Role of Innate Immune Cells and Pathways in Ventilated Lung Ischemia Reperfusion

先天免疫细胞和通路在通气肺缺血再灌注中的作用

• 批准号: 8679175
• 负责人: Arun Prakash Budde
• 金额: $ 19.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679175
• 关键词: Acute; Adult; Affect; Alveolar Macrophages; Bacterial Infections; Blood flow; Cause of Death; Cells; Chest; Clinical; Coculture Techniques; Critical Illness; Data; Economic Burden; Endothelial Cells; Endotoxemia; Focal Infection; Functional disorder; Genes; Goals; Head; Human; Immune; Immune response; Immune system; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intensive Care Units; Interleukin-1; Interruption; Intervention; Ischemia; Kinetics; Knowledge; Lead; Life; Lung; Macrophage Activation; Mediating; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; Nature; Neutrophil Infiltration; Nosocomial Infections; Organ; Outcome; Pathway interactions; Patients; Pneumonia; Preventive; Process; Public Health; Receptor Signaling; Recruitment Activity; Reperfusion Injury; Reperfusion Therapy; Research; Respiratory physiology; Role; Sepsis; Signal Transduction; Site; Sterility; Systemic infection; TLR4 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Trauma; Trauma patient; United States; aged; base; commensal microbes; fighting; improved; injured; intercellular communication; lung injury; lung ischemia; macrophage; mortality; neutrophil; novel strategies; prevent; public health relevance; research study; response; social; targeted treatment; therapy development

DESCRIPTION (provided by applicant): Lung injury following trauma is a major cause of morbidity and mortality. Severe trauma can often generate conditions of ischemia reperfusion (IR) and result in sterile inflammatory injury directly or indirectly affecting the lung. The situaion can then be worsened by the later onset of infection. We are currently unable to predict the strength of the inflammatory response within the lung to severe trauma and individual patients' likelihood of developing lung injury, pneumonia, and long-term multi-organ dysfunction. Moreover, we are unable to effectively influence these processes therapeutically. The overall research goal is to understand how the innate immune system recognizes and responds to sterile injury and tissue damage, and how this response overlaps with and differs from that to infection. The objective of this proposal is to define the molecular and cellular pathways that control ventilated lung IR injury in mice and determine how conserved these pathways are with the patient response to lung IR injury in trauma. My central hypothesis is that pure lung IR injury is an acute but self-resolving inflammatory process, the strength and nature of which is coordinated by resident lung cells (alveolar macrophages) and whose manipulation can affect IR and subsequent responses to infection. The rationale for the proposed research is that once targets for lung IR therapy have been identified, and the periods of infectious vulnerability defined, novel approaches to treating trauma patients can be developed. The proposed experiments seek to investigate the innate immune responses to sterile lung injury in trauma and subsequent infection and to devise ways to manipulate these responses. Specifically, Aim 1 will determine if inflammatory responses elicited by ventilated lung ischemia reperfusion in mice cause long-term dysfunction and also establish a correlation with human immune responses to trauma and lung IR. The goal of Aim 2 is to determine how toll-like receptor (TLR) signaling and inflammasome activity in alveolar macrophages are regulated in ventilated lung IR responses in mice. Lastly, Aim 3 will determine the effect of lung IR inflammation on the pathophysiology of subsequent local and systemic infections (i.e., a two-hit model) in mice. The proposed research is expected to uncover the molecular and cellular pathways in alveolar macrophages that are important for the immune response to lung IR injury. This contribution will be significant because the research is expected to lead to the identification of targets for therapies and medical management interventions that can prevent unnecessary lung damage early in trauma while preserving the immune system's ability to stave off infections later.

描述（由申请人提供）：创伤后肺损伤是发病率和死亡率的主要原因。严重的创伤通常会产生缺血再灌注（IR）的条件，并导致直接或间接影响肺的无菌性炎性损伤。这种情况可能会因感染的后期发作而恶化。我们目前无法预测肺部对严重创伤的炎症反应强度以及个体患者发生肺损伤、肺炎和长期多器官功能障碍的可能性。此外，我们无法在治疗上有效地影响这些过程。总体研究目标是了解先天免疫系统如何识别和响应无菌损伤和组织损伤，以及这种响应如何与感染重叠和不同。本提案的目的是确定控制小鼠通气性肺IR损伤的分子和细胞途径，并确定这些途径与创伤中患者对肺IR损伤的反应的保守程度。我的中心假设是单纯的肺IR损伤 是一种急性但自行消退的炎症过程，其强度和性质由驻留的肺细胞（肺泡巨噬细胞）协调，其操作可影响IR和随后对感染的反应。拟议研究的基本原理是，一旦确定了肺IR治疗的目标，并确定了感染脆弱性的时期，就可以开发治疗创伤患者的新方法。拟议的实验旨在研究先天免疫反应无菌肺损伤创伤和随后的感染，并设计方法来操纵这些反应。具体而言，目标1将确定是否引起的炎症反应，在小鼠通气肺缺血再灌注引起长期功能障碍，也建立了与人类的免疫反应创伤和肺IR的相关性。目标2是确定如何在小鼠通气肺IR反应中调节肺泡巨噬细胞中的Toll样受体（TLR）信号传导和炎性小体活性。最后，目标3将确定肺IR炎症对随后的局部和全身感染的病理生理学的影响（即，两次打击模型）。这项研究有望揭示肺泡巨噬细胞中的分子和细胞途径，这些途径对肺IR损伤的免疫反应至关重要。这一贡献将是重要的，因为该研究预计将导致确定治疗和医疗管理干预的目标，这些目标可以在创伤早期预防不必要的肺损伤，同时保留免疫系统避免感染的能力。