SCOR IN THE PATHOBIOLOGY OF FIBROTIC LUNG DISEASE

这项研究的长远目标，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认识 开发新的治疗策略。该SCOR的核心假设是 建议是：实质/基质细胞表型的获得性改变 创造组织微环境， 进行性纤维化的重塑，而不是恢复 正常的肺泡结构。这种表型变化导致 通过效应分子的加工过程中的变化而延续， 通过自分泌和旁分泌环影响纤维化过程。这些 改变的分泌表型代表了治疗的潜在靶点。 干预措施。本SCOR中的具体假设是： 1.血管生成在纤维增生发病过程中的作用 间质性肺病依赖于CXC趋化因子的成员 作为血管生成或血管抑制因子的家族。生物 这些CXC趋化因子表达的平衡表明， 与纤维增生相关的新血管形成， 退化或进展为终末期肺纤维化。 2.前列腺素E2（PGE 2）合成减少是一个重要的 纤维形成和表型改变的决定因素， 表征从IPF患者获得的成纤维细胞。 3.组织纤维化中的成纤维细胞活化依赖于 表达特征在于以下的特定疾病表型： Th 2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 伴有炎性肺损伤。 5.肺泡上皮细胞和巨噬细胞参与了一个双- 定向旁分泌相互作用，其中AEC衍生的GM-CSF导致 巨噬细胞介质的表达，如HGF和uPA， 正常的肺泡结构。此外，HGF是正常的， 损伤后牙槽膜的非纤维化愈合， 上皮细胞中uPA活性的诱导。 该SCOR将采取多学科方法来测试这些 假设经过内科培训的研究者的专业知识， 病理学、细胞和分子生物学、生物化学和生物统计学 将被利用。这项提案的优势在于调查人员 长期致力于纤维化肺病， 临床医生和基础科学家的合作研究， 对于大量IPF和结节病患者， 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.