Corticosteroid Therapy Benefits Septic Mice With Adrenal Insufficiency But Harms Septic Mice Without Adrenal Insufficiency*

Ai, Junting; Guo, Ling; Zheng, Zhong; Wang, Shuxia; Huang, Bing; Li, Xiang-An

doi:10.1097/ccm.0000000000001264

Cited by 16 publications

(22 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was reported that adrenal SR-BI is required for the production of inducible glucocorticoid (iGC) in sepsis in a relative adrenal insufficiency mouse model generated by adrenal transplantation 38 . Adrenal transplantation has few limitations such as technique issue and the cut-off of the neuron and chromaffin cells communication.…”

Section: Mice With Adrenal Insufficiency Were Susceptible To Clp-indumentioning

confidence: 99%

“…Another data showed that basal plasma cortisol>20μg/dl and Δmax≤9μg/dl resulted in significantly high mortality (82%) in septic patients 53 . In animal studies, mice with adrenal insufficiency were very susceptible to sepsis-induced death as well 35,37,38,54 . These suggest that adrenal functions were strongly correlated with sepsisrelated mortality.…”

Section: Adrenal Insufficiency Worsens the Outcomes Of Sepsismentioning

confidence: 99%

“…To address this hypothesis, we generated a specific mouse model having RAI, called SF1creSR-BI fl/fl mice (adrenocortical SR-BI knockout mice). Recent studies of our laboratory and others reported that scavenger receptor class B type I (SR-BI), a high-density lipoprotein (HDL) receptor facilitating the uptake of cholesterol from HDL into target tissues 33,34 , is critical for the protection against sepsis [35][36][37][38] and also essential for GC production in adrenal glands 35,39,40 . In the present study, we demonstrated that iGC modulates the inflammatory responses in sepsis.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Guo

Wang

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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-BI fl/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. Measurements and Main Results:Using SF1CreSR-BI fl/fl mice as a RAI model, we found that mice with RAI were susceptible to CLP-induced sepsis compared to controls (6.7% survival in SF1CreSR-BI fl/fl mice versus 86.4% in SR-BI fl/fl mice; p=0.0001). Supplementation of hydrocortisone significantly improved survival in CLP-treated SF1CreSR-BIfl/fl mice. Surprisingly, wild type mice receiving GC treatment exhibited significantly less survival compared to wild type mice without GC treatment. We further found that, in contrast to wild type mice which displayed a well-controlled systemic inflammatory response, the mice with RAI featured a persisted systemic response as shown by high levels of plasma inflammatory cytokines/chemokines 20 hours post CLP, and supplementation of GC kept the inflammatory response under control. In vitro analysis revealed that stress level of GC is required to suppress inflammatory response through modulating MAPK signaling in macrophages. Conclusions:We demonstrate that RAI is a risk factor and an endotype for sepsis, and GC treatment benefits mice with RAI but harms mice without RAI. We further demonstrate that inducible GC functions to keep the systemic inflammatory response under control through modulating MAPK signaling, but mice with RAI lose such protection and supplementation of GC regains the protection. Our study provides a proof of concept to support the use of a precision medicine approach for sepsis therapyselectively applying GC therapy for a subgroup of patients with RAI.

show abstract

Section: Mice With Adrenal Insufficiency Were Susceptible To Clp-indumentioning

confidence: 99%

Section: Adrenal Insufficiency Worsens the Outcomes Of Sepsismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Guo

Wang

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…SRBI whole-body knockout mice show much more susceptible to septic death. Macrophage SRBI via TLR4 signaling modulate immune response during sepsis (16) and adrenal SRBI deficiency mice fail to generate inducible corticosteroid (iCS) leading to aberrant inflammatory response during sepsis (17). We have reported that hepatic SR-BI significantly protects against CLP induced sepsis using Scarb1 I179N mice which is a mutant SR-BI mouse model with 90% depletion in hepatic SR-BI.…”

