Pathogenesis of Aspiration Pneumonitis

吸入性肺炎的发病机制

• 批准号: 7780039
• 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/7780039
• 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）：胃抽吸是急性肺损伤（ALI）和ARDS发展的主要危险因素。该提案研究了增加与抽吸相关病理风险的细胞机制。尽管对许多宿主变化的了解很少，但我们先前的工作表明了Fortnfalpha，IL-1U，IL-6，IL-10，CXC趋化因子，MCP-1和有毒的炎性炎性产物在抽吸诱导的ALI的发病机理中的作用。 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) A​​im 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和肺泡上皮细胞（AEC）在由酸和小颗粒（CASP）诱导的严重ALI的发病机理中发挥作用。我们假设CASP对AM0和AEC响应的组件的相互作用导致协同的，持续的ALI，并加速了AM0凋亡/坏死，并募集具有细胞因子表达谱改变的新M0人群。还将评估FAS/FASL系统的作用和招募白细胞在CASP ALI发病机理中的凋亡。 AIM 2将检查炎症过渡的特定介质的作用，包括使用重组IL-6，IL-10，MCP-1，TNFALPHA的研究，或通过转基因小鼠或有缺陷的腺病毒载体的这些细胞因子过度表达，或者通过使用抗cytokine抗体抗体或基因deleties或Genee deletien iles。我们预测TNFALPHA诱导的IL-6，IL-10和/或MCP-1细胞因子在从急性到胃攻击后急性炎症反应较低的过渡中起着重要作用。在最终目的中，我们将采用一种蛋白质组学方法，利用一种新型的多重微阵列ELISA技术来识别本地和系统的生物标志物和AM0表型，以比较患者和小鼠的反应，以提供对吸入诱导的ALI的病因和发病机理的机械洞察力，并提供针对治疗策略的基本策略。此外，这将提供用于开发诊断和预后生物标志物的试验数据，以将抽吸事件与细菌性肺炎区分开。