis is a major health issue with a mortality rate of 30%. Sepsis induces huge stress
responses, including a 5-10 folds 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, 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. Our
findings demonstrate that relative adrenal insufficiency is a risk factor for sepsis 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 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 and save lives.
Status | Active |
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Effective start/end date | 5/1/21 → 4/30/26 |
Funding
- National Institute of General Medical Sciences: $745,866.00
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