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: 10300052
• 负责人: Bruce A Cairns
• 金额: $ 36.36万
• 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/10300052
• 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.

摘要