Control of airway remodeling by TNFR family molecules

项目总结(见说明)： 哮喘的过敏性形式是由对空气传播的过敏原的免疫反应驱动的，并可能因包括接触病毒在内的许多因素而加剧。疾病的典型特征是Th2淋巴细胞、嗜酸性粒细胞、肥大细胞、成纤维细胞和巨噬细胞在肺内聚集。哮喘急性期的特点主要是肺部细胞的快速渗透，而慢性哮喘的特点是 通过进行性的气道重塑，包括上皮细胞粘液化生、平滑肌肥大/增生、上皮下纤维化和血管生成增加。纤维化是由于细胞外基质蛋白的沉积，如胶原、纤维连接蛋白、肌腱蛋白和层粘连蛋白，主要由分化的成纤维细胞或上皮细胞产生，还可以被诱导表达α-平滑。 肌肉肌动蛋白和有助于增加的平滑肌质量。所有这些细胞类型是如何被控制的，在很大程度上是未知的。这项建议将集中在肿瘤坏死因子(TNF)及其受体超家族的几个成员上，并检验OX40(CD134)与OX40L(CD252)相互作用的假设，以及LIGH(CD258)与两个受体hvem(CD270)和LTbR(淋巴毒素β受体)相互作用的假设 在不同严重程度的哮喘患者中，过敏原诱导的炎症和重塑的特征；这些分子将在暴露于鼻病毒的患者的肺中被进一步诱导；鼻病毒是一种与哮喘加重有关的病原体；它们将在功能上与支气管上皮细胞、肺巨噬细胞、成纤维细胞、 和T细胞。目前，哮喘患者的治疗选择有限。了解这些肿瘤坏死因子/肿瘤坏死因子受体家族分子在何时何地表达，以及它们相互作用所产生的功能活动，可能会为急性和慢性哮喘的治疗干预带来新的新靶点。

PROJECT SUMMARY (See instructions): The allergic form of asthma is driven by an immune response to airborne allergens, and can be exacerbated by a number of factors including exposure to viruses. A typical signature of disease is the accumulation in the lungs of Th2 lymphocytes, eosinophils, mast cells, fibroblasts, and macrophages. Whereas the acute phase of asthma is characterized largely by rapid cell infiltration in the lungs, chronic asthma is characterized by progressive airway remodeling which includes epithelial cell mucus metaplasia, smooth muscle hypertrophy/hyperplasia, subepithelial fibrosis, and increased angiogenesis. Fibrosis is due to deposition of extracellular matrix proteins such as collagen, fibronectin, tenascin, and laminin, thought produced largely from differentiating fibroblasts or epithelial cells, which can additionally be induced to express alpha smooth muscle actin and contribute to the enhanced smooth muscle mass. How all of these cell types are controlled is largely unknown. This proposal will focus on several members of the tumor necrosis factor (TNF) and TNF receptor superfamily, and test the hypotheses that OX40 (CD134) interacting with OX40L (CD252), and LIGHT (CD258) interacting with two receptors, HVEM (CD270) and LTBR (lymphotoxin beta receptor), are signatures of allergen-induced inflammation and remodeling in lungs of patients with varying severity of asthma; that these molecules will be further induced in the lungs of patients that are exposed to rhinovirus, a pathogen that has been associated with asthma exacerbations; and that they will be functionally relevant to the inflammatory and remodeling activities of bronchial epithelial cells, and lung macrophages, fibroblasts, and T cells. The treatment options for asthmatics are currently limited. Understanding when and where these TNF/TNFR family molecules are expressed, and the functional activities that result from their interactions, might lead to new and novel targets for therapeutic intervention in both acute and chronic asthma.