A murine model of Pseudomonas aeruginosa pneumonia secondary to hemorrhagic shock

失血性休克继发铜绿假单胞菌肺炎小鼠模型

基本信息

批准号：
9294349
负责人：
CRAIG THOMAS LEFORT
金额：
$ 8.05万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-10 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294349
关键词：
Acute Adaptor Signaling Protein Address Adhesives Adult Respiratory Distress Syndrome Affinity Animal Model Animals Anti-Bacterial Agents Antibiotic Therapy Attenuated Bacteria Bacterial Pneumonia Binding Biology Blood Circulation Blood Vessels Cause of Death Cells Complement Complication Containment Critical Illness Cytoplasmic Tail Dose Drug resistance Elements Emigrations Endothelium Equilibrium Extracellular Matrix Goals Hemorrhage Hemorrhagic Shock Host Defense Hypovolemics Immune Immune System Diseases Immune System and Related Disorders Immune system Immunity Immunosuppression Infection Inflammatory Response Innate Immune Response Integrins Lead Ligand Binding Ligands Lung Mediating Mediator of activation protein Modeling Mus Natural Immunity Neutrophil Infiltration Nosocomial pneumonia Pathogenesis Patients Peritoneum Play Pneumonia Predisposition Pseudomonas aeruginosa Pseudomonas aeruginosa pneumonia Pulmonary Edema Recruitment Activity Regulation Respiratory Tract Infections Role Secondary to Talin Testing Therapeutic Therapeutic Intervention Time Tissues Trauma Trauma patient Treatment Efficacy Work adhesion receptor clinically relevant drug resistant bacteria experimental study immune function improved outcome indexing insight interstitial lung injury mortality mouse model neutrophil pathogen postcapillary venule prevent respiratory response secondary infection small molecule targeted treatment tool trafficking vascular bed

项目摘要

Abstract Secondary infections due to compromised immune function are a significant cause of mortality in hospitalized trauma patients that have survived hemorrhagic shock. The Gram-negative bacterial pathogen Pseudomonas aeruginosa is one of the most common causes of secondary pneumonia in these patients. Neutrophil recruitment into the airspaces of the lung is critical for host defense against P. aeruginosa pneumonia, and studies suggest that this element of innate immunity is compromised following hemorrhagic shock. Animal models of critical illness and associated immune dysfunction have been developed to probe pathogenesis of secondary infection and evaluate potential therapies. However, a mouse model of pseudomonal pneumonia secondary to hemorrhagic shock has not been characterized. Here, we propose to develop and characterize a mouse model of P. aeruginosa pneumonia secondary to hemorrhagic shock as a more clinically relevant format to evaluate potential neutrophil-targeted therapeutic strategies. β2 integrins are adhesion receptors that regulate neutrophil trafficking, and must become activated to bind to their ligands expressed on endothelium or extracellular matrix. Our previous studies suggest a strategy of attenuating β2 integrin activation to promote neutrophil emigration from the pulmonary vasculature and recruitment into the airspaces during acute respiratory P. aeruginosa infection in mice with a fully competent innate immune response. In the second part of this study, we will use the new mouse model to evaluate the efficacy of XVA143, a small molecule antagonist that prevents β2 integrins from achieving their highest ligand-binding affinity. We will additionally assess the effects of modulating neutrophil recruitment on lung injury and pulmonary edema, as neutrophils are also mediators of bystander tissue damage that can lead to acute respiratory distress syndrome. These studies may identify regulators of β2 integrin activation as effective therapeutics for promoting host defense of the lung against secondary bacterial pneumonia while maintaining tissue protection.

抽象的免疫功能受损导致的继发感染是导致死亡的重要原因失血性休克幸存的外伤住院患者革兰氏阴性细菌病原体。铜绿假单胞菌是这些患者继发性肺炎的最常见原因之一。中性粒细胞募集到肺空间对于宿主防御铜绿假单胞菌至关重要肺炎，研究表明先天免疫的这一要素在出血后受到损害已开发出危重疾病和相关免疫功能障碍的动物模型来探索。然而，继发感染的发病机制并评估潜在的治疗方法。在此，我们建议继发失血性休克的假单胞菌肺炎的特征。开发并表征继发失血性休克的铜绿假单胞菌肺炎小鼠模型评估潜在的中性粒细胞靶向治疗策略的更具临床相关性的格式是。调节中性粒细胞运输的粘附受体，必须被激活才能与其配体结合我们之前的研究提出了减弱 β2 的策略。整合素激活促进中性粒细胞从肺血管迁移并招募到肺血管具有完全先天免疫能力的小鼠急性呼吸道铜绿假单胞菌感染期间的空腔在本研究的第二部分中，我们将使用新的小鼠模型来评估疗效。 XVA143，一种小分子拮抗剂，可防止 β2 整合素实现最高配体结合我们还将评估调节中性粒细胞募集对肺损伤的影响。肺水肿，因为中性粒细胞也是旁观者组织损伤的介质，可导致急性肺水肿这些研究可能确定 β2 整合素激活的调节剂是有效的。促进宿主肺部防御继发性细菌性肺炎的疗法，同时维持组织保护。