Pathogenesis of Aspiration Pneumonitis

描述（由申请人提供）：胃误吸是发生急性肺损伤（ALI）和急性呼吸窘迫综合征（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。尽管对许多宿主的变化知之甚少，但我们先前的工作已经证实了TNF α、IL-1U、IL- 6、IL-10、CXC趋化因子、MCP-1和毒性炎症产物在吸入诱导的ALI发病机制中的作用。我们还证明了胃物质中的低pH分泌物协同增加了随后损伤后ALI的急性严重性和可持续性（即，目的1将利用药物诱导的肺泡巨噬细胞（aM 0）消耗和重建、转基因（基因缺失和过表达）小鼠和流式细胞术策略来详细检查驻留和募集的aM 0以及肺泡上皮细胞（AEC）在由酸和小颗粒组合（CASP）诱导的严重ALI的发病机制中所起的作用。我们假设CASP组分对aM 0和AEC反应的相互作用导致协同的、持续的ALI，加速aM 0凋亡/坏死，并招募新的M0群体，改变细胞因子表达谱。还将评估Fas/FasL系统和募集的白细胞凋亡在CASP ALI发病机制中的作用。目的2将研究炎症转化的特异性介质的作用，包括使用重组IL-6，IL-10，MCP-1，TNF α，或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TNF α诱导的IL-6、IL-10和/或MCP-1细胞因子在胃抽吸后从急性炎症反应向较低强度炎症反应的转变中起重要作用。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技术来鉴定局部和全身生物标志物和aM 0表型，以比较患者和小鼠的反应，从而提供对吸入诱导的ALI的病因学和发病机制的机理见解，并提供测试治疗策略的基本原理。此外，这将为开发诊断和预后生物标志物提供试点数据，以区分吸入事件和细菌性肺炎。

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.