Pathogenesis of Aspiration Pneumonitis

吸入性肺炎的发病机制

• 批准号: 7577426
• 负责人: PAUL R KNIGHT III
• 金额: $ 39.63万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577426
• 关键词: Acids; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Affinity; Alveolar; Alveolar Cell; Alveolar Macrophages; Antibodies; Apoptosis; Bacterial Pneumonia; Biological Markers; Bronchoalveolar Lavage; CCL2 gene; CXC Chemokines; Caspase; Cells; Cellular Stress; Chronic; Clinical; Cohort Studies; Constitution; Data; Development; Diagnostic; Emergency Situation; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Etiology; Event; Food; Gene Deletion; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-6; Lead; Leukocytes; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Necrosis; Operative Surgical Procedures; Outcome; Oxidants; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Play; Pneumonia; Population; Proteomics; Pulmonary aspiration of gastric contents; Recombinants; Recruitment Activity; Research; Risk; Risk Factors; Role; S-nitro-N-acetylpenicillamine; Severities; Signal Transduction; Stomach; System; Technology; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Translating; Trauma; Whole Blood; Work; comparative; cytokine; defective adenoviral vector; design; insight; lung injury; mortality; mouse model; neutrophil; novel; particle; prognostic; receptor; reconstitution; response; response to injury

DESCRIPTION (provided by applicant): Gastric aspiration is a major risk factor for the development of acute lung injury (ALI) and ARDS. This proposal examines cellular mechanisms that increase the risk of aspiration-associated pathology. Although many host changes are poorly understood, our prior work has demonstrated a role forTNFalpha, IL-1U, IL- 6, IL-10, CXC chemokines, MCP-1, and toxic inflammatory products in the pathogenesis of aspiration- induced ALI. We have also demonstrated that low pH secretions in the gastric material synergistically increase the acute severity and sustainability of ALI following a subsequent insult (i.e., small food particles) Aim 1 will utilize drug-induced alveolar macrophage (aM0) depletion and reconstitution, transgenic (gene deletion and over-expression) mice, and flow cytometric strategies to examine in detail the role resident and recruited aM0, and alveolar epithelial cells (AEC) play in the pathogenesis of the severe ALI induced by combined acid and small particles (CASP). We hypothesize that the interaction of the components of CASP on aM0 and AEC responses leads to a synergistic, sustained ALI with accelerated aM0 apoptosis/necrosis and recruitment of a new M0 population with altered cytokine expression profiles. The role of the Fas/FasL system and apoptosis of recruited leukocytes in the pathogenesis of CASP ALI will also be assessed. Aim 2 will examine the roles of specific mediators of the inflammatory transition, including studies using recombinant IL-6, IL-10, MCP-1, TNFalpha, or over expression of these cytokines with transgenic mice or defective adenovirus vectors, or by employing anti-cytokine antibodies or gene deletion mice. We predict that TNFalpha-induced IL-6, IL-10, and/or MCP-1 cytokines play an important role in the transition from an acute to a less intense inflammatory response following gastric aspiration. In the final aim, we will employ a proteomic approach utilizing a novel multiplex microarray ELISA technology to identify local and systemic biomarkers and aM0 phenotypes to compare responses in patients and mice in order to provide mechanistic insight into the etiology and pathogenesis of aspiration-induced ALI and provide a rationale on which to test therapeutic strategies. Additionally, this will provide pilot data for developing diagnostic and prognostic biomarkers to differentiate aspiration events from bacterial pneumonia.

描述（由申请人提供）：胃误吸是急性肺损伤（ALI）和ARDS发生的主要危险因素。本建议探讨细胞机制，增加吸入相关病理的风险。尽管许多宿主的变化尚不清楚，但我们之前的工作已经证明了tnfalpha、IL- 1u、IL- 6、IL-10、CXC趋化因子、MCP-1和毒性炎症产物在误吸诱导ALI发病机制中的作用。我们也证明了胃物质中的低pH分泌物在随后的损伤（即小食物颗粒）后协同增加ALI的急性严重程度和可持续性。Aim 1将利用药物诱导的肺泡巨噬细胞（aM0）消耗和重建，转基因（基因缺失和过表达）小鼠，以及流式细胞术策略来详细检查aM0的作用。和肺泡上皮细胞（AEC）在酸和小颗粒联合（CASP）诱导的严重ALI的发病机制中起重要作用。我们假设CASP成分对aM0和AEC反应的相互作用导致了协同的、持续的ALI，加速了aM0的凋亡/坏死和新的M0群体的募集，改变了细胞因子的表达谱。Fas/FasL系统和募集的白细胞凋亡在CASP ALI发病机制中的作用也将被评估。目的2将检查炎症转化的特定介质的作用，包括使用重组IL-6、IL-10、MCP-1、TNFalpha，或使用转基因小鼠或缺陷腺病毒载体过度表达这些细胞因子，或使用抗细胞因子抗体或基因缺失小鼠的研究。我们预测tnfalpha诱导的IL-6、IL-10和/或MCP-1细胞因子在胃误吸后炎症反应从急性到轻度的转变中发挥重要作用。在最后的目标中，我们将采用蛋白质组学方法，利用一种新型的多重微阵列ELISA技术来识别局部和全身生物标志物和aM0表型，以比较患者和小鼠的反应，从而为吸入性ALI的病因和发病机制提供机制见解，并为测试治疗策略提供理论依据。此外，这将为开发诊断和预后生物标志物提供试点数据，以区分吸入性事件和细菌性肺炎。