KGF and Inhibition of Pulmonary Fibrosis

特发性肺纤维化（IPF）的了解很少，但认为涉及反复发作的肺损伤 然后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。一种被认为是 在维持肺上皮完整性中起作用的是角质细胞生长因子（KGF），其作用于 上皮细胞KGF在小鼠肺中的过表达提供了对博来霉素（bleo）诱导的肺损伤的保护作用。 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， CXCL10和CXCL11在肺中的作用，先前已在动物模型中显示出保护免受纤维化。 体外KGF处理上皮细胞导致STAT1磷酸化，这可能是增加细胞凋亡的基础。 KGF诱导的特异性趋化因子的表达。发现KGF + bleo治疗的Tg小鼠显示 肺上皮细胞中D-连环蛋白的细胞质和细胞核存在增加。表达多个 Wnt/D-连环蛋白信号转导通路的成员，在肺中显著上调， 这些老鼠我们还观察到KGF阻止上皮细胞向肌成纤维细胞的进化 表型。最后，KGF治疗肺上皮细胞可防止TGF-D1介导的Id1下调 蛋白质，一种已知的肌生成抑制剂。基于这些数据，我们的假设是：1。 KGF在上皮细胞中诱导的因子如CXCL9、CXCL10和CXCL11抑制肺纤维化。 2. KGF通过促进正常上皮再生减轻肺纤维化。3. KGF拮抗TGFD- 诱导上皮细胞的信号传导机制，从而抑制向成纤维细胞的分化 表型。为了验证这些假设，我们将： 艾姆岛表征趋化因子CXCL9、CXCL10和CXCL11以及IFN-D和STAT1在 KGF介导的对bleo诱导的肺纤维化的保护作用。 Aim II.表征Wnt/D-catenin信号传导在KGF介导的TGF-D1效应抑制中的作用 在上皮细胞上。 Aim III.表征分化抑制因子1（Id1）分子在KGF介导的保护性抗肿瘤作用中的作用。 博莱霉素诱导肺纤维化。

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.