Effects of ozone on CFTR expression and HIF signaling

描述(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。肺上皮细胞为许多此类病原体提供了一线防御。囊性纤维化跨膜电导调节因子(CFTR)在正常的上皮细胞动态平衡中起着关键作用，包括维持上皮衬里液体(ELF)中正常的谷胱甘肽水平，ELF是防御空气传播毒素的关键组成部分。在慢性肺疾病中，HIP信号通路的激活，如可能由组织低氧血症引起的，导致CFTRmRNA和蛋白水平下调(细胞培养和小鼠研究表明)。已有研究表明，肺内臭氧暴露所产生的活性氧能激活HIF信号通路。CFTR缺乏导致ELF中谷胱甘肽水平显著降低，使肺容易受到氧化/抗氧化失衡和环境毒素的额外伤害。通过低氧和臭氧等污染物产生的ROS激活的HIF信号通路抑制CFTR，是肺部疾病发病的一种新机制。本研究的目的是研究1)臭氧对HIF信号和CFTR表达和功能的特定影响，以及2)ROS和低氧诱导的HIF信号抑制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.