TSG-6: Novel Regulator of Viral-Induced Hyaluronan Synthesis in Inflamed Airways

TSG-6：炎症气道中病毒诱导的透明质酸合成的新型调节剂

• 批准号: 8704198
• 负责人: MARK E LAUER
• 金额: $ 31.07万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704198
• 关键词: Allergens; Amplifiers; Asthma; Automobile Driving; Avidity; Behavior; Binding; Blood; Bronchi; Cell Surface Receptors; Cells; Chronic; Clinical; Complex; Coughing; Cystic Fibrosis; Data; Disease; Double-Stranded RNA; Enzymes; Event; Extracellular Matrix; Genes; Genetic; Goals; Hyaluronan; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Influenza; Investigation; Knowledge; Length; Leukocytes; Libraries; Life; Ligands; Lung; Lung diseases; Macrophage Activation; Mediating; Medical; Modification; Mus; Names; Outcome; Pathology; Patients; Physiology; Play; Pneumonia; Poly I-C; Process; Protein Biosynthesis; Proteins; Proteoglycan; Pulmonary Hypertension; Receptor Signaling; Recurrence; Role; Series; Serum; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Structure; Symptoms; TNF gene; Testing; Tissues; Tumor Necrosis Factor-alpha; Vertebral column; Viral; Virus; Virus Diseases; Wheezing; airway hyperresponsiveness; airway obstruction; behavior influence; biological adaptation to stress; density; design; improved; in vivo; inhibitor/antagonist; leukocyte activation; mimetics; monocyte; novel; novel therapeutic intervention; pollutant; public health relevance; receptor; research study; respiratory smooth muscle; respiratory virus

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease of the airways that is typically accompanied by increased airway hyper-responsiveness to various stimuli, including allergens, pollutants and viruses, resulting in airway obstruction that leads to recurrent episodes of wheezing and coughing. The accumulation of inflammatory cells into the airway wall is a hallmark feature of asthma and is one of the key factors driving inflammation in this disease. We have found that these cells are embedded in an extensive hyaluronan-rich extracellular matrix produced by smooth muscle cells surrounding airway vasculature and bronchi. This hyaluronan (HA) matrix is abnormal in the sense that it is decorated with heavy chains (HCs) derived from a component found in blood. This HC-HA modification is important because it creates an HA ligand that is "sticky" for inflammatory cells which bind to HC-HA via an unidentified receptor(s). The decoration of HA matrices with HCs is accomplished by the enzyme "tumor-necrosis-factor-stimulated-gene-6" (TSG-6). As its name implies, synthesis of this protein is induced by tumor-necrosis-factor-alpha (TNF¿), a well-known mediator of inflammation in asthma. Furthermore, TSG-6 is known to play a role in a variety of inflammatory diseases. Over the course of our investigations, we discovered that TSG-6 not only possesses the enzymatic ability to decorate HA with HCs but that it significantly stimulates HA synthesis by airway smooth muscle cells (ASMCs). Interestingly, this induction did not occur when TSG-6 was applied alone, but rather, only in combination with double-stranded RNA (dsRNA) that provides a stimulus mimicking a viral infection. For decades, the connection between viral infections and the exacerbation of asthmatic symptoms has been well known, but the mechanism whereby viruses trigger this pathology remains a medical mystery. Our observation that TSG-6 is a potent amplifier of the HA stress response by airway smooth muscle cells when challenged by a viral mimetic implies that the dual functionality of TSG-6 may be an important part of the mechanism whereby viral infections trigger asthma pathology. Our long-term goal is to understand how HC-HA directs inflammatory events and to apply this knowledge to design novel therapeutic approaches to restore these matrices to their normal state and improve clinical outcomes in patients with chronic inflammatory diseases. Our hypothesis is that TSG-6 amplifies HA synthesis by ASMCs via engagement of its enzymatic product (i.e. HC-HA) with a cell surface receptor that is induced during inflammation. We also hypothesize that HC-HA influences the behavior and activation of leukocytes embedded within the HC-HA matrix. We will test this hypothesis in the following specific aims: (i) identify the signaling pathways, receptors and ligands whereby TSG-6 stimulates HA synthesis, (ii) determine the effect HC-HA has on monocyte/macrophage activation, and (iii) evaluate the ability of TSG-6 to amplify HA synthesis in cooperation with a "live" respiratory virus.

描述（由申请人提供）：哮喘是一种气道慢性炎症性疾病，通常伴随着气道对各种刺激（包括过敏原、污染物和病毒）的高反应性增加，导致气道阻塞，从而导致哮喘