Netosis in Trauma mediated Acute Lung Injury

创伤介导的急性肺损伤中的网沉着

基本信息

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
项目类别：
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

项目摘要

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.

项目概要多达 40% 的重伤创伤患者在住院期间会出现严重的感染性并发症众所周知，住院和呼吸道感染是导致受伤患者败血症的最常见原因。创伤性损伤会引发无菌炎症反应，从而导致急性肺损伤（ALI），其机制这一现象及其对肺炎等继发感染的影响尚不清楚。这项研究的首要目标是了解先天免疫系统在创伤引起的肺损伤中的作用为了为治疗和预防提供新的靶点，我们最近建立了多发性创伤的小鼠模型。这概括了重伤患者对革兰氏阴性肺炎的易感性增加。初步研究表明，仅创伤就会引起急性肺损伤并增加对肺损伤的易感性我们进一步发现第二次损伤后中性粒细胞网病增加。假单胞菌 NETosis 是一种强烈的中性粒细胞抗菌反应，从而激活中性粒细胞。挤出一张布满细胞毒性颗粒的 DNA 网，其作用是固定和杀死入侵的病原体。 NETosis 是一种重要的抗感染途径，过量的 NETosis 已被证明会导致对我们还表明，来自创伤性损伤小鼠的血清可以启动未激活的中性粒细胞进行 NETosis。根据这些数据，我们导致创伤导致中性粒细胞出现 NETosis ALI 和过度活跃为了检验这一假设，我们提出了两个具体目标。目标 1：确定多发伤诱发的 ALI 引发的中性粒细胞 NETosis 是否会导致肺炎恶化。目标 2：确定 GCSF 在促进多发伤后 NETosis 中的作用 AIM3：定义中性粒细胞 NETosis 对继发性免疫反应失调的影响外伤后感染。成功实现这些目标所获得的知识将为预防和治疗 ALI 提供新的途径。创伤，并且可以临床转化，因为目前 FDA 批准的几种治疗方法已知具有对抗创伤的活性目前正在开发 NETosis 所需的关键酶和多种特定疗法。至关重要，以便伦纳德博士的实验室能够将这些转化为可能改善病情的机械疗法的开发患者的结果。