Pathogenesis of Aspiration Pneumonitis

吸入性肺炎的发病机制

• 批准号: 7388230
• 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/7388230
• 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; Chronic; Clinical; Cohort Studies; Constitution; Data; Development; Diagnostic; Emergency Situation; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Etiology; Event; Food; Gene Deletion; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-6; Lead; Leukocytes; Mediator of activation protein; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Necrosis; Newborn Respiratory Distress Syndrome; 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; Stress; 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）：胃误吸是发生急性肺损伤 (ALI) 和 ARDS 的主要危险因素。该提案研究了增加误吸相关病理风险的细胞机制。尽管对许多宿主变化知之甚少，但我们之前的工作已经证明了TNFα、IL-1U、IL-6、IL-10、CXC趋化因子、MCP-1和有毒炎症产物在吸入性ALI的发病机制中的作用。我们还证明，胃物质中的低 pH 分泌物会协同增加后续损伤（即小食物颗粒）后 ALI 的急性严重性和可持续性。目标 1 将利用药物诱导的肺泡巨噬细胞 (aM0) 耗竭和重建、转基因（基因缺失和过度表达）小鼠以及流式细胞术策略来详细检查驻留和招募的角色 aM0 和肺泡上皮细胞 (AEC) 在酸与小颗粒联合 (CASP) 诱导的严重 ALI 的发病机制中发挥作用。我们假设 CASP 成分对 aM0 和 AEC 反应的相互作用导致协同、持续的 ALI，加速 aM0 凋亡/坏死，并招募具有改变的细胞因子表达谱的新 M0 群体。还将评估 Fas/FasL 系统和募集白细胞凋亡在 CASP ALI 发病机制中的作用。目标 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、TNFα 进行研究，或使用转基因小鼠或有缺陷的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进行研究。我们预测 TNFα 诱导的 IL-6、IL-10 和/或 MCP-1 细胞因子在胃误吸后从急性炎症反应转变为不太强烈的炎症反应中发挥重要作用。在最终目标中，我们将采用蛋白质组学方法，利用新型多重微阵列 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，以便深入了解吸入性 ALI 的病因和发病机制，并为测试治疗策略提供依据。此外，这将为开发诊断和预后生物标志物提供试点数据，以区分误吸事件和细菌性肺炎。