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: 10651857
• 负责人: Bruce A Cairns
• 金额: $ 34.34万
• 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/10651857
• 关键词: Acute; Acute Lung Injury; Address; Agonist; American; Animal Model; Anti-Inflammatory Agents; Antioxidants; Bacterial Infections; Binding; Biological Response Modifiers; Burn Centers; Burn injury; Cell Culture System; Cell Nucleus; Cell physiology; Cells; Cellular Stress; Cessation of life; Clinical; Combined Modality Therapy; Complex; Data; Development; Dissociation; Drug Metabolic Detoxication; Elements; Enterobacteria phage P1 Cre recombinase; Epithelial Cells; FRAP1 gene; Formulation; Genes; Genetic Transcription; Homeostasis; Human; Immune; Immune System Diseases; Immune system; Immunologic Receptors; Infection; Infectious Agent; Inflammation; Inflammatory; Inhalation; Inhalation Burns; Injury; Knockout Mice; Knowledge; Lung; Macrophage; Mediating; Molecular; Morbidity - disease rate; Mouse Strains; Mus; Outcome; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Persons; Physiological; Pre-Clinical Model; Predisposition; Primary Cell Cultures; Proteins; Pulmonary Edema; Reactive Oxygen Species; Regulation; Respiratory Tract Infections; Risk; Role; Saline; Sampling; Specimen; Superoxides; Technology; Testing; Therapeutic; Tissues; Transcriptional Activation; Translations; United States; Wild Type Mouse; burn model; burn therapy; chemokine; cohort; cytokine; efficacy evaluation; immune activation; improved; infection risk; mortality; mouse model; multimodality; neutrophil; novel; nuclear factor-erythroid 2; oxidative damage; particle; pharmacologic; predictive modeling; prevent; recruit; response; risk prediction; transcription factor

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，烧伤受伤每年约3,500人死亡。有 对烧伤患者的发病率和死亡率的多种影响，最重要的 由于它导致对机会性细菌感染以及相关的发病率和相关的发病率的敏感性增加 死亡。临床需求的三fecta与此临床问题有关：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 受伤后，免疫系统对体内平衡，以使能够充分控制感染剂。总体目标 此应用的是描述负责不受控制的注射周期的机制 烧伤以完善预测模型患者的预后和完善恢复免疫的治疗方法 稳态，从而降低了感染的敏感性，并阻止了相关的发病率和死亡率。 我们和其他人在燃烧和燃烧 +吸入的人类样品和小鼠模型中都证明了（b + i） 损伤会产生许多与损伤相关的分子模式（湿）的局部和全身释放。 通过关键的免疫调节剂，潮湿促进相互作用，例如雷帕霉素的哺乳动物靶标（MTOR） 诱导活性氧（ROS），炎性细胞因子和趋化因子，从而导致组织损伤 和免疫细胞募集。免疫稳态通常至少部分由转录因子恢复 核因子 - 果蝇-2相关因子（NRF2）。我们的初步数据表明NRF2 - / - 敲除小鼠 B+I受伤后具有严重的死亡率。但是，我们的初步数据还表明，虽然肺部 在野生型小鼠中B+I后，免疫细胞NRF2蛋白翻译迅速增加，未翻译为 核。这是我们假设燃烧和B+I损伤后NRF2介导的稳态不足， 但是，NRF2途径的药理激活具有降低急性免疫功能障碍的潜力。 使用我们的临床前烧伤和B+I损伤模型，我们将定义急性免疫的NRF2特异性机制 烧伤或B+I伤害后功能障碍，并在我们的大量内部验证这些发现 燃烧中心。此外，我们将利用微粒技术来开发和表征NRF2驱动的疗法 改善伤害后免疫功能障碍。当我们感谢对Burn和B+I的响应是多因素的， 我们将利用这项技术将NRF2激活与第二种方法相结合，并抑制MTOR提供 一种新型的多模式疗法。这些方法的效率将使用我们的预先评估 烧伤和B+i的临床模型。我们很毒 我们填补现有的知识差距并改善烧伤和B+I患者的长期结果。