Regulation of fibrosis by alveolar cells expressing CCR2

(申请人摘要)肺纤维化是一个斑片状、局灶性的过程， 从肺泡开始。在导致纤维化的侮辱后进行修复 严重依赖于肺泡上皮细胞(AEC)的重建 受伤的肺泡。慢性炎症细胞为这两种疾病提供关键信号 AEC和成纤维细胞在修复肺泡壁的过程中。我们 认为趋化因子受体-2(CCR2)对维持 再生肺泡反应和纤维化肺泡反应之间的动态平衡。 假设：CCR2激活通过转位促进病理性纤维化反应 关闭分子的局部表达，否则就会支持正常修复。 在CCR2缺乏激活的情况下，AEC和肺泡巨噬细胞(AMO)在 损伤部位表现为支持修复的表型，并有局部表达 联合应用GM-CSF、PGE2和干扰素以抑制纤维化。在CCR2激活的情况下， 这些保护性因子的局部表达减少，导致 抑制NEC增殖，增加AEC凋亡并增加基质 证词。 这一假设将使用一个模型来解决，在该模型中，单个 异硫氰酸荧光素(FITC)气管内激发导致 最初区域的慢性炎症和斑片状、局灶性肺纤维化 牵涉到受伤。肺纤维增生性反应是持续性的 并且不会自发倒退。CCR2表达小鼠(CCR2+/+)和小鼠 缺乏CCR2(CCR2-/-)的将被利用。我们将确定动力学 和CCR2、IFNy、GM-CSF的表达部位以及与 前列腺素E_2合成。我们将确定CCR2和GM-CSF对AEC的影响 FITC诱导的肺纤维化中的增殖和凋亡。的角色 干扰素和前列腺素E_2作为CCR2-/-小鼠增强修复的介体 下定决心。 将探讨CCR2在AMO和小鼠血管内皮细胞上的表达调控。最后， GM-CSF和MCP-1对前列腺素E_2合成的影响将被确定。

(Applicant's Abstract) Pulmonary fibrosis is a patchy, focal process that begins in the alveolus. Repair following insults which induce fibrosis is critically dependent on alveolar epithelial cell (AEC) reconstitution in the injured alveolus. Chronic inflammatory cells provide crucial signals to both AEC and fibroblasts during the processes that repair the alveolar wall. We believe that chemokine receptor-2 (CCR2) is crucial to the maintenance of a homeostatic balance between regenerative and fibrotic alveolar responses. Hypothesis: CCR2 activation promotes a pathologic fibrotic response by turning off local expression of molecules that otherwise would support normal repair. In the absence of CCR2 activation, AEC and alveolar macrophages (AMO) at the site of injury display a phenotype that supports repair, with local expression of GM-CSF, PGE2 and IFN to limit fibrosis. In the presence of CCR2 activation, local expression of these protective factors is reduced, resulting in decreased NEC proliferation, increased AEC apoptosis and increased matrix deposition. This hypothesis will be addressed using a model in which a single intratracheal challenge with fluorescein isothiocyanate (FITC) leads to chronic inflammation and patchy, focal pulmonary fibrosis in areas initially involved in injury. The pulmonary fibroproliferative response is persistent and does not spontaneously regress. CCR2 expressing mice (CCR2 +/+) and mice which lack CCR2 (CCR2 -/-) will be utilized. We will determine the kinetics and sites of expression of CCR2, IFNy, GM-CSF and the enzymes responsible for PGE2 synthesis. We will determine the effects of CCR2 and GM-CSF on AEC proliferation and apoptosis in FITC-induced pulmonary fibrosis. The roles of IFN and PGE2 as mediators of enhanced repair in CCR2 -/- mice will be determined. Regulation of CCR2 expression on AMO and murine AEC will be explored. Finally, the effects of GM-CSF and MCP-1 on Al,.C synthesis of PGE2 will be determined.