Department of Physiology, University of Utah School of Medicine, Salt Lake City, USA.
Am J Physiol Lung Cell Mol Physiol. 2011 Dec;301(6):L985-92. doi: 10.1152/ajplung.00132.2011. Epub 2011 Sep 2.
Previously we demonstrated that chronic hypoxia (CH) induces an inflammatory condition characterized by immune cell invasion and increased expression of inflammatory cytokines in rat carotid body. It is well established that chronic inflammatory pain induces the expression of acid-sensitive ion channels (ASIC) in primary sensory neurons, where they contribute to hyperalgesia and allodynia. The present study examines the effect of CH on ASIC expression in petrosal ganglion (PG), which contains chemoafferent neurons that innervate oxygen-sensitive type I cells in the carotid body. Five isoforms of ASIC transcript were increased ∼1.5-2.5-fold in PG following exposure of rats to 1, 3, or 7 days of hypobaric hypoxia (380 Torr). ASIC transcript was not increased in the sympathetic superior cervical ganglion (SCG). In the PG, CH also increased the expression of channel-interacting PDZ domain protein, a scaffolding protein known to enhance the surface expression and the low pH-induced current density mediated by ASIC3. Western immunoblot analysis showed that CH elevated ASIC3 protein in PG, but not in SCG or the (sensory) nodose ganglion. ASIC3 transcript was likewise elevated in PG neurons cultured in the presence of inflammatory cytokines. Increased ASIC expression was blocked in CH rats concurrently treated with the nonsteroidal anti-inflammatory drug ibuprofen (4 mg·kg(-1)·day(-1)). Electrophysiological recording of carotid sinus nerve (CSN) activity in vitro showed that the specific ASIC antagonist A-317567 (100 μM) did not significantly alter hypoxia-evoked activity in normal preparations but blocked ∼50% of the hypoxic response following CH. Likewise, a high concentration of ibuprofen, which is known to block ASIC1a, reduced hypoxia-evoked CSN activity by ∼50% in CH preparations. Our findings indicate that CH induces inflammation-dependent phenotypic adjustments in chemoafferent neurons. Following CH, ASIC are important participants in chemotransmission between type I cells and chemoafferent nerve terminals, and these proton-gated channels appear to enhance chemoreceptor sensitivity.
先前我们已经证明，慢性缺氧（CH）会导致炎症状态，其特征是免疫细胞浸润和炎症细胞因子表达增加，这种情况发生在大鼠颈动脉体中。众所周知，慢性炎性疼痛会导致初级感觉神经元中酸敏感离子通道（ASIC）的表达，而这些通道有助于痛觉过敏和感觉异常。本研究检查了 CH 对 PG 中 ASIC 表达的影响，PG 包含化学传入神经元，这些神经元支配颈动脉体中氧敏感的 I 型细胞。在大鼠暴露于低压缺氧（380 托）1、3 或 7 天后，PG 中 5 种 ASIC 转录本增加了约 1.5-2.5 倍。在交感神经颈上神经节（SCG）中，ASIC 转录本没有增加。在 PG 中，CH 还增加了通道相互作用的 PDZ 结构域蛋白的表达，这种支架蛋白已知可增强 ASIC3 介导的表面表达和低 pH 诱导的电流密度。Western 免疫印迹分析显示，CH 使 PG 中的 ASIC3 蛋白升高，但在 SCG 或（感觉）结状神经节中则没有。在存在炎性细胞因子的情况下，PG 神经元中的 ASIC3 转录本也升高。在同时用非甾体抗炎药布洛芬（4 mg·kg(-1)·day(-1)）治疗的 CH 大鼠中，ASIC 表达增加被阻断。体外颈动脉窦神经（CSN）活性的电生理记录显示，特异性 ASIC 拮抗剂 A-317567（100 μM）在正常制剂中不会显著改变缺氧引起的活性，但在 CH 后阻断约 50%的缺氧反应。同样，高浓度的布洛芬（已知可阻断 ASIC1a）可使 CH 制剂中缺氧引起的 CSN 活性降低约 50%。我们的发现表明，CH 诱导化学传入神经元中依赖炎症的表型调整。CH 后，ASIC 是 I 型细胞和化学传入神经末梢之间化学传递的重要参与者，这些质子门控通道似乎增强了化学感受器的敏感性。
