The Biology of LIF During Pneumonia

肺炎期间 LIF 的生物学

• 批准号: 8371498
• 负责人: Lee Quinton
• 金额: $ 40.93万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8371498
• 关键词: Accounting; Acute Lung Injury; Acute-Phase Proteins; Address; Alveolar; Apoptosis; Bacterial Pneumonia; Biological; Biological Assay; Biology; Blood; Cells; Cessation of life; Clinical; Communities; Data; Disease; Dissection; Engineering; Epithelial; Epithelial Cells; Equilibrium; Extravasation; Family; Future; Genes; Genetic; Goals; Homeostasis; Host Defense; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Injury; Interleukin-6; Intervention; Knowledge; Laboratories; Leukocytes; Liquid substance; Liver; Lower Respiratory Tract Infection; Lung; Measures; Mediating; Microbe; Molecular; Molecular Target; Mucous Membrane; Mus; Natural Immunity; Pathway interactions; Patients; Phenotype; Physiological; Plasma; Pneumonia; Population; Prevention; Process; Production; Public Health; Recombinants; Recruitment Activity; Regulation; Risk; STAT3 gene; Serum; Signal Transduction; Site; Source; System; Testing; Tissues; Variant; antimicrobial; base; burden of illness; cell type; cytokine; in vivo; indexing; innovation; insight; leukemia inhibitory factor; leukemia inhibitory factor receptor; lung injury; neutrophil; novel; research study; response; transcription factor

DESCRIPTION (provided by applicant): Lung infections account for a tremendous burden of disease worldwide, representing the most frequent cause of infection-related deaths and a leading cause of acute lung injury. Overcoming lower respiratory tract infection requires a critica yet dangerous innate immune response, typified by robust inflammation. The biological signals eliciting innate immunity must be delicately balanced by mechanisms maintaining tissue integrity and homeostasis. How these pathways converge to promote adequate host defense while limiting inflammatory injury is poorly understood. We have recently shown that during bacterial pneumonia, the cytokine leukemia inhibitory factor (LIF) is critical for activation of the transcription factor STAT3, which has emerged as an important signaling hub for both antimicrobial defense and tissue protection in the lungs and other mucosal tissue sites. However, the regulation and functional significance of LIF during lung infection is virtually unknown. Preliminary results indicate that LIF neutralization causes a profound increase in lung injury in pneumonic mice, suggesting that LIF serves to offset inflammatory injury in response to infectious microbes. By pursuing the following aims, we will test the central hypothesis that LIF is a critical determinant of tissue protection during pneumonia: Aim 1) Test the hypothesis that LIF is necessary and sufficient for STAT3- mediated protection against lung injury during pneumonia; Aim 2) Test the hypothesis that during pneumonia neutrophils elaborate LIF in a RelA-dependent manner to counter inflammatory lung injury; and Aim 3) Test the hypothesis that the soluble variant of the LIF receptor is a negative acute phase protein regulating LIF biological activity during pneumonia. By elucidating the biology of this understudied and poorly understood pathway, pursuit of these aims will provide novel insights regarding the cellular and molecular mechanisms of tissue protection during pneumonia. Moreover, dissection of the LIF-STAT3 pathway during lung infection has clear potential for future translational directions, as it is anticipated to reveal candidate molecular targets for better identifying and/or treating patient with or at risk for acute lung injury. PUBLIC HEALTH RELEVANCE: Lung infections are a major public health concern, accounting for the greatest burden of disease in both poor and wealthy communities. However, the immune response to this important disease often results in acute lung injury. The goal of our laboratory and this proposal is to identify biological pathways that balance the consequences of infection and immunity during pneumonia, possibly revealing novel targets for clinical intervention.

描述（由申请人提供）：肺部感染在全世界造成巨大的疾病负担，是感染相关死亡的最常见原因，也是急性肺损伤的主要原因。克服下呼吸道感染需要关键但危险的先天免疫反应，以强烈的炎症为代表。引发先天免疫的生物信号必须通过维持组织完整性和体内平衡的机制进行微妙的平衡。这些途径如何汇聚以促进充分的宿主防御，同时限制炎症损伤，人们知之甚少。我们最近发现，在细菌性肺炎期间，细胞因子白血病抑制因子 (LIF) 对于转录因子 STAT3 的激活至关重要，STAT3 已成为肺部和其他粘膜组织部位抗菌防御和组织保护的重要信号传导中枢。然而，LIF 在肺部感染期间的调节和功能意义实际上尚不清楚。初步结果表明，LIF 中和会导致肺炎小鼠肺损伤显着增加，这表明 LIF 可以抵消感染性微生物引起的炎症损伤。通过追求以下目标，我们将检验 LIF 是肺炎期间组织保护的关键决定因素这一中心假设： 目标 1) 检验 LIF 对于 STAT3 介导的肺炎期间肺损伤保护是必要且充分的假设；目标 2) 检验以下假设：在肺炎期间，中性粒细胞以 RelA 依赖性方式精心设计 LIF，以抵抗炎症性肺损伤；目标 3) 检验 LIF 受体的可溶性变体是一种负性急性期蛋白，在肺炎期间调节 LIF 生物活性这一假设。通过阐明这一尚未充分研究且知之甚少的途径的生物学，对这些目标的追求将为肺炎期间组织保护的细胞和分子机制提供新的见解。此外，在肺部感染期间对 LIF-STAT3 通路的解剖对于未来的转化方向具有明显的潜力，因为它有望揭示候选分子靶标，以更好地识别和/或治疗患有或有急性肺损伤风险的患者。 公共卫生相关性：肺部感染是一个主要的公共卫生问题，是贫穷和富裕社区的最大疾病负担。然而，对这种重要疾病的免疫反应常常导致急性肺损伤。我们实验室和本提案的目标是确定平衡肺炎期间感染和免疫后果的生物途径，可能揭示临床干预的新目标。