Effects of ozone on CFTR expression and HIF signaling

描述（由申请人提供）：许多慢性肺部疾病是由环境因素引起或加重的，如香烟烟雾（慢性阻塞性肺病）和包括臭氧在内的空气污染物。肺上皮细胞提供了对许多这些药剂的第一线防御。囊性纤维化跨膜传导调节因子（CFTR）在正常上皮内稳态中起关键作用，包括维持上皮衬里液（ELF）中的正常谷胱甘肽水平，这是防御空气传播毒素的关键组分。在慢性肺部疾病中，HIP信号传导途径的激活，例如可能由组织低氧血症引起，导致CFTR mRNA和蛋白质水平的下调（如细胞培养物和小鼠中的研究所表明的）。活性氧物质，如肺中臭氧暴露产生的活性氧物质，已被证明能激活HIF信号通路。CFTR缺乏导致ELF中谷胱甘肽水平显著降低，使肺易受氧化剂/抗氧化剂失衡和环境毒素的额外损伤。通过低氧和来自污染物如臭氧的ROS激活的HIF信号通路对CFTR的抑制代表了肺部疾病发病机制的新机制。本提案的目标是研究1）臭氧对HIF信号传导和CFTR表达和功能的具体影响，以及2）ROS和低氧诱导的HIF信号传导抑制CFTR的分子机制。

DESCRIPTION (provided by applicant): Many chronic lung diseases are caused or exacerbated by environmental factors such as cigarette smoke (chronic obstructive pulmonary disease) and air pollutants including ozone. The lung epithelia provides a first line defense against many of these agents. The cystic fibrosis transmembrane conductance regulator (CFTR) serves a pivotal role in normal epithelial homeostasis, including the maintenance of normal glutathione levels in the epithelial lining fluid (ELF), a critical component of the defense against airborne toxins. In chronic lung conditions, the activation of HIP signaling pathways, such as may be caused by tissue hypoxemia, result in the down-regulation of CFTR mRNA and protein levels (as suggested by studies in cell culture and mice). Reactive oxygen species, such as those produced by ozone exposure in the lung, have been shown to activate HIF signaling pathways. CFTR deficiency results in a significantly decreased level of glutathione in the ELF, predisposing the lung to oxidant/antioxidant imbalance and additional injury from environmental toxins. The repression of CFTR by HIF signaling pathways, activated by both hypoxia and ROS from pollutants like ozone, represents a novel mechanism for lung disease pathogenesis. The goals of this proposal are to investigate 1) the specific effects of ozone on HIF signaling and CFTR expression and function and 2) the molecular mechanisms by which ROS- and hypoxia-induced HIF signaling repress CFTR.