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

相对肾上腺功能不全是脓毒症的危险因素和内型

• 批准号: 10400083
• 负责人: XIANG-AN LI
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400083
• 关键词: Address; Adrenal Glands; Adrenal gland hypofunction; Animal Model; Cessation of life; Corticotropin; Glucocorticoids; Goals; Health; Knockout Mice; Laboratories; Modeling; Mus; Patients; Production; Reporting; Risk Factors; SR-BI receptor; Sepsis; Septic Shock; Stress; Subgroup; Supplementation; Translations; biological adaptation to stress; high density lipoprotein receptor; improved; mortality; precision medicine; protective factors; response; septic; septic patients

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.

概括 脓毒症是一个重大的健康问题，死亡率高达 30%。脓毒症会带来巨大的压力。 反应，包括诱导肾上腺糖皮质激素 (GC) 产生 5-10 倍 然而，这种诱导型 GC (iGC) 的功能仍然知之甚少。 重要的是，25-60% 的脓毒症患者患有相对肾上腺功能不全——不足 鉴于肾上腺的潜在并发症，iGC 的产生是为了应对压力。 然而，GC治疗经常用于脓毒性休克患者。 肾上腺皮质功能不全对脓毒症的影响以及 GC 治疗的疗效都非常高 虽然引起争论的因素有很多，但缺乏相对的因素。 肾上腺功能不全动物模型限制了我们解决这些问题的能力。 清道夫受体 BI (SR-BI) 是一种成熟的高密度受体 脂蛋白（HDL）受体，首先在我们的实验室被鉴定为关键的保护性物质 包括我们在内的许多实验室最近报告说 SR-BI 是败血症的一个因素。 null 小鼠无法响应 ACTH 刺激产生 iGC，建立 SR-BI null 使用这种独特的模型，我们将小鼠作为相对肾上腺功能不全模型。 证明具有相对肾上腺功能不全的小鼠容易患败血症 死亡，更重要的是，补充 GC 拯救了具有相对肾上腺功能的小鼠 但令人惊讶的是，缺乏相对肾上腺的小鼠会导致更多的死亡 我们的研究结果表明，肾上腺功能不全是一个危险因素。 我们的研究结果还提供了支持“概念证明”的证据。 指导使用 GC 治疗脓毒症的精准医学方法，具体来说， 选择性地对具有相对肾上腺功能的脓毒症患者亚组使用 GC 疗法 在这个R35/MIRA应用中，我们建议使用我们新开发的。 肾上腺特异性 SR-BI 缺失小鼠作为独特的相对肾上腺功能不全动物模型 了解为什么相对肾上腺功能不全是脓毒症的危险因素以及为什么要进行 GC 治疗小鼠对相对肾上腺功能不全的小鼠有益，但对没有相对肾上腺功能不全的小鼠有害。 这项研究的转化将提高脓毒症治疗的整体疗效并节省 生活。