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

摘要 影响烧伤患者发病率和死亡率的因素是多方面的，其中吸入性损伤的影响最大。 意义重大。烧伤合并吸入性损伤(I+B)在所有烧伤患者中占5%-30%，其特点是 由于上皮剥离，肺内白细胞(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在一起，会导致烧伤的发病率和死亡率增加 患者包括肺损伤增加、移植物排斥反应和细菌感染。 尽管以前的研究已经探讨了烧伤时的免疫功能障碍，但还没有研究证实 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 免疫状态，导致患者预后不佳。我们提出并进行了重要的初步和 已发表的数据支持烧伤诱导的潮湿释放诱导Toll样受体(TLR)信号，驱动 中性粒细胞、巨噬细胞和肺上皮细胞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，导致 患者的长期预后不佳。此外，我们已经确定了烧伤诱导免疫的关键方面。 可预测烧伤后肺功能不良、移植物排斥反应和细菌感染易感性的功能障碍 和吸入性损伤。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。我们建议利用我们现有的知识开发一个索引，以快速 评估和客观确定烧伤患者预后不良的风险，以帮助做出临床决策 关心。 为此，我们将利用创新的临床适用的烧伤和烧伤吸入性损伤(B+I)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 与观察到的表型相关。此外，我们将利用从烧伤和B+I收集的临床样本 北卡罗来纳州杰西烧伤中心的住院患者评估所定义的机制和 评估预测不良患者预后的指标。这项提议的意义在于它的潜力 该领域在两个关键方面向前发展：1)定义和描绘细胞和分子机制的动力学 烧伤后免疫功能障碍的基础，2)建立和验证一个模型来预测烧伤患者 基于免疫功能障碍的不良结局的风险。共同努力，成功完成这项提案将 告知治疗干预的类型和时机，以提高烧伤患者的发病率和死亡率。

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.