APOPTOTIC PATHWAYS IN LUNG EPITHELIAL CELLS

描述：传导性呼吸上皮是 在许多肺部疾病中，如急性肺损伤， 病毒感染、自身免疫性疾病和间质性肺病。 T细胞 通过释放细胞因子诱导肺上皮细胞凋亡， 凋亡途径的激活。 细胞凋亡途径之一是 T细胞涉及Fas/APO-1，其是T细胞的跨膜受体成员。 肿瘤坏死因子超家族 细胞因子如IFN-γ（IFN）可 协同Fas通路，增强受损肺的清除 上皮细胞，但过度凋亡可导致慢性免疫 活化和肺纤维化。 初步数据显示，单独使用IFN和 与Fas协同诱导肺上皮细胞系凋亡。 在 此外，肺上皮细胞中Fas通路的激活激活了 特异性半胱天冬酶，以前称为半胱氨酸蛋白酶， 粘着斑激酶（FAK）的裂解。 地塞米松，广泛用作 治疗炎症性肺病，是IFN的有效抑制剂， Fas介导的细胞死亡。 干扰素在Fas介导的细胞凋亡中的作用 以及地塞米松如何抑制这一过程， 然而，这是未知的。 本提案的目的是描述Fas 肺上皮细胞系中的信号通路。 为了做到这一点，具体 目的是：1）表征caspase介导的FAK切割的作用 在Fas触发的肺上皮细胞凋亡过程中; 2）表征 干扰素诱导肺上皮细胞凋亡的机制 使细胞对Fas介导的细胞凋亡敏感;和3）表征 hIAP-1作为糖皮质激素诱导的抑制的介质的作用 肺上皮细胞凋亡。 这些研究将 揭示FAK在肺上皮细胞中裂解的功能意义 细胞凋亡，IFN如何诱导细胞凋亡和肺上皮细胞对 Fas介导的细胞凋亡以及地塞米松如何阻断Fas的激活 信号通路

DESCRIPTION: The conducting respiratory epithelium is a target for immune-mediated damage in many lung diseases, such as acute lung injury, viral infection, autoimmune disease, and interstitial lung disease. T cells induce apoptosis of lung epithelial cells by release of cytokines and activation of apoptotic pathways. One of the apoptotic pathways utilized by T cells involves Fas/APO-1, which is transmembrane receptor member of the tumor necrosis factor superfamily. Cytokines such as IFN-gamma (IFN) can cooperate with the Fas pathway to enhance elimination of damaged lung epithelial cells, but excessive apoptosis can lead to chronic immune activation and lung fibrosis. Preliminary data show that IFN alone and in cooperation with Fas induces apoptosis in lung epithelial cell lines. In addition, activation of the Fas pathway in lung epithelial cells activates specific caspases, previously known as cysteine proteases, that induce cleavage of focal adhesion kinase (FAK). Dexamethasone, widely used as a treatment for inflammatory lung diseases, is a potent inhibitor of IFN and FAS-mediated cell death. The specific role of IFN in FAS-mediated apoptosis of lung epithelial cells, and how dexamethasone inhibit this process, however, is unknown. The goal of this proposal is to describe th Fas pathway in lung epithelial cell lines. To accomplish this, the specific aims are: 1) to characterize the role of caspase-mediated cleavage of FAK during Fas-triggered apoptosis in lung epithelial cells; 2) to characterize th mechanism by which IFN induces apoptosis in lung epithelial cells and sensitizes the cells to Fas-mediated apoptosis; and 3) to characterize the rol of hIAP-1 as a mediator of glucocorticoid-induced inhibition of apoptosis in lung epithelial cells. Taken together these studies will reveal the functional significance of FAK cleavage in lung epithelial cell apoptosis, how IFN induce apoptosis and sensitizes lung epithelial cells to Fas-mediated apoptosis, and how dexamethasone blocks activation of the Fas signaling pathway.