Netosis in Trauma mediated Acute Lung Injury

创伤介导的急性肺损伤中的网沉着

• 批准号: 10371817
• 负责人: Jennifer Leonard
• 金额: $ 18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-14 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371817
• 关键词: Activation Analysis; Acute Lung Injury; Address; Adoptive Transfer; Anti-Infective Agents; Antibodies; Bacteria; Bacterial Pneumonia; Biological; Biological Assay; Bronchoalveolar Lavage; CD28 gene; CD3 Antigens; CSF3 gene; Chemicals; Complication; Cytoplasmic Granules; DNA; Data; Development; Enzyme-Linked Immunosorbent Assay; Enzymes; FDA approved; Flow Cytometry; Generations; Genetic; Goals; Histone H3; Hospitalization; Host Defense; Immobilization; Immune System Diseases; Immune response; Immunologics; Immunophenotyping; Incubated; Infection; Inflammation; Inflammatory Response; Injury; Innate Immune System; Inpatients; Interferon Type II; Internet; Invaded; K-Series Research Career Programs; Knowledge; Laboratories; Leukocytes; Lymphocyte; Lymphocyte Function; Measures; Mediating; Multiple Trauma; Mus; Nosocomial pneumonia; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Physicians; Plasma; Pneumonia; Predisposition; Prevention; Production; Protocols documentation; Pseudomonas; Pseudomonas aeruginosa; Pseudomonas aeruginosa pneumonia; Research; Respiratory Tract Infections; Risk; Role; Scientist; Secondary to; Sepsis; Serum; Signal Transduction; Splenocyte; Stains; Sterility; TNF gene; Technology; Testing; Therapeutic; Tissues; Training; Translating; Trauma; Trauma patient; Traumatic injury; Up-Regulation; antimicrobial; base; clinically translatable; cytokine; cytotoxic; defined contribution; experimental study; extracellular; immunocytochemistry; improved; improved outcome; inhibitor/antagonist; injured; insight; intravital microscopy; leukocyte activation; lung injury; monocyte; mouse model; neutrophil; novel; pathogen; peripheral blood; post-trauma; prevent; response; secondary infection; severe injury; skills; systemic inflammatory response; therapy development; time interval; tissue injury; tool

PROJECT SUMMARY Up to 40% of critically injured trauma patients will develop a serious infectious complication during their inpatient hospitalization and respiratory infections are the most common cause of sepsis in injured patients. While it is known that traumatic injury triggers a sterile inflammatory response that can result in acute lung injury (ALI), the mechanism of this and its contribution to the development of secondary infections such as pneumonia is not well understood. The overarching goal of this research is to understand the role of the innate immune system in trauma induced lung injury in order to provide new targets for treatment and prevention. We have recently established a mouse model of polytrauma that recapitulates the increased susceptibility to gram negative pneumonia seen in critically injured patients. In preliminary studies, we demonstrate that trauma alone induces both an acute lung injury and increased susceptibility to Pseduomonas pneumonia. We further find an increase in neutrophil NETosis following a second insult with pseudomonas bacteria. Neutrophil NETosis is a strong antimicrobial neutrophil response whereby activated neutrophils extrude a web of DNA studded with cytotoxic granules which function to immobilize and kill invading pathogens. While NETosis is a critical anti-infective pathway, excessive NETosis has been demonstrated to result in collateral damage to host tissues. We also show that serum from traumatically injured mice can prime unactivated neutrophils for NETosis. Based on these data we hypothesize that trauma primes neutrophils for NETosis causing ALI and an overexuberant response to gram negative bacterial pneumonia after trauma. To test this hypothesis we propose two specific aims. Aim 1: Determine if neutrophil NETosis triggered by polytrauma-induced ALI exacerbates pneumonia. Aim 2: Define the the role of GCSF in promoting NETosis after polytrauma AIM3: Define the contribution of neutrophil NETosis to the dysregulated immune response induced by a secondary infection after trauma. The knowledge gained from successfully achieving these aims will provide a novel pathway to prevent and treat ALI after trauma and are clinically translatable as several current FDA approved therapeutics are known to have activity against key enzymes required for NETosis and multiple specific therapeutics are currently being developed. This knowledge is crucial so that Dr. Leonard’s laboratory can translate these to development of mechanistic therapies that may improve patient outcomes.

项目摘要 高达40％的重伤创伤患者在住院期间会出现严重的感染并发症 住院和呼吸道感染是受伤患者败血症的最常见原因。虽然已知 这种创伤性损伤触发了无菌炎症反应，可能导致急性肺损伤（ALI） 这及其对肺炎等继发感染的发展的贡献尚不清楚。这 这项研究的总体目标是了解先天免疫系统在创伤中的作用 为了提供新的治疗和预防目标。我们最近建立了一种多发性小鼠模型 这概括了严重受伤的患者对革兰氏阴性肺炎的敏感性增加。在 初步研究，我们证明创伤仅引起急性肺损伤和增加的易感性 pseduomonas肺炎。我们进一步发现第二次受伤后中性粒细胞增生 假单胞菌细菌。中性粒细胞肠病是一种强烈的抗菌嗜中性粒细胞反应，从而激活中性粒细胞 挤出了带有细胞毒性颗粒的DNA网，这些颗粒可固定和杀死入侵的病原体。尽管 netosis是一种关键的抗感染途径，已证明过量的Netosis会导致附带损害 宿主组织。我们还表明，来自创伤损伤的小鼠的血清可以为肠病中的未激活中性粒细胞促进。 基于这些数据，我们假设创伤质质粒细胞是netosis，导致Ali和过度效应 创伤后革兰氏阴性细菌肺炎的反应。为了检验这一假设，我们提出了两个具体目标。 AIM 1：确定中性粒细胞的肠病是否是由多发性诱导的Ali execererbates肺炎触发的。 AIM 2：定义GCSF在促进多发性腹膜内的Netosis中的作用 AIM3：定义中性粒细胞Netosis对次级诱导的免疫激素失调的贡献 创伤后感染。 成功实现这些目标而获得的知识将为预防和治疗Ali提供新的途径 创伤并在临床上可以翻译，因为已知当前的几种FDA批准的疗法具有活性 目前正在开发Netosis和多种特定治疗剂所需的关键酶。这些知识是 至关重要的是，伦纳德博士的实验室可以将其转化为可能改善的机械疗法 患者的结果。