Regulation of Inflammation in Asthma by Fas Ligand

Fas 配体对哮喘炎症的调节

• 批准号: 7149156
• 负责人: JAMES G ZANGRILLI
• 金额: $ 35.45万
• 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 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7149156
• 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(申请人提供)：呼吸道炎症与哮喘的发病机制高度相关，其特征是Th2淋巴细胞、嗜酸性粒细胞激活，在某些情况下还包括中性粒细胞。大多数白细胞表达Fas死亡受体的事实表明，这一途径应该是消除它们的重要内源性手段。然而，关于FasL在呼吸道中的表达的数据很少，而且FasL机制在多大程度上调节哮喘的呼吸道炎症尚不清楚。我们假设，在呼吸道产生的FasL和FasL诱骗活性(可溶性Fas亚型和DcR3)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活性应该有助于限制哮喘的炎症反应，并且对于消退是重要的，而FasL诱骗在这种情况下应该促进炎症，并且在启动过程中可能是重要的。这项提议包括四个相互关联的目标。第一个需要确定在呼吸道炎症过程中负责产生FasL和FasL诱饵的主要细胞类型，并证明它们可以通过可溶性配体或诱骗受体活性来调节自身的生存能力(自分泌效应)或相关的Fas承载靶标的活性(旁分泌效应)。第二个需要通过驻留的呼吸道巨噬细胞中的细胞因子来调节这些物种，我们发现这种细胞类型在抗原挑战后强烈表达FasL蛋白，这是作为Pl先前K08项目的一部分所做的工作。第三，内源性sFas异构体的特征，以及在炎症高峰期产生的潜在的FasL：sFas和FasL：DcR3复合体的分子水平的特征。虽然在实验系统中和我们的初步数据中暗示了这种复合体的存在，但它们在体内的存在和相关性尚不清楚。这项建议的主要研究材料来源将来自使用节段性抗原挑战(SAC)的哮喘人类呼吸道模型，重点是支气管肺泡灌洗室。将对组织柜中的结构单元S进行有限分析。最后，为了帮助支持这样的假设，即人类呼吸道细胞中具有促凋亡作用的FasL活性是真正生理学的，我们将在FasL中和条件下对小鼠进行挑战研究。