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 对烧伤患者的发病率和死亡率有多种影响，受伤最多 重要的。烧伤和吸入损伤（I+B）发生在所有烧伤患者中的5-30％中，并被表征 通过上皮剥夺，肺中的白细胞（中性粒细胞和巨噬细胞）升高，增强 局部和全身性炎症，合并后会导致发病率和烧伤死亡率的增加 包括增加肺部损伤，移植排斥和细菌感染的患者。 尽管以前的研究探索了烧伤期间的免疫功能障碍，但尚未建立研究 烧伤后免疫功能障碍与TLR/MTOR/PPARγ信号轴之间的机械联系。 同样，目前没有生物标志物，可以告知临床决策以评估患者的 免疫状态，导致差的患者预后。我们提出并拥有重要的初步 已发布的数据以支持燃烧引起的潮湿释放引起类似收费的接收器（TLR）信号传导 中性粒细胞巨噬细胞和肺部上皮细胞中MTOR/PPARγ轴的激活 炎症和进一步的组织损伤，因此是未解决但无效感染的循环 长期患者结局不良。此外，我们已经确定了燃烧引起的免疫的关键方面 能够预测肺部感染后肺功能不良的功能障碍，移植物排斥和易感性 和吸入损伤。在这里，我们建议评估TLR/MTOR/PPARγ诱导的动力学和机制 烧伤后免疫功能障碍。我们建议利用我们当前的知识来开发一个索引来快速 评估并客观地确定烧伤患者的预后不良风险，以帮助有关临床的决定 关心。 为此，我们将利用创新的临床适用燃烧和烧伤的动物模型（B+I）损伤， 再加上新技术，采取定向和系统生物学方法来描述机制 与观察到的表型相关。此外，我们将利用从Burn和B+I收集的临床样本 北卡罗来纳州Jaycee Burn中心的住院患者评估定义机制的转换性 评估指标以预测患者的不良预后。该提议的重要性在于它有潜力 该领域以两种关键方式前进：1）定义和描述细胞和分子机制的动力学 烧伤后的免疫功能障碍的基础，2）开发和验证模型以预测烧伤患者 因免疫功能障碍而出现不良预后的风险。该提议的成功完成将在一起 告知理论干预措施的类型和时机，以提高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