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%的严重创伤患者在住院期间会出现严重的感染性并发症 住院治疗和呼吸道感染是受伤病人败血症的最常见原因。虽然已知 创伤性损伤触发无菌炎症反应，可导致急性肺损伤（ALI）， 这一点及其对继发性感染如肺炎的发展的作用还没有得到很好的理解。的 本研究的首要目标是了解先天免疫系统在创伤性肺损伤中的作用， 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 这概括了在严重受伤的病人中看到的对革兰氏阴性肺炎的易感性增加。在 我们的初步研究表明，创伤单独诱导急性肺损伤和增加易感性 肺炎假单胞菌。我们进一步发现，在第二次损伤后中性粒细胞NETosis增加， 假单胞菌中性粒细胞增多症是一种强烈的抗微生物中性粒细胞反应， 挤压出一个布满细胞毒性颗粒的DNA网，这些颗粒的功能是抑制和杀死入侵的病原体。而 NETosis是一种重要的抗感染途径，已证明过度NETosis会导致 宿主组织我们还表明，创伤性损伤小鼠的血清可以引发未活化的中性粒细胞NETosis。 基于这些数据，我们假设创伤引发中性粒细胞NETosis导致ALI和过度兴奋。 对创伤后革兰氏阴性菌肺炎的反应。为了验证这一假设，我们提出了两个具体目标。 目的1：确定多发性创伤诱导的ALI引发的中性粒细胞NETosis是否加重肺炎。 目的2：明确GCSF在多发伤后促NETosis中的作用 目的3：确定中性粒细胞NETosis对继发性免疫缺陷诱导的免疫应答失调的作用。 创伤后感染 从成功实现这些目标中获得的知识将为预防和治疗急性肺损伤提供新的途径。 创伤，并且是临床上可转化的，因为已知几种目前FDA批准的治疗剂具有抗 目前正在开发NETosis所需的关键酶和多种特异性治疗剂。这种知识是 因此，伦纳德博士的实验室可以将这些转化为机械疗法的发展， 患者结局。