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: 9069956
• 负责人: VINCENT CHARLES HASCALL
• 金额: $ 31.7万
• 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/9069956
• 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; Health; 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; Poly I-C; Process; Protein Biosynthesis; Proteins; Proteoglycan; Pulmonary Inflammation; Receptor Signaling; Recurrence; Role; Series; Serum; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Stimulus; Structure; Symptoms; TNF gene; Testing; Vertebral column; Viral; Virus; Virus Diseases; Wheezing; airway hyperresponsiveness; airway obstruction; asthmatic; behavior influence; biological adaptation to stress; density; design; improved; in vivo; inter-alpha-inhibitor; leukocyte activation; mimetics; monocyte; novel; novel therapeutic intervention; pollutant; primary pulmonary hypertension; 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）：哮喘是一种慢性气道炎症性疾病，通常伴有气道对各种刺激（包括过敏原、污染物和病毒）的过度反应性增加，导致气道阻塞，从而导致 反复发作的喘息和咳嗽。炎症细胞在气道壁中的积累是哮喘的标志特征，也是导致该疾病炎症的关键因素之一。我们发现这些细胞嵌入由气道脉管系统和支气管周围的平滑肌细胞产生的广泛的富含透明质酸的细胞外基质中。这种透明质酸 (HA) 基质是异常的，因为它装饰有源自血液中发现的成分的重链 (HC)。这种 HC-HA 修饰很重要，因为它产生了一种对炎症细胞具有“粘性”的 HA 配体，炎症细胞通过未识别的受体与 HC-HA 结合。 HA 基质的 HC 修饰是通过“肿瘤坏死因子刺激基因 6”(TSG-6) 酶完成的。顾名思义，这种蛋白质的合成是由肿瘤坏死因子-α (TNF¿) 诱导的，肿瘤坏死因子是众所周知的哮喘炎症介质。此外，已知 TSG-6 在多种炎症性疾病中发挥作用。在我们的研究过程中，我们发现 TSG-6 不仅具有用 HC 修饰 HA 的酶促能力，而且还能显着刺激气道平滑肌细胞 (ASMC) 合成 HA。有趣的是，当单独应用 TSG-6 时，这种诱导不会发生，而是仅与提供模拟病毒感染刺激的双链 RNA (dsRNA) 结合使用。几十年来，病毒感染与哮喘症状恶化之间的联系已众所周知，但病毒引发这种病理的机制仍然是一个医学之谜。我们观察到，当受到病毒模拟物的挑战时，TSG-6 是气道平滑肌细胞 HA 应激反应的有效放大器，这意味着 TSG-6 的双重功能可能是病毒感染引发哮喘病理机制的重要部分。我们的长期目标是了解 HC-HA 如何引导炎症事件，并应用这些知识来设计新的治疗方法，将这些基质恢复到正常状态，并改善慢性炎症性疾病患者的临床结果。我们的假设是，TSG-6 通过其酶产物（即 HC-HA）与炎症期间诱导的细胞表面受体结合，放大 ASMC 的 HA 合成。我们还假设 HC-HA 影响 HC-HA 基质中嵌入的白细胞的行为和激活。我们将在以下具体目标中检验这一假设：（i）确定信号传导途径、受体 以及 TSG-6 刺激 HA 合成的配体，(ii) 确定 HC-HA 对单核细胞/巨噬细胞活化的影响，以及 (iii) 评估 TSG-6 与“活”呼吸道病毒合作放大 HA 合成的能力。