Department of Human Physiology, University of Oregon , Eugene, Oregon.
J Appl Physiol (1985). 2018 Aug 1;125(2):504-512. doi: 10.1152/japplphysiol.01051.2017. Epub 2018 Mar 22.
Inflammation undermines respiratory motor plasticity, yet we are just beginning to understand the inflammatory signaling involved. Because interleukin-1 (IL-1) signaling promotes or inhibits plasticity in other central nervous system regions, we tested the following hypotheses: 1) IL-1 receptor (IL-1R) activation after systemic inflammation is necessary to undermine phrenic long-term facilitation (pLTF), a model of respiratory motor plasticity induced by acute intermittent hypoxia (AIH), and 2) spinal IL-1β is sufficient to undermine pLTF. pLTF is significantly reduced 24 h after lipopolysaccharide (LPS; 100 μg/kg ip, 12 ± 18%, n = 5) compared with control (57 ± 25%, n = 6) and restored by peripheral IL-1R antagonism (63 ± 13%, n = 5, AF-12198, 0.5 mg/kg ip, 24 h). Furthermore, acute, spinal IL-1R antagonism (1 mM AF-12198, 15 μl it) restored pLTF (53 ± 15%, n = 4) compared with LPS-treated rats (11 ± 10%; n = 5), demonstrating IL-1R activation is necessary to undermine pLTF after systemic inflammation. However, in healthy animals, pLTF persisted after spinal, exogenous recombinant rat IL-1β (rIL-1β) (1 ng ± AIH; 66 ± 26%, n = 3, 10 ng ± AIH; 102 ± 49%, n = 4, 100 ng + AIH; 93 ± 51%, n = 3, 300 ng ± AIH; 37 ± 40%, n = 3; P < 0.05 from baseline). In the absence of AIH, spinal rIL-1β induced progressive, dose-dependent phrenic amplitude facilitation (1 ng; -3 ± 5%, n = 3, 10 ng; 8 ± 22%, n = 3, 100 ng; 31 ± 12%, P < 0.05, n = 4, 300 ng; 51 ± 17%, P < 0.01 from baseline, n = 4). In sum, IL-1R activation, both systemically and spinally, undermines pLTF after LPS-induced systemic inflammation, but IL-1R activation is not sufficient to abolish plasticity. Understanding the inflammatory signaling inhibiting respiratory plasticity is crucial to developing treatment strategies utilizing respiratory plasticity to promote breathing during ventilatory control disorders. NEW & NOTEWORTHY This study gives novel insights concerning mechanisms by which systemic inflammation undermines respiratory motor plasticity. We demonstrate that interleukin-1 signaling, both peripherally and centrally, undermines respiratory motor plasticity. However, acute, exogenous interleukin-1 signaling is not sufficient to undermine respiratory motor plasticity.
炎症会破坏呼吸运动的可塑性，但我们才刚刚开始了解其中涉及的炎症信号。因为白细胞介素-1（IL-1）信号在其他中枢神经系统区域中促进或抑制可塑性，所以我们提出了以下假设：1）全身炎症后 IL-1 受体（IL-1R）的激活对于破坏急性间歇性低氧（AIH）诱导的膈神经长期易化（pLTF），即呼吸运动可塑性模型，是必要的；2）脊髓中的 IL-1β足以破坏 pLTF。与对照组（57±25%，n=6）相比，脂多糖（LPS；100μg/kg 腹腔注射，12±18%，n=5）后 24 小时 pLTF 显著降低，并且外周 IL-1R 拮抗作用可恢复（63±13%，n=5，AF-12198，0.5mg/kg 腹腔注射，24 小时）。此外，急性、脊髓 IL-1R 拮抗作用（1mM AF-12198，15μl 腹腔内注射）可恢复 LPS 处理大鼠的 pLTF（11±10%，n=5），证明全身炎症后 IL-1R 的激活对于破坏 pLTF 是必要的。然而，在健康动物中，脊髓外源性重组大鼠 IL-1β（rIL-1β）（1ng±AIH；66±26%，n=3，10ng±AIH；102±49%，n=4，100ng+AIH；93±51%，n=3，300ng±AIH；37±40%，n=3；与基线相比，P<0.05）仍可保持 pLTF。在没有 AIH 的情况下，脊髓 rIL-1β 可诱导膈神经幅度进行性、剂量依赖性易化（1ng；-3±5%，n=3，10ng；8±22%，n=3，100ng；31±12%，P<0.05，n=4，300ng；51±17%，P<0.01，与基线相比，n=4）。总之，LPS 诱导的全身炎症后，无论是系统还是脊髓的 IL-1R 激活都会破坏 pLTF，但 IL-1R 激活不足以消除可塑性。了解抑制呼吸可塑性的炎症信号对于开发利用呼吸可塑性在通气控制障碍期间促进呼吸的治疗策略至关重要。
本研究提供了关于全身炎症破坏呼吸运动可塑性的机制的新见解。我们证明了白细胞介素-1 信号在周围和中枢神经系统中都会破坏呼吸运动的可塑性。然而，急性外源性白细胞介素-1 信号不足以破坏呼吸运动的可塑性。
