MECHANISMS OF TNFA INDUCED ICAM 1 IN AIRWAY EPITHELIUM

这一提议的总体假设是，细胞因子、肿瘤 肿瘤坏死因子α(TNFpha)在血管紧张素转换酶的表达中起重要作用 呼吸道疾病的病理生理学，如哮喘。我们建议 肿瘤坏死因子α与呼吸道上皮细胞相互作用 细胞间黏附分子-1(ICAM-1)表面及基因表达 这是由活性氧中间体(ROI)介导的。这项建议 将研究与以下相关的复杂信号转导级联 肿瘤坏死因子α诱导ICAM-1基因和表面表达。 这项提议中要解决的假设是： 肿瘤坏死因子α与呼吸道上皮细胞表面受体的结合 激活Pertuss毒素(PT)敏感G蛋白的细胞 磷脂酰胆碱特异性磷脂酶C(PC-PLC)。激活PC- PLC导致二酰基甘油(DAG)的产生，DAG可激活蛋白质 蛋白激酶C(PKC)。PKC的激活反过来又激活了氧化剂 敏感核转录因子激活蛋白-1(AP-1)和 核因子kappaB(NFkappaB)。这可以直接和/或通过PKC进行 细胞内ROI增强。因此，PKC的相互作用， 转录因子NFkappaB和AP-1与细胞的氧化还原状态 结果ICAM-1基因和表面表达增强。 为了解决这一假设，正常人支气管上皮(NBHE) 细胞与永生化人支气管上皮细胞系(BEAS-2B) 将会被利用。这些研究将阐明 嗜多性细胞因子TNFpha与呼吸道的相互作用 上皮细胞ICAM-1的表达。最终，这些信息将是 有助于开发新的治疗潜在生命威胁的方法 肺部疾病。

The overall hypothesis of this proposal is that the cytokine, tumor necrosis factor alpha (TNFalpha) plays an important role in the pathophysiology of airway diseases, such as asthma. We propose that TNFalpha interacts with airway epithelial cells provoking enhanced intercellular adhesion molecule-1 (ICAM-1) surface and gene expression which is mediated by reactive oxygen intermediates (ROI). This proposal will investigate the complex signal transduction cascade associated with TNFalpha - induced ICAM-1 gene and surface expression. The HYPOTHESIS to be addressed in this proposal is: TNFalpha binds to a specific cell-surface receptor on airway epithelial cells activating a Pertuss-toxin (PT) sensitive G protein linked to a phosphatidylcholine-specific phospholipase C (PC-PLC). Activation of PC- PLC results in production of diacylglycerol (DAG) which activates protein kinase C (PKC). Activation of PKC activates, in turn, the oxidant sensitive nuclear transcription factors activator protein-1 (AP-1) and nuclear factor kappa B (NFkappaB). This can occur directly and/or via PKC enhancement of intracellular ROI. Thus, interactions of PKC, transcription factors NFkappaB and AP-1, and the redox state of the cells results in enhanced ICAM-1 gene and surface expression. To address this hypothesis, normal human bronchial epithelial (NBHE) cells and the immortalized human bronchial epithelial cell line (BEAS-2B) will be utilized. These studies will elucidate mechanistic aspects of interactions between the pleuripotent cytokine TNFalpha: and airway epithelial cell ICAM-1 expression. Ultimately, this information will be helpful in developing new therapies for potentially life threatening pulmonary diseases.