The Biology of LIF During Pneumonia

肺炎期间 LIF 的生物学

• 批准号: 9066165
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066165
• 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; Goals; Homeostasis; Host Defense; Immune response; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Injury; Interleukin-6; Intervention; Knowledge; LIF gene; 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; genetic approach; in vivo; indexing; innovation; insight; 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.

描述（由申请人提供）：肺部感染是全球范围内的巨大疾病负担，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一个关键但危险的先天免疫反应，典型的是强烈的炎症。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来微妙地平衡。这些途径如何汇聚以促进足够的宿主防御，同时限制炎症损伤还知之甚少。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STAT 3的激活至关重要，STAT 3已成为肺和其他粘膜组织部位抗菌防御和组织保护的重要信号枢纽。然而，LIF在肺部感染过程中的调节和功能意义几乎是未知的。初步结果表明，LIF中和导致肺炎小鼠肺损伤的显著增加，表明LIF用于抵消响应于感染性微生物的炎性损伤。通过追求以下目标，我们将检验中心假设，即LIF是肺炎期间组织保护的关键决定因素：目的1）检验LIF对于肺炎期间STAT 3介导的肺损伤保护是必要和充分的假设;目的2）检验肺炎期间中性粒细胞以RelA依赖性方式阐述LIF以对抗炎性肺损伤的假设;和目的3）检验LIF受体的可溶性变体是在肺炎期间调节LIF生物活性的负急性期蛋白的假设。通过阐明这一研究不足和了解甚少的途径的生物学，追求这些目标将提供有关肺炎期间组织保护的细胞和分子机制的新见解。此外，在肺部感染期间对LIF-STAT 3通路的解剖对于未来的翻译方向具有明确的潜力，因为预计它将揭示候选分子靶标，用于更好地鉴定和/或治疗患有急性肺损伤或有急性肺损伤风险的患者。