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

摘要 烧伤患者的发病率和死亡率受到多种影响，其中吸入性损伤是最重要的影响因素 显著烧伤和吸入性损伤（I + B）发生在所有烧伤患者的5 - 30%中， 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， 局部和全身炎症，当两者结合时，导致烧伤发病率和死亡率增加 患者包括肺损伤增加、移植物排斥和细菌感染。 虽然以前的研究已经探讨了烧伤时的免疫功能障碍，但没有研究证实 烧伤后免疫功能障碍与TLR/mTOR/PPAR γ信号轴的机制联系。 类似地，目前没有生物标志物可以告知临床决策以评估患者的健康状况。 免疫状态，导致患者预后不良。我们建议并有重大的初步和 已发表的数据支持烧伤诱导的DAMP释放诱导Toll样受体（TLR）信号传导， 中性粒细胞、巨噬细胞和肺上皮细胞中mTOR/PPAR γ轴的激活， 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， 患者长期预后差。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差、移植物排斥反应和细菌感染易感性的功能障碍 和吸入性损伤在此，我们拟对TLR/mTOR/PPAR γ诱导的细胞凋亡的动力学和机制进行研究。 烧伤后免疫功能紊乱我们建议利用我们现有的知识来开发一个索引， 评估和客观地确定烧伤患者的不良结局风险，以帮助为临床决策提供信息 在乎 为此，我们将利用创新的临床适用的烧伤和烧伤-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 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Jaycee烧伤中心的住院患者，以评估定义的机制的可翻译性， 评估指标以预测不良患者结局。这一提议的意义在于它有可能推动 这一领域的发展有两个关键方面：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）建立并验证烧伤患者免疫功能预测模型， 基于免疫功能障碍的不良结局风险。共同成功完成这项提案， 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。

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.