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）和空气污染物，包括臭氧。肺上皮提供了抵抗这些药物的第一道防线。囊性纤维化跨膜传导调节剂（CFTR）在正常上皮稳态中起关键作用，包括维持上皮内层液（ELF）中正常谷胱甘肽水平，这是防御空气传播毒素的关键组成部分。在慢性肺部疾病中，HIP信号通路的激活，如可能由组织低氧血症引起，导致CFTR mRNA和蛋白水平下调（细胞培养和小鼠研究表明）。活性氧，如肺部臭氧暴露产生的活性氧，已被证明可以激活HIF信号通路。CFTR缺乏导致ELF中谷胱甘肽水平显著降低，使肺部容易发生氧化/抗氧化失衡，并受到环境毒素的额外伤害。缺氧和来自臭氧等污染物的ROS激活的HIF信号通路抑制CFTR，代表了肺部疾病发病的新机制。本研究的目的是研究1)臭氧对HIF信号通路和CFTR表达和功能的具体影响；2)ROS和缺氧诱导的HIF信号通路抑制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.