Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States.
Saha Cardiovascular Research Center, University of Kentucky College of Medicine, Lexington, KY, United States.
Front Immunol. 2023 Jan 12;13:1110516. doi: 10.3389/fimmu.2022.1110516. eCollection 2022.
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.
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.
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.
25%-60%的脓毒症患者存在相对肾上腺功能不全（RAI），糖皮质激素（GC）经常被用于脓毒症患者。然而，GC 治疗的疗效以及是否应根据 RAI 状态进行 GC 治疗存在很大争议。我们对 RAI 发病机制的理解不足，以及缺乏 RAI 动物模型，这给解决这些关键问题带来了重大障碍。
清道夫受体 BI（SR-BI）调节应激诱导的 GC（iGC）产生，以响应应激。我们生成了 SF1CreSR-BIfl/fl 小鼠，并利用这些小鼠作为 RAI 模型，以阐明脓毒症中 RAI 和 GC 治疗的发病机制。SF1CreSR-BIfl/fl 小鼠的肾上腺中不表达 SR-BI，且在 ACTH 刺激下缺乏 iGC 产生，因此它们存在 RAI。
RAI 小鼠易发生盲肠结扎穿刺（CLP）诱导的脓毒症（SF1CreSR-BIfl/fl 小鼠的存活率为 6.7%，而 SR-BIfl/fl 小鼠为 86.4%；p=0.0001）。与 SR-BIfl/fl 小鼠中得到良好控制的全身性炎症反应相比，SF1CreSR-BIfl/fl 小鼠表现出持续的过度炎症反应。向 SF1CreSR-BIfl/fl 小鼠补充低应激剂量的 GC 可控制炎症反应并挽救小鼠。然而，接受 GC 治疗的 SR-BIfl/fl 小鼠的存活率明显低于未接受 GC 治疗的 SR-BIfl/fl 小鼠。总之，我们证明 RAI 是该脓毒症小鼠模型死亡的一个危险因素。我们进一步证明，RAI 是脓毒症的一个表型，其特征是持续的过度炎症反应。我们发现 GC 治疗对 RAI 小鼠有益，但对无 RAI 小鼠有害。我们的研究提供了一个概念验证，支持脓毒症治疗的精准医学方法-选择性地将 GC 治疗应用于存在 RAI 的患者亚组。
