Abstract
Introduction: 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 GC therapy should be based on the status of RAI are highly controversial. Our poor understanding about the pathogenesis of RAI and a lack of RAI animal model present significant barriers to address these critical issues.
Methods: Scavenger receptor BI (SR-BI) regulates stress-induced GC (iGC) production in response to stress. We generated SF1CreSR-BIfl/fl mice and utilized the mice as a RAI model to elucidate the pathogenesis of RAI and GC therapy in sepsis. SF1CreSR-BIfl/fl mice did not express SR-BI in adrenal gland and lacked iGC production upon ACTH stimulation, thus, they are RAI.
Results and Discussion: RAI mice were susceptible to cecal ligation and puncture (CLP)-induced sepsis (6.7% survival in SF1CreSR-BIfl/fl mice versus 86.4% in SR- BIfl/fl mice; p = 0.0001). Compared to a well-controlled systemic inflammatory response in SR-BIfl/fl mice, SF1CreSR-BIfl/fl mice featured a persistent hyperinflammatory response. Supplementation of a low stress dose of GC to SF1CreSR-BIfl/fl mice kept the inflammatory response under control and rescued the mice. However, SR-BIfl/fl mice receiving GC treatment exhibited significantly less survival compared to SR-BIfl/fl mice without GC treatment. In conclusions, we demonstrated that RAI is a risk factor for death in this mouse model of sepsis. We further demonstrated that RAI is an endotype of sepsis, which features persistent hyperinflammatory response. We found that GC treatment benefits mice with RAI but harms mice without RAI. Our study provides a proof of concept to support a precision medicine approach for sepsis therapy – selectively applying GC therapy for a subgroup of patients with RAI.
Document Type
Article
Publication Date
1-2023
Digital Object Identifier (DOI)
https://doi.org/10.3389/fimmu.2022.1110516
Funding Information
This study was supported by Grants NIH R01GM121796, R35GM141478 and VA 1I01BX004639 (to X-AL). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or VA.
Repository Citation
Wu, Chia-Hua; Guo, Ling; Hao, Dan; Wang, Qian; Ye, Xiang; Ito, Misa; Huang, Bin; Mineo, Chieko; Shaul, Philip W.; and Li, Xiang-An, "Relative adrenal insufficiency is a risk factor and endotype of sepsis - A proof-of- concept study to support a precision medicine approach to guide glucocorticoid therapy for sepsis" (2023). Saha Cardiovascular Research Center Faculty Publications. 94.
https://uknowledge.uky.edu/cvrc_facpub/94
Included in
Cardiology Commons, Circulatory and Respiratory Physiology Commons, Immunology and Infectious Disease Commons
Notes/Citation Information
© 2023 Wu, Guo, Hao, Wang, Ye, Ito, Huang, Mineo, Shaul and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.