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Fine-tuning the Neutrophilic Response to Pneumonia

微调中性粒细胞对肺炎的反应

基本信息

批准号：
9157282
负责人：
MARK ROBERTS LOONEY
金额：
$ 45.18万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9157282
关键词：
Acute Acute Lung Injury Acute Pneumonia Adoptive Transfer Adult Respiratory Distress Syndrome Affect Antibiotics Apoptosis Bacteria Bacterial Infections Bacterial Pneumonia Biological Cells Chromatin Cleaved cell Clinical Complement Containment Critical Illness DNA Data Development Dose Equilibrium Event Extracellular Space FPR2 gene Goals Histones Host Defense Human Immune response Infection Influenza Lead Life Ligands Lipoxins Lung Lung Inflammation Mechanical ventilation Mediating Mediator of activation protein Modeling Molecular Mus Necrosis Neurofibrillary Tangles Organism Outcome Pathogenicity Pathway interactions Patients Plasma Pneumonia Positioning Attribute Process Production Proteins Pseudomonas aeruginosa Regulation Role Sampling Sepsis Severities Signal Transduction Staphylococcus aureus Sterility Stimulus Structure of parenchyma of lung Supportive care Syndrome Techniques Testing Viral Viral Pneumonia Virus Diseases abstracting antimicrobial extracellular gain of function genetic approach in vivo inhibitor/antagonist killings lipid mediator loss of function lung injury lung preservation microbial mouse development mouse model neutrophil novel novel strategies pathogen prevent protein structure response translational study

项目摘要

Project Summary/Abstract The lung is a portal of entry for a variety of pathogenic organisms that may cause pneumonia or even the acute respiratory distress syndrome (ARDS), which is a life-threatening syndrome that has no specific treatments except for the provision of gentle mechanical ventilation and supportive care. The neutrophil is a critical cellular mediator of the early immune response to pathogenic lung infections, but an overly exuberant neutrophil response may cause collateral damage to the lung and lead to acute lung injury. In this application, a new function of neutrophils, the release of neutrophil extracellular traps (NETs), will be investigated in mouse models of acute lung infection. NETs are composed of extracellular chromatin decorated with neutrophil granular proteins and have been proposed to serve an important role in the trapping and killing of bacteria and other pathogens. However, we propose that NETs are toxic to adjacent cells and are on balance a maladaptive and dispensible host response in pneumonia and acute lung injury. Aim 1 of this application will investigate the role of NETs in mouse models of bacterial and viral pneumonia using novel techniques to visualize and quantify NETs. We will also test the role of lipoxin mediators signaling through Fpr2 on neutrophils in regulating NET production and the progression to acute lung injury. Aim 2 will test the role of DNase1 in regulating the degradation of NETs in the lung and the important effects of DNase1 treatment on the containment of infection and preservation of the lung barrier. In translational studies, Aim 2 will also use biological samples from critically ill patients with severe infections to test if NETs and DNase1 bioactivity (a) predict the progression to ARDS or (b) are associated with poor clinical outcomes in ARDS. The factors that determine whether a localized lung infection progresses to acute lung injury are not known, but this application proposes that NETs are critical mediators in this process and targetable. Our studies using live bacterial and viral infections, novel approaches to visualize acute lung inflammation and injury, and NETs, pharmacologic and genetic approaches to neutralize NETs, and translational studies to complement our mouse models, are well-positioned to provide definitive evidence on the in vivo significance of NETs, and to position NETs as a novel target for the treatment of pathogen-induced lung injury.

项目总结/文摘