Liu X, He L, Stensaas L, Dinger B, Fidone S
Dept. of Physiology, Univ. of Utah School of Medicine, Salt Lake City, UT 84108-6500, USA.
Am J Physiol Lung Cell Mol Physiol. 2009 Feb;296(2):L158-66. doi: 10.1152/ajplung.90383.2008. Epub 2008 Oct 31.
Exposure to chronic hypoxia (CH; 3-28 days at 380 Torr) induces adaptation in mammalian carotid body such that following CH an acute hypoxic challenge elicits an abnormally large increase in carotid sinus nerve impulse activity. The current study examines the hypothesis that CH initiates an immune response in the carotid body and that chemoreceptor hyperexcitability is dependent on the expression and action of inflammatory cytokines. CH resulted in a robust invasion of ED1(+) macrophages, which peaked on day 3 of exposure. Gene expression of proinflammatory cytokines, IL-1beta, TNFalpha, and the chemokine, monocyte chemoattractant protein-1, was increased >2-fold after 1 day of hypoxia followed by a >2-fold increase in IL-6 on day 3. After 28 days of CH, IL-6 remained elevated >5-fold, whereas expression of other cytokines recovered to normal levels. Cytokine expression was not restricted to immune cells. Studies of cultured type I cells harvested following 1 day of in vivo hypoxia showed elevated transcript levels of inflammatory cytokines. In situ hybridization studies confirmed expression of IL-6 in type I cells and also showed that CH induces IL-6 expression in supporting type II cells. Concurrent treatment of CH rats with anti-inflammatory drugs (ibuprofen or dexamethasone) blocked immune cell invasion and severely reduced CH-induced cytokine expression in carotid body. Drug treatment also blocked the development of chemoreceptor hypersensitivity in CH animals. Our findings indicate that chemoreceptor adaptation involves novel neuroimmune mechanisms, which may alter the functional phenotypes of type I cells and chemoafferent neurons.
长期暴露于低氧环境（CH；在380托下持续3 - 28天）会诱导哺乳动物颈动脉体产生适应性变化，使得在CH之后，急性低氧刺激会引发颈动脉窦神经冲动活动异常大幅增加。本研究检验了以下假设：CH在颈动脉体引发免疫反应，且化学感受器的过度兴奋依赖于炎症细胞因子的表达和作用。CH导致ED1(+)巨噬细胞大量侵入，在暴露第3天达到峰值。在低氧1天后，促炎细胞因子白细胞介素-1β（IL-1β）、肿瘤坏死因子α（TNFα）以及趋化因子单核细胞趋化蛋白-1（MCP-1）的基因表达增加了2倍以上，随后在第3天IL-6又增加了2倍以上。CH持续28天后，IL-6仍升高5倍以上，而其他细胞因子的表达恢复到正常水平。细胞因子的表达并不局限于免疫细胞。对体内低氧1天后收获的I型细胞进行培养研究显示，炎症细胞因子的转录水平升高。原位杂交研究证实I型细胞中存在IL-6的表达，同时也表明CH可诱导支持性II型细胞中IL-6的表达。用抗炎药物（布洛芬或地塞米松）同时处理CH大鼠可阻断免疫细胞的侵入，并严重降低CH诱导的颈动脉体中细胞因子的表达。药物处理还可阻断CH动物化学感受器超敏反应的发展。我们的研究结果表明，化学感受器的适应性变化涉及新的神经免疫机制，这可能会改变I型细胞和化学传入神经元的功能表型。
