Damage-Induced Activation of the TLR/mTOR/PPARg Axis Regulates the Immune Response After Burn and Inhalation Injury

损伤诱导的 TLR/mTOR/PPARg 轴激活调节烧伤和吸入性损伤后的免疫反应

• 批准号: 10531808
• 负责人: Bruce A Cairns
• 金额: $ 4.18万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531808
• 关键词: Address; American; Animal Model; Anti-Inflammatory Agents; Bacterial Infections; Binding; Biological Markers; Burn Centers; Burn injury; Cells; Cessation of life; Clinical; Coupled; Cutaneous; Data; Enzymes; Epithelial; Epithelial Cells; Exhibits; FRAP1 gene; Functional disorder; Glycolysis; Graft Rejection; Hyaluronic Acid; Immune; Immune System Diseases; Immune response; Immunosuppression; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Inhalation Burns; Injury; Inpatients; Interleukin-10; Intervention; Kinetics; Knowledge; Lead; Leukocytes; Link; Lung; Metabolic; Modeling; Molecular; Morbidity - disease rate; North Carolina; Outcome; PPAR gamma; Pathology; Pathway interactions; Patient risk; Patient-Focused Outcomes; Patients; Pattern; Pattern recognition receptor; Persons; Phenotype; Predisposition; Publishing; Receptor Activation; Receptor Signaling; Sampling; Signal Transduction; Stimulus; Systems Biology; Testing; Therapeutic Intervention; Tissues; Toll-like receptors; United States; arginase; base; burn model; clinical application; clinical care; clinical decision-making; cytokine; ds-DNA; high risk; immune activation; immunological status; improved; indexing; innovation; lung injury; macrophage; mortality; neutrophil; new technology; pulmonary function; receptor expression; recruit; systemic inflammatory response; therapeutic target; wood smoke

ABSTRACT There are multiple influences on morbidity and mortality in burn patients, with inhalation injury among the most significant. Combined burn and inhalation injury (I+B) occurs in 5-30% of all burn patients and is characterized by epithelial denudation, elevated leukocyte (neutrophil and macrophage) activity in the lung, with enhanced local and systemic inflammation which when combined, lead to an increased morbidity and mortality of burn patients including increased lung damage, graft-rejection and bacterial infections. Although previous studies have explored immunological dysfunction during burn injury, no study has established a mechanistic link between the immune dysfunction and the TLR/mTOR/PPARγ signaling axis after burn injury. Similarly, there are currently no biomarkers, which can inform the clinical decision-making as to assess patients' immune status, contributing to poor patient outcomes. We propose and have significant preliminary and published data to support that burn-induced DAMP release induces toll-like receptor (TLR) signaling that drives activation of the mTOR/PPARγ axis in neutrophils macrophages and pulmonary epithelial cells that promotes inflammation and further tissue damage and thus a cycle of unresolved yet ineffective inflammation leading to poor long-term patient outcomes. In addition, we have identified key aspects of burn-induced immune dysfunction that can predict poor lung function, graft-rejection and susceptibility to bacterial infection after burn and inhalation injury. Here we propose to evaluate the dynamics and mechanisms of TLR/mTOR/PPARγ induced immune dysfunction post-burn injury. We propose to use our current knowledge to develop an index to rapidly assess and objectively determine a burn patient's risk for poor outcomes to help inform decisions on clinical care. To this end, we will utilize innovative clinically applicable animal models of burn and burn-inhalation (B+I) injury, coupled with novel technologies, to take directed and systems biology approaches to delineate mechanisms associated with phenotypes observed. In addition, we will utilize clinical samples collected from burn and B+I inpatients at the North Carolina Jaycee Burn Center to evaluate the translatability of mechanisms defined and evaluate indices to predict poor patient outcomes. The significance of this proposal lies in its potential to move the field forward in two key ways: 1) to define and delineate the kinetics of cellular and molecular mechanisms underlying the immune dysfunction after burn injury, 2) to develop and validate a model to predict burn patients' risk for poor outcomes based on immune dysfunction. Together the successful completion of this proposal will inform the type and timing of therapeutic interventions to improve the morbidity and mortality of burn patients.

抽象的 烧伤患者的发病率和死亡率受到多种影响，其中吸入性损伤影响最大 5-30% 的烧伤患者发生合并烧伤和吸入性损伤 (I+B)，其特征是明显的。 通过上皮剥脱，肺中白细胞（中性粒细胞和巨噬细胞）活性升高，并增强 局部和全身炎症结合起来会导致烧伤发病率和死亡率增加 患者的症状包括肺损伤增加、移植物排斥和细菌感染。 尽管之前的研究已经探讨了烧伤期间的免疫功能障碍，但没有研究证实 烧伤后免疫功能障碍与 TLR/mTOR/PPARγ 信号轴之间的机制联系。 同样，目前还没有生物标志物可以为临床决策提供信息以评估患者的健康状况。 我们提出并有重要的初步和研究成果。 已发表的数据支持烧伤诱导的 DAMP 释放会诱导 Toll 样受体 (TLR) 信号传导，从而驱动 中性粒细胞、巨噬细胞和肺上皮细胞中 mTOR/PPARγ 轴的激活，促进 炎症和进一步的组织损伤，从而导致未解决但无效的炎症循环 此外，我们还确定了烧伤引起的免疫的关键方面。 烧伤后可预测肺功能不良、移植排斥和细菌感染易感性的功能障碍 在这里，我们建议评估 TLR/mTOR/PPARγ 诱导的动力学和机制。 我们建议利用我们现有的知识来快速制定烧伤后免疫功能障碍的指数。 评估并客观地确定烧伤患者预后不良的风险，以帮助为临床决策提供信息 关心。 为此，我们将利用创新的临床适用的烧伤和烧吸入（B+I）损伤动物模型， 结合新技术，采用定向和系统生物学方法来描述机制 此外，我们将利用从烧伤和 B+I 收集的临床样本。 北卡罗来纳州房祖名烧伤中心的住院患者评估已定义和 评估指标来预测不良的患者治疗结果该提案的意义在于其具有变革的潜力。 该领域以两种关键方式向前发展：1）定义和描述细胞和分子机制的动力学 烧伤后免疫功能障碍的潜在原因，2）开发并验证预测烧伤患者的模型 免疫功能障碍导致不良结果的风险将共同成功完成该提案。 告知治疗干预的类型和时机，以改善烧伤患者的发病率和死亡率。

项目成果

Rat Burn Model to Study Full-Thickness Cutaneous Thermal Burn and Infection.

用于研究全层皮肤热烧伤和感染的大鼠烧伤模型。

• DOI: 10.3791/64345
• 发表时间: 2022
• 期刊: Journal of visualized experiments : JoVE
• 作者: Sharma,Rajnikant;Yeshwante,Shekhar;Vallé,Quentin;Hussein,Maytham;Thombare,Varsha;McCann,SeanMichael;Maile,Robert;Li,Jian;Velkov,Tony;Rao,Gauri
• 通讯作者: Rao,Gauri

Involvement of extracellular vesicles in the progression, diagnosis, treatment, and prevention of whole-body ionizing radiation-induced immune dysfunction.

• DOI: 10.3389/fimmu.2023.1188830
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3