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：
10678655
负责人：
Jennifer Leonard
金额：
$ 18.02万
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/10678655
关键词：
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 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 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 Visualization antimicrobial clinical translation cytokine cytotoxic defined contribution experimental study extracellular immunocytochemistry improved improved outcome inhibitor injured insight intravital microscopy leukocyte activation lung injury monocyte mouse model neutrophil novel pathogen peripheral blood pharmacologic 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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ludwig's Angina: Higher Incidence and Worse Outcomes Associated With the Onset of the Coronavirus Disease 2019 Pandemic.

路德维希心绞痛：与 2019 年冠状病毒病大流行相关的更高发病率和更糟糕的结果。

DOI：
10.1089/sur.2023.163
发表时间：
2023
期刊：
Surgical infections
影响因子：
2
作者：
Canas,Melissa;Fonseca,Ricardo;DeFilippis,Alejandro;Diaz,Leonardo;Afzal,Hussain;Day,Aaron;Leonard,Jennifer;Bochicchio,Kelly;Bochicchio,GrantV;Hoofnagle,Mark
通讯作者：
Hoofnagle,Mark

Defining the Microbiome Components (Bacteria, Viruses, Fungi) and Microbiome Geodiversity.

定义微生物组组成（细菌、病毒、真菌）和微生物组地理多样性。