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

• 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
• 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

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.

摘要 由于免疫功能受损而引起的继发感染是导致 在失血性休克中幸存下来的住院创伤患者。革兰氏阴性杆菌 铜绿假单胞菌是这些患者继发性肺炎最常见的原因之一。 中性粒细胞重新聚集到肺的空间对宿主防御铜绿假单胞菌至关重要。 肺炎，研究表明，这种先天免疫成分在出血后受到损害 令人震惊。已经建立了危重疾病和相关免疫功能障碍的动物模型来探索 继发感染的发病机制和评估潜在的治疗方法。然而，一种小鼠模型 失血性休克继发的假单胞性肺炎尚未明确诊断。在此，我们建议 失血性休克继发铜绿假单胞菌肺炎小鼠模型的建立和鉴定 更具临床相关性的格式，以评估潜在的中性粒细胞靶向治疗策略。β2整合素是 调节中性粒细胞转运的黏附受体，必须被激活才能与其配体结合 表达于内皮细胞或细胞外基质。我们之前的研究提出了一种减弱β-2的策略 整合素激活促进中性粒细胞从肺血管系统向外迁移并重新进入肺组织 具有完全天然免疫功能的小鼠在急性呼吸道铜绿假单胞菌感染期间的空间 回应。在本研究的第二部分，我们将使用新的小鼠模型来评价丹参的疗效。 XVA143，一种阻止β2整合素达到最高配体结合的小分子拮抗剂 亲和力。此外，我们还将评估调节中性粒细胞募集对肺损伤和 肺水肿，因为中性粒细胞也是旁观者组织损伤的媒介，可导致急性 呼吸窘迫综合征。这些研究可能确定β2整合素激活的调节剂是有效的 促进肺对继发性细菌性肺炎宿主防御的治疗方法 组织保护。