SCOR IN THE PATHOBIOLOGY OF FIBROTIC LUNG DISEASE

这项SCOR的长期目标是加深我们对 特发性肺纤维化(IPF)和结节病的发病机制。 需要对这些疾病的发病机制有更清楚的了解。 开发新的治疗策略。这一SCOR的中心假设 建议是：实质/基质细胞表型的获得性改变 创造引导组织发展的组织微环境 重建为进行性纤维化，而不是恢复 肺泡结构正常。这种表型的变化导致和正在 效应器分子的变化使之永恒不变 通过自分泌和旁分泌环路影响纤维化过程。这些 分泌表型的改变是潜在的治疗靶点 干预措施。这份SCOR中的具体假设是： 1.成纤维细胞增生性疾病发病过程中的血管生成 间质性肺疾病依赖于CXC趋化因子成员 作为血管生成因子或血管抑制因子的家族。生物学的 这些CXC趋化因子表达的平衡决定了 与纤维增殖相关的新生血管形成 消退或进展为终末期肺纤维化。 2.前列腺素E_2(PGE_2)合成减少是 纤维化形成和表型改变的决定因素 鉴定从特发性肺纤维化患者获得的成纤维细胞。 3.成纤维细胞在组织纤维化中的激活依赖于 一种特定疾病表型的表达，其特征是 Th2型细胞因子占优势。 4.增强肺泡腔内的纤维溶解活性 基因转移技术将减少肺纤维化 伴有炎症性肺损伤。 5.肺泡上皮细胞和巨噬细胞参与了一种 AEC来源的GM-CSF导致定向旁分泌相互作用 巨噬细胞介质的表达，如HGF和uPA 肺泡结构正常。此外，HGF是正常、 损伤后肺泡衬里的非纤维性愈合 上皮细胞uPA活性的诱导。 该SCOR将采取多学科方法来测试这些 假设。受过内科训练的调查人员的专业知识， 病理学、细胞和分子生物学、生物化学和生物统计学 将会被利用。这项提议的强项是调查人员 对纤维性肺病的长期兴趣，已被证明致力于 临床医生和基础科学家的合作研究，访问 对于大量的IPF和结节病患者，以及非常罕见的 生物医学研究的机构资源。

The long-term objective of this SCOR is to further our understanding of the pathogenesis of idiopathic pulmonary fibrosis (IPF) and sarcoidosis. A clearer understanding of the pathogenesis of these diseases is required to develop new treatment strategies. The central hypothesis for this SCOR proposal is: acquired alterations in parenchymal/stromal cell phenotype create tissue micro environments which steer the progression of tissue remodeling towards progressive fibrosis rather than the restoration of normal alveolar architecture. This change in phenotype results in and is perpetuated by changes in the elaboration of effector molecules which influence the fibrotic process via autocrine and paracrine loops. These altered secretory phenotypes represent potential targets for therapeutic interventions. The specific hypotheses in this SCOR are: 1. Angiogenesis during the pathogenesis of fibroproliferation in interstitial lung disease is dependent on members of the CXC chemokine family acting as either angiogenic or angiostatic factors. The biological balance in expression of these CXC chemokines dictates that neovascularization, in association with fibroproliferation, either regresses or progresses to end-stage pulmonary fibrosis. 2. Diminished prostaglandin E2 (PGE2) synthesis is an important determinant of fibrogenesis and of the phenotypic alterations which characterize fibroblasts obtained from patients with IPF. 3. Fibroblast activation in tissue fibrosis is dependent upon the expression of a specific disease phenotype characterized by the predominance of Th2 type cytokines. 4. Enhancement of fibrolytic activity within the alveolar space using gene transfer technology will reduce the pulmonary fibrosis that accompanies inflammatory lung injury. 5. Alveolar epithelial cells and macrophages participate in a bi- directional paracrine interaction in which AEC-derived GM-CSF leads to the expression of macrophage mediators, such as HGF and uPA that preserve normal alveolar architecture. Furthermore, HGF is required for normal, non-fibrotic healing of the alveolar lining following injury and for the induction of uPA activity in epithelial cells. This SCOR will take a multi-disciplinary approach to testing these hypotheses. The expertise of investigators trained in Internal Medicine, Pathology, Cell and Molecular Biology, Biochemistry, and Biostatistics will be utilized. The strength of this proposal are the investigators long-standing interests in fibrotic lung disease, a proven commitment to collaborative research by both clinicians and basic scientists, access to a large population of IPF and sarcoid patients, and extra-ordinary institutional resources for biomedical research.