Section: Introductionmentioning

confidence: 99%

Deficiency in reverse cholesterol transport in mice augments sepsis

Wang

Guo

Hao

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Sepsis claims over 215,000 lives and costs $16.7 billion per year in America alone. Recent studies revealed that HDL receptor scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. Using Scarb1I179N mice, a mutant SR-BI mouse model with 90% depletion in hepatic SR-BI, we previously reported that the mutant mice are susceptible to cecal ligation and puncture (CLP)-induced sepsis. However, using a hypo-AlbCreSR-BIfl/fl mouse model, Huby's group showed that the liver-specific SR-BI KO mice are not more susceptible to CLP-induced sepsis. In this study, we generated a new floxed SR-BI mouse model to clarify the contribution of hepatic SR-BI in sepsis. SR-BI is known as a receptor that plays a key role in reverse cholesterol transport (RCT) by uptaking cholesterol to the liver. So, our established AlbCreSR-BIfl/fl mice (liverspecific SR-BI KO) is an RCT deficiency mice model that can be used to understand the mechanisms of RCT protecting against sepsis and may provide new insight into the pathogenesis of sepsis.Methods and Results: We generated SR-BIfl/fl mice by flanking exon 2. We bred the floxed mice with AlbCre mice to generate AlbCreSR-BIfl/fl mice (liver-specific SR-BI KO mice), then the mice were backcrossed to C57BL/6J for 10 generations. As shown in Fig 1, the liver SR-BI expression was normal in SR-BIfl/fl mice as compared to C57BL/6J (B6) mice, but completely depleted in AlbCreSR-BIfl/fl mice. Using this liverspecific SR-BI KO model, we observed that a deficiency in RCT rendered the mice highly susceptible to CLP-induced sepsis as shown by 80% and 14.3% survival of SR-BIfl/fl and AlbCreSR-BIfl/fl mice, respectively. We found aggravated inflammatory cytokine production, altered leukocyte recruitment and slightly increased in the blood and peritoneal bacteria. Moreover, we found RCT deficiency mice increased both free and total cholesterol levels in serum and showed severer hemolysis in AlbCreSR-BIfl/fl mice than SR-BIfl/fl mice during CLP-induced sepsis. Importantly, when we fed AlbCreSR-BIfl/fl mice with probucol to decrease the cholesterol level in serum before performing CLP, the survival rate of AlbCreSR-BIfl/fl mice improved to 88.9%.Conclusions: Deficiency RCT resulting in abnormal metabolism of cholesterol and lipid metabolism is a risk factor in sepsis and maintain normal 2 metabolism of cholesterol may provide a new insight for sepsis therapies.

show abstract

“…A recent animal study showed that corticosteroid treatment is only beneficial in septic mice with an absolute adrenal insufficiency, while it harmed the mice without such adrenal insufficiency (52). Besides the importance of accurately determining 'who' to treat, it also should be further investigated 'how' to best treat these patients.…”

Section: E Boonen and G Van Den Berghementioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: New concepts to further unravel adrenal insufficiency during critical illness

Boonen

Berghe

2016

European Journal of Endocrinology

View full text Add to dashboard Cite

The concept of 'relative' adrenal insufficiency during critical illness remains a highly debated disease entity. Several studies have addressed how to diagnose or treat this condition but have often yielded conflicting results, which further fuelled the controversy. The main reason for the controversy is the fact that the pathophysiology is not completely understood. Recently, new insights in the pathophysiology of the hypothalamic-pituitary-adrenal axis response to critical illness were generated. It was revealed that high circulating levels of cortisol during critical illness are explained more by reduced cortisol breakdown than by elevated cortisol production. Cortisol production rate during critical illness is less than doubled during the day but lower than in healthy subjects during the night. High plasma cortisol concentrations due to reduced breakdown in turn reduce plasma ACTH concentrations via feedback inhibition, which with time may lead to an understimulation and hereby a dysfunction of the adrenal cortex. This could explain the high incidence of adrenal insufficiency in the prolonged phase of critical illness. These novel insights have created a new framework for the diagnosis and treatment of adrenal failure during critical illness that has redirected future research.

show abstract

Corticosteroid Therapy Benefits Septic Mice With Adrenal Insufficiency But Harms Septic Mice Without Adrenal Insufficiency*

Cited by 16 publications

References 53 publications

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

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

Deficiency in reverse cholesterol transport in mice augments sepsis

MECHANISMS IN ENDOCRINOLOGY: New concepts to further unravel adrenal insufficiency during critical illness

Contact Info

Product

Resources

About