Hocker Austin D, Huxtable Adrianne G
Department of Human Physiology, University of Oregon, Eugene, OR, United States.
Front Physiol. 2019 Aug 13;10:1039. doi: 10.3389/fphys.2019.01039. eCollection 2019.
Inflammation arises from diverse stimuli eliciting distinct inflammatory profiles, yet little is known about the effects of different inflammatory stimuli on respiratory motor plasticity. Respiratory motor plasticity is a key feature of the neural control of breathing and commonly studied in the form of phrenic long-term facilitation (pLTF). At least two distinct pathways can evoke pLTF with differential sensitivities to bacterial-induced inflammation. The Q-pathway is abolished by bacterial-induced inflammation, while the S-pathway is inflammation-resistant. Since viral-induced inflammation is common and elicits distinct temporal inflammatory gene profiles compared to bacterial inflammation, we tested the hypothesis that inflammation induced by a viral mimetic (polyinosinic:polycytidylic acid, polyIC) would abolish Q-pathway-evoked pLTF, but not S-pathway-evoked pLTF. Further, we hypothesized Q-pathway impairment would occur later relative to bacterial-induced inflammation. PolyIC (750 μg/kg, i.p.) transiently increased inflammatory genes in the cervical spinal cord (3 h), but did not alter medullary and splenic inflammatory gene expression, suggesting region specific inflammation after polyIC. Dose-response experiments revealed 750 μg/kg polyIC (i.p.) was sufficient to abolish Q-pathway-evoked pLTF at 24 h (17 ± 15% change from baseline, = 5, > 0.05). However, polyIC (750 μg/kg, i.p.) at 3 h was not sufficient to abolish Q-pathway-evoked pLTF (67 ± 21%, = 5, < 0.0001), suggesting a unique temporal impairment of pLTF after viral-mimetic-induced systemic inflammation. A non-steroidal anti-inflammatory (ketoprofen, 12.5 mg/kg, i.p., 3 h) restored Q-pathway-evoked pLTF (64 ± 24%, = 5, < 0.0001), confirming the role of inflammatory signaling in pLTF impairment. On the contrary, S-pathway-evoked pLTF was unaffected by polyIC-induced inflammation (750 μg/kg, i.p., 24 h; 72 ± 25%, = 5, < 0.0001) and was not different from saline controls (65 ± 32%, = 4, = 0.6291). Thus, the inflammatory-impairment of Q-pathway-evoked pLTF is generalizable between distinct inflammatory stimuli, but differs temporally. On the contrary, S-pathway-evoked pLTF is inflammation-resistant. Therefore, in situations where respiratory motor plasticity may be used as a tool to improve motor function, strategies targeting S-pathway-evoked plasticity may facilitate therapeutic outcomes.
炎症源于多种引发不同炎症特征的刺激，但对于不同炎症刺激对呼吸运动可塑性的影响却知之甚少。呼吸运动可塑性是呼吸神经控制的一个关键特征，通常以膈神经长期易化（pLTF）的形式进行研究。至少有两条不同的途径可以诱发pLTF，它们对细菌诱导的炎症具有不同的敏感性。Q途径会被细菌诱导的炎症所消除，而S途径则对炎症具有抗性。由于病毒诱导的炎症很常见，并且与细菌炎症相比会引发不同的炎症基因时间表达谱，我们测试了这样一个假设，即由病毒模拟物（聚肌苷酸：聚胞苷酸，polyIC）诱导的炎症会消除Q途径诱发的pLTF，但不会消除S途径诱发的pLTF。此外，我们假设Q途径损伤相对于细菌诱导的炎症会发生得更晚。PolyIC（750μg/kg，腹腔注射）可使颈脊髓中的炎症基因短暂增加（3小时），但不会改变延髓和脾脏中的炎症基因表达，这表明polyIC后存在区域特异性炎症。剂量反应实验表明，750μg/kg的polyIC（腹腔注射）足以在24小时时消除Q途径诱发的pLTF（相对于基线变化17±15%，n = 5，P>0.05）。然而，3小时时的polyIC（750μg/kg，腹腔注射）不足以消除Q途径诱发的pLTF（67±21%，n = 5，P<0.0001），这表明病毒模拟物诱导的全身炎症后pLTF存在独特的时间性损伤。一种非甾体抗炎药（酮洛芬，12.5mg/kg，腹腔注射，3小时）恢复了Q途径诱发的pLTF（64±24%，n = 5，P<0.0001），证实了炎症信号在pLTF损伤中的作用。相反，S途径诱发的pLTF不受polyIC诱导的炎症影响（750μg/kg，腹腔注射，24小时；72±25%，n = 5，P<0.0001），并且与生理盐水对照组无差异（65±32%，n = 4，P = 0.6291）。因此，Q途径诱发的pLTF的炎症损伤在不同的炎症刺激之间具有普遍性，但在时间上有所不同。相反，S途径诱发的pLTF对炎症具有抗性。因此，在呼吸运动可塑性可被用作改善运动功能的工具的情况下，针对S途径诱发可塑性的策略可能会促进治疗效果。
