Project-002

项目-002

• 批准号: 10869418
• 负责人: DAVID H BROIDE
• 金额: $ 44.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10869418
• 关键词: Project; 002

Asthma can manifest with varying levels of severity. Whereas the acute phase of mild and moderate asthma is characterized largely by rapid infiltration of a number of immune cell types within the lungs, such as T lymphocytes, eosinophils, and mast cells, severe asthma has additional inflammatory and remodeling features that are thought to strongly contribute to decline in lung function. These include smooth muscle changes (hypertrophy, hyperplasia and contractile hyperresponsiveness), and subepithelial fibrosis. Fibrosis is due to deposition of extracellular matrix proteins such as collagen, fibronectin, fibrillin, and laminin, thought to be produced largely by differentiating fibroblasts, but which might also be products of smooth muscle cells. Fibroblasts can additionally be induced to express α-smooth muscle actin and other contractile proteins and may further contribute to increased rigidity of the airways together with the mature smooth muscle cells that line the bronchioles. The changes in activity of lung fibroblasts and smooth muscle cells linked to severe asthma are not fully understood, but are thought to be driven by factors derived from immune cells, of which IL-13 and IL-17 have been proposed to be key contributors. However, the true diversity and range of activities of fibroblasts and smooth muscle cells in severe asthmatics is not known nor how they differ from those in the lungs of mild asthmatics. Recent data are finding that multiple phenotypes of structural cells are seen in the tissues of patients with chronic immune diseases, such as ulcerative colitis, rheumatoid arthritis, systemic sclerosis, and atopic dermatitis, suggesting that cooperative and synergistic effects of several inflammatory factors might lead to these alternate pathogenic phenotypes that are important for severe disease. In this regard, we have found, in animal models of severe asthma, that two members of the tumor necrosis factor (TNF) superfamily, LIGHT (TNFSF14) interacting with its two receptors HVEM (TNFRSF14) and LTβR (TNFRSF3), and TL1A (TNFSF15) interacting with its receptor DR3 (TNFRSF25), are central mediators and drivers of the fibrotic and remodeling activity in the lungs resulting from chronic exposure to allergen. Furthermore, the receptors for LIGHT and TL1A are expressed on human lung fibroblasts and human airway smooth muscle cells, and both cytokines have strong activity in modulating inflammatory or contractile proteins in these cells. This proposal will pursue the hypothesis that both LIGHT and TL1A are new mediators of human airway remodeling in severe asthma and that these factors cooperate together, and with IL-13 and IL-17, to drive distinct pathogenic phenotypes in lung fibroblasts and smooth muscle cells that are associated with severe asthma. The treatment options for asthmatics are currently limited. Understanding the functional response that is elicited from the signals delivered by LIGHT and TL1A to human airway fibroblasts and smooth muscle cells, and how these integrate with those from more classical cytokines such as IL-13 and IL-17, might lead to new and novel therapies for severe asthma.

轻度和中度哮喘的急性期哮喘的严重程度各不相同。 其主要特征是肺部内多种免疫细胞类型的快速浸润，例如 T 淋巴细胞、嗜酸性粒细胞和肥大细胞，严重哮喘具有额外的炎症和重塑特征 据认为，这些因素会导致肺功能下降，其中包括平滑肌的变化。 （肥大、增生和收缩过度反应）和上皮下纤维化是由于。 细胞外基质蛋白如胶原蛋白、纤连蛋白、原纤维蛋白和层粘连蛋白的沉积，被认为是 主要由分化的成纤维细胞产生，但也可能是平滑肌细胞的产物。 成纤维细胞还可以被诱导表达 α-平滑肌肌动蛋白和其他收缩蛋白 可能进一步有助于增加气道的硬度以及成熟的平滑肌细胞 细支气管内的成纤维细胞和平滑肌细胞的活性变化与严重相关。 哮喘尚未完全了解，但被认为是由免疫细胞衍生的因素驱动的，其中 IL-13 和 IL-17 被认为是关键贡献者，但其真正的多样性和活动范围。 严重哮喘患者中成纤维细胞和平滑肌细胞的变化尚不清楚，也不知道它们与哮喘患者中的成纤维细胞和平滑肌细胞有何不同。 最近的数据发现，轻度哮喘患者的肺部存在多种结构细胞表型。 慢性免疫疾病患者的组织，如溃疡性结肠炎、类风湿性关节炎、全身性 硬化症和特应性皮炎，表明几种炎症的协同作用 这些因素可能导致这些对严重疾病很重要的替代致病表型。 就此而言，我们在严重哮喘的动物模型中发现，肿瘤坏死因子的两个成员 (TNF) 超家族 LIGHT (TNFSF14) 与其两个受体 HVEM (TNFRSF14) 和 LTβR 相互作用 (TNFRSF3) 和 TL1A (TNFSF15) 与其受体 DR3 (TNFRSF25) 相互作用，是中枢介质， 长期接触过敏原导致肺部纤维化和重塑活动的驱动因素。 此外，LIGHT 和 TL1A 受体在人肺成纤维细胞和人气道上表达 平滑肌细胞，两种细胞因子在调节炎症或收缩蛋白方面具有很强的活性 该提案将提出 LIGHT 和 TL1A 都是新的介导物的假设。 严重哮喘中的人类气道重塑，这些因素与 IL-13 和 IL-17 共同作用，驱动相关肺成纤维细胞和平滑肌细胞中不同的致病表型 目前对哮喘患者的功能性治疗选择有限。 LIGHT 和 TL1A 向人类气道成纤维细胞传递的信号引起的反应， 平滑肌细胞，以及它们如何与更经典的细胞因子（例如 IL-13 和 IL-17）整合，可能会带来治疗严重哮喘的新疗法。