Role of cell and debris removal in fibrosis

(申请人摘要)长期以来，组织损伤和炎症 与创面愈合过程中的纤维化改变和肺组织 纤维化症。炎性病变的解决需要切除病变部位 炎症细胞通过摄取巨噬细胞和周围组织细胞， 如上皮细胞和成纤维细胞。我们认为，吞噬 细胞凋亡是由多种黏附配体作用于 与磷脂酰丝氨酸的关键受体(PS受体)结合 或PSR)，实际上介导了吞噬作用的信号。通过以下途径摄取 该受体还启动活性转化生长因子的产生。那么这位调解人 在限制炎症的进一步产生方面具有重要作用 介体，以及启动成纤维细胞向肌成纤维细胞转化的可能性 表型转化和纤维化过程。进一步的建议是 细胞碎片和膜碎片是通过类似的机制去除的， 类似的后果。为了探讨这些建议，我们将审查PSR 1)其潜在的启动肌成纤维细胞转化的能力 转化生长因子的相互反馈诱导；2)其在细胞中的上调 与受损区域相邻，并由此摄取受损细胞 和片段以及局部产生的转化生长因子；3)其潜在的 在调节炎症消退和进展为纤维化中的作用。 由于PSR连接能够启动转化生长因子的合成和分泌 从体外和体内的各种细胞类型来看，这项提议还将 通过测定转化生长因子中的点来研究这种诱导的机制 受影响的合成、分泌和激活并开始检测 涉及的信号通路。实验将在上皮细胞中进行 细胞、成纤维细胞和巨噬细胞，因为每一个细胞都表达PSR， 细胞凋亡和对转化生长因子的诱导反应，尽管与 后果。体内研究将在小鼠模型中进行 炎症和纤维化，并将利用一些有价值的基因敲除 菌株。总体目标是详细检查一个潜在的 诱导肺内肌成纤维细胞生成的重要机制。

(Applicant's Abstract) Tissue damage and inflammation have long been associated with fibrotic changes during wound healing and in pulmonary fibrosis. Resolution of inflammatory lesions involves removal of apoptopic inflammatory cells by uptake into macrophages and surrounding tissue cells, such as epithelial cells and fibroblasts. We suggest that the engulfment of apoptotic cells is driven by a variety of adhesion ligands acting in conjunction with a critical receptor for phosphatidylserine (the PS receptor or PSR) that actually mediates the signaling for phagocytosis. Ingestion via this receptor also initiates the production of active TGF. This mediator then has important effects in limiting further generation of inflammatory mediators, as well as the potential to initiate fibroblast to myofibroblast phenotypic conversion and the process of fibrosis. It is further suggested that cell debris and membrane fragments are removed by similar mechanisms with similar consequences. To explore these suggestions, the PSR will be examined 1) for its potential ability to initiate myofibroblast conversion via a reciprocal feedback induction of TGF; 2) for its upregulation in cells adjacent to an area of damage with resultant ingestion of the damaged cells and fragments as well as local generation of TGF; and 3) for its potential role in mediating resolution of inflammation and progression to fibrosis. Because of the ability of PSR ligation to initiate TGF synthesis and secretion from a variety of cell types in vitro and in vivo, this proposal will also examine the mechanisms of this induction by determining the points in TGF synthesis, secretion and activation that are affected and to begin to examine the signaling pathways involved. Experiments will be performed in epithelial cells, fibroblasts and macrophages since each of these express the PSR, ingest apoptotic cells and respond by induction of TGF, although with different consequences. The in vivo studies will be carried out in murine models of inflammation and fibrosis and will make use of a number of valuable knockout strains. The overall objective is to examine in detail one potentially important mechanism for inducing the generation of myofibroblasts in the lung.