KGF and Inhibition of Pulmonary Fibrosis

特发性肺纤维化(IPF)了解甚少，但被认为与反复发作的肺损伤有关 然后是异常愈合。肺上皮细胞和成纤维细胞之间的相互作用是关键 正常愈合或纤维化进展的决定因素。其中一个秘密因素被认为是 在维持肺上皮完整性中起作用的是角质细胞生长因子(KGF)，它作用于 上皮细胞。KGF在小鼠肺内过表达对博莱霉素(BLO)诱导的小鼠肺损伤的保护作用 肺纤维化。我们的初步数据表明，KGF诱导趋化因子基因CXCL9的表达， 肺中的CXCL10和CXCL11，先前已被证明在动物模型中可以防止纤维化。 KGF对体外培养上皮细胞的作用导致STAT1的磷酸化，这可能是其增加的原因 KGF诱导特异性趋化因子的表达。KGF BLOO处理的TG小鼠被发现显示 肺上皮细胞内D-连环蛋白胞浆和胞核出现增多。多项式的表达 Wnt/D-catenin信号转导通路成员在小鼠肺组织中显著上调 这些老鼠。我们还观察到KGF阻止上皮细胞向肌成纤维细胞进化 表型。最后，KGF对肺上皮细胞的处理可阻止转化生长因子-D_1介导的ID1下调 蛋白质，一种已知的肌肉生成抑制因子。基于这些数据，我们在本提案中的假设是：1. KGF诱导的上皮细胞因子CXCL9、CXCL10和CXCL11抑制肺纤维化。 2.KGF通过促进正常的上皮细胞再生来减轻肺纤维化。3.KGF拮抗TGFD- 上皮细胞的诱导信号机制，进而抑制向成纤维细胞的分化 表型。为了检验这些假设，我们将： 目的I.研究趋化因子CXCL9、CXCL10和CXCL11以及干扰素-D和信号转导通路1在肿瘤中的作用。 KGF介导的肺纤维化保护作用。 目的II.鉴定Wnt/D-catenin信号在KGF介导的抑制转化生长因子-D_1作用中的作用 在上皮细胞上。 目的III.鉴定分化抑制因子1(Id1)分子在KGF介导的细胞免疫保护中的作用 博莱霉素性肺纤维化。

Idiopathic pulmonary fibrosis (IPF) is poorly understood, but is felt to involve repeated episodes of lung injury followed by aberrant healing. The interactions between lung epithelial cells and fibroblasts are key determinants of normal healing or the progression of fibrosis. One of the secreted factors that is believed to play a role in the maintenance of lung epithelial integrity is keratinocyte growth factor (KGF) which acts on epithelial cells. Overexpression KGF in the mouse lung provides protection against bleomycin (bleo)-induced lung fibrosis. Our preliminary data indicate that KGF induces expression of the chemokine genes CXCL9, CXCL10 and CXCL11 in the lung that have been previously shown to protect from fibrosis in animal models. KGF treatment of epithelial cells in vitro results in STAT1 phosphorylation that may underlie the increased KGF-induced expression of the specific chemokines. KGF+bleo-treated Tg mice were found to display increased cytoplasmic and nuclear presence of D-catenin in lung epithelial cells. The expression of multiple members of the Wnt/D-catenin signal transduction pathway, was significantly upregulated in the lungs of these mice. We have also observed that KGF prevents the evolution of epithelial cells toward a myofibroblast phenotype. Finally, KGF treatment of lung epithelial cells prevents TGF-D1-mediated downregulation of Id1 protein, a known inhibitor of myogenesis. Based on these data, our hypotheses in this proposal are: 1. Factors induced by KGF in epithelial cells such as CXCL9, CXCL10 and CXCL11 inhibit pulmonary fibrosis. 2. KGF attenuates pulmonary fibrosis by fostering normal epithelial regeneration. 3. KGF antagonizes TGFD- induced signaling mechanisms in epithelial cells that in turn inhibit differentiation towards a fibroblastic phenotype. To test these hypotheses we will: Aim I. Characterize the role of the chemokines CXCL9, CXCL10 and CXCL11, and of IFN-D and STAT1 in KGF-mediated protection from bleo-induced pulmonary fibrosis. Aim II. Characterize the role of Wnt/D-catenin signaling in KGF-mediated inhibition of the effects of TGF-D1 on epithelial cells. Aim III. Characterize the role of inhibitor of differentiation 1 (Id1) molecule in KGF mediated protection from bleomycin induced pulmonary fibrosis.