Regulation of Inflammation in Asthma by Fas Ligand

Fas 配体对哮喘炎症的调节

• 批准号: 7325699
• 负责人: JAMES G ZANGRILLI
• 金额: $ 26.46万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7325699
• 关键词: Affect; Allergens; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Aspergillus; Asthma; Biopsy; Bronchoalveolar Lavage; Caspase; Cells; Cellular Infiltration; Cessation of life; Collaborations; Complement; Complex; Condition; Cytokine Signaling; Data; Down-Regulation; Effector Cell; End Point; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Equilibrium; Flow Cytometry; Gene Expression; Histologic; Human; IgE; Immunoblotting; Inbred BALB C Mice; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response; Interleukin-10; Interleukin-18; Interleukin-4; Kinetics; Leukocytes; Ligands; Liquid substance; Lymphocyte; Maintenance; Mediating; Mediator of activation protein; Mentors; Metalloproteases; Minor; Mitochondria; Modeling; Molecular; Mus; Nature; Operating System; Pathogenesis; Pathway interactions; Pattern; Phase; Physiological; Physiology; Production; Protein Isoforms; Proteins; Protocols documentation; RNA Splicing; Range; Regulation; Research; Resolution; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Source; Structure of parenchyma of lung; System; Time; Tissues; Transcript; Tumor Necrosis Factor Ligand Superfamily Member 6; Upper arm; Work; airway inflammation; airway obstruction; antigen challenge; asthmatic airway; autocrine; cell type; crosslink; cytokine; decoy receptor 3; eosinophil; functional loss; immunocytochemistry; in vivo; interest; macrophage; monocyte; mouse model; neutrophil; novel; paracrine; receptor; research study; response

DESCRIPTION (provided by applicant): Airway inflammation is highly associated with asthma pathogenesis and is characterized by activated Th2 lymphocytes, eosinophils and, in some cases neutrophils. The fact that the most leukocytes express the Fas death receptor implies that this pathway should be an important endogenous means of their elimination. However, there is a paucity of data regarding FasL expression in the airway, and the extent to which FasL mechanisms regulate airway inflammation in asthma is unknown. We hypothesize that the balance of FasL and FasL decoy activity (soluble Fas isoforms and DcR3) generated in the airway will be an important determinant of the intensity and duration of an IgE-mediated inflammatory response. Pro-apoptotic FasL activity should serve to limit the inflammatory response in asthma and be important for resolution, while FasL decoys should promote inflammation in this setting and may be important during initiation. This proposal consists of four interrelated aims. The first entails the definitive characterization of the principal cell types responsible for production of FasL and FasL decoys during airway inflammation and demonstrating that they can regulate their own viability (autocrine effect), or that of relevant Fas-bearing targets (paracrine effect), via soluble ligand or decoy receptor activity. The second entails regulation of these species by cytokines in resident airway macrophages, a cell type that we have found strongly expresses FasL protein after antigen challenge in work done as part of the Pl's previous K08 project. Third, endogenous sFas isoforms will be characterized, and potential FasL:sFas and FasL:DcR3 complexes generated during peak inflammation will be characterized on a molecular level. Whilethe existence of such complexes is implied in experimental systems and by our preliminary data, their existence and relevance in vivo is not known. The major source of research materials for this proposal will be derived from a human airway model of asthma using segmental antigen challenge (SAC), with a focus on the bronchoalveolar lavage compartment. There will be a limited analysis of structural cel!s in the tissue compartment. Finally, in order to help support the hypothesis that pro-apoptotic FasL activity characterized in human airway cells is truly physiologic, we will perform challenge studies in mice under FasL neutralizing conditions.

描述（由申请人提供）：气道炎症与哮喘发病机制高度相关，其特征在于活化的Th 2淋巴细胞、嗜酸性粒细胞和某些情况下的嗜中性粒细胞。事实上，大多数白细胞表达Fas死亡受体意味着这一途径应该是一个重要的内源性手段，他们的消除。然而，关于FasL在气道中表达的数据很少，并且FasL机制在多大程度上调节哮喘中的气道炎症尚不清楚。我们假设气道中产生的FasL和FasL诱饵活性（可溶性Fas亚型和DcR 3）的平衡将是IgE介导的炎症反应的强度和持续时间的重要决定因素。促凋亡的FasL活性应该用于限制哮喘中的炎症反应，并且对于消退是重要的，而FasL诱饵应该在这种情况下促进炎症，并且在启动过程中可能是重要的。这项建议包括四个相互关联的目标。第一个需要明确的表征的主要细胞类型负责生产的FasL和FasL诱饵在气道炎症，并证明他们可以调节自己的生存能力（自分泌效应），或相关的Fas轴承目标（旁分泌效应），通过可溶性配体或诱饵受体活性。第二个需要通过驻留气道巨噬细胞中的细胞因子来调节这些物种，所述细胞类型是我们在作为PI先前K 08项目的一部分所做的工作中发现的在抗原攻击后强烈表达FasL蛋白的细胞类型。第三，将表征内源性sFas同种型，并将在分子水平上表征炎症高峰期间产生的潜在FasL：sFas和FasL：DcR 3复合物。虽然在实验系统中和我们的初步数据中暗示了这种复合物的存在，但它们在体内的存在和相关性尚不清楚。本提案的研究材料的主要来源将来自于使用节段性抗原激发（SAC）的人类哮喘气道模型，重点是支气管肺泡灌洗室。将有一个有限的分析结构细胞！在组织室里。最后，为了帮助支持这一假设，即在人气道细胞中表征的促凋亡FasL活性是真正的生理性的，我们将在FasL中和条件下在小鼠中进行激发研究。