Multi-modal rescue of pulmonary NRF2-insufficiency after burn and burn + inhalation injury to regulate innate immune dysfunction

烧伤及烧伤吸入性损伤后肺NRF2不足的多模式抢救调节先天免疫功能障碍

• 批准号: 10732822
• 负责人: Bruce A Cairns
• 金额: $ 35.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732822
• 关键词: Multi; modal; rescue; pulmonary; NRF2

SUMMARY The American Burn Association estimates that there are ~3,500 deaths each year from burn injuries. There are multiple influences on morbidity and mortality in burn patients, with inhalation injury among the most significant as it leads to increased susceptibility to opportunistic bacterial infections and the associated morbidity and mortality. A trifecta of clinical need is associated with this clinical problem: 1) we lack the ability to predict risk of infection, 2) we do not understand the mechanism of infectious risk, and 3) we are unable to restore a patient’s immune system to homeostasis after injury to enable adequate control of infectious agents. The overall objective of this application is to delineate mechanisms responsible for the cycle of uncontrolled inflammation following burn-injury to refine prediction models patient outcomes and to refine therapeutic approaches to restore immune homeostasis, thus decreasing susceptibility to infection and preventing the associated morbidity and mortality. We and others have demonstrated in human samples and mouse models that burn and burn + inhalation (B+I) injury generates the local and systemic release of numerous Damage-Associated Molecular Patterns (DAMPs). DAMPs promote interactions, via key immune regulators, such as mammalian Target of Rapamycin (mTOR) to induce reactive oxygen species (ROS), inflammatory cytokines, and chemokines which results in tissue damage and immune cell recruitment. Immune homeostasis is normally restored at least in part by the transcription factor Nuclear Factor-Erythroid-2-Related Factor (NRF2). Our preliminary data demonstrate that Nrf2-/- knockout mice have profound mortality after B+I injury. However, our preliminary data also demonstrate that while pulmonary immune cell NRF2 protein translation is rapidly increased after B+I in wildtype mice, it is not translocated to the nucleus. Thus, we hypothesize that the NRF2-mediated homeostasis following burn and B+I injury is insufficient, but that pharmacological activation of the NRF2 pathway has the potential to reduce acute immune dysfunction. Using our pre-clinical models of burn and B+I injury, we will define NRF2-specific mechanisms of acute immune dysfunction following burn or B+I injury and validate these findings in human cohorts within in our high-volume burn center. In addition, we will utilize microparticle technology to develop and characterize NRF2-driven therapy to improve post-injury immune dysfunction. As we appreciate that the response to burn and B+I is multifactorial, we will leverage this technology to combine NRF2 activation with a second approach and inhibit mTOR to provide a novel multimodal therapeutic approach. The efficacy of these approaches will be evaluated using our pre- clinical models of burn and B+I. We are uniquely poised to successful complete this proposal which will allow us to fill the existing knowledge gaps and improve long-term outcomes of burn and B+I patients.

概括 美国烧伤协会估计每年约有 3,500 人死于烧伤。有 对烧伤患者的发病率和死亡率有多重影响，其中吸入性损伤最为重要 因为它会导致机会性细菌感染的易感性增加以及相关的发病率和 死亡。这个临床问题与三个临床需求相关：1）我们缺乏预测风险的能力 感染，2）我们不了解感染风险的机制，3）我们无法恢复患者的状态 免疫系统在受伤后保持体内平衡，从而能够充分控制传染源。总体目标 该应用的目的是描述导致以下不受控制的炎症循环的机制 烧伤以完善患者结果的预测模型并完善恢复免疫的治疗方法 体内平衡，从而降低对感染的易感性并预防相关的发病率和死亡率。 我们和其他人已经在人体样本和小鼠模型中证明了燃烧和燃烧+吸入（B+I） 损伤会导致大量损伤相关分子模式 (DAMP) 的局部和全身释放。 DAMP 通过关键的免疫调节剂促进相互作用，例如哺乳动物雷帕霉素靶点 (mTOR) 诱导活性氧 (ROS)、炎症细胞因子和趋化因子，导致组织损伤 和免疫细胞招募。免疫稳态通常至少部分由转录因子恢复 核因子-红细胞-2 相关因子 (NRF2)。我们的初步数据表明 Nrf2-/- 基因敲除小鼠 B+I 损伤后死亡率很高。然而，我们的初步数据也表明，虽然肺 在野生型小鼠中 B+I 后，免疫细胞 NRF2 蛋白翻译迅速增加，它不会转位到 核。因此，我们假设烧伤和 B+I 损伤后 NRF2 介导的体内平衡不足， 但 NRF2 通路的药理激活有可能减少急性免疫功能障碍。 使用我们的烧伤和 B+I 损伤的临床前模型，我们将定义急性免疫的 NRF2 特异性机制 烧伤或 B+I 损伤后功能障碍，并在我们的大容量人类队列中验证这些发现 烧伤中心。此外，我们将利用微粒技术来开发和表征 NRF2 驱动的疗法 改善损伤后的免疫功能障碍。正如我们所知，烧伤和 B+I 的反应是多因素的， 我们将利用这项技术将 NRF2 激活与第二种方法结合起来并抑制 mTOR 以提供 一种新颖的多模式治疗方法。这些方法的有效性将使用我们的预评估进行评估 烧伤和 B+I 的临床模型。我们完全准备好成功完成这项提案，这将使 我们将填补现有的知识空白并改善烧伤和 B+I 患者的长期结果。