Huxtable Adrianne G, Kopp Elizabeth, Dougherty Brendan J, Watters Jyoti J, Mitchell Gordon S
Department of Comparative Biosciences, University of Wisconsin, Madison, WI, 53706, United States; Department of Human Physiology, University of Oregon, Eugene, OR, 97403, United States.
Department of Comparative Biosciences, University of Wisconsin, Madison, WI, 53706, United States.
Respir Physiol Neurobiol. 2018 Oct;256:21-28. doi: 10.1016/j.resp.2017.12.004. Epub 2017 Dec 9.
Although inflammation is prevalent in many clinical disorders challenging breathing, we are only beginning to understand the impact of inflammation on neural mechanisms of respiratory control. We recently demonstrated one form of respiratory motor plasticity is extremely sensitive to even mild inflammation induced by a single night (8 h) of intermittent hypoxia (IH-1), mimicking aspects of obstructive sleep apnea. Specifically, phrenic long-term facilitation (pLTF) following moderate acute intermittent hypoxia (AIH) is abolished by IH-1, but restored by high doses of the non-steroidal anti-inflammatory drug, ketoprofen. Since a major target of ketoprofen is cyclooxygenase (COX) enzymes, we tested the involvement of COX in IH-1 suppression of pLTF using the selective COX inhibitor NS-398. Systemic COX inhibition (3 mg/kg, i.p., 3 h before AIH) had no effect on pLTF in normoxia treated rats (76 ± 40% change from baseline, n = 6), and did not restore pLTF in IH-1 treated rats (-9 ± 7% baseline, n = 6). Similarly, spinal COX inhibition (27 mM, 12 μl, i.t.) had no effect on pLTF in normoxic rats (76 ± 34% baseline, n = 7), and did not significantly restore pLTF after IH-1 (37 ± 18% baseline, n = 7). COX-2 protein is expressed in identified phrenic motor neurons of both normoxia and IH-1 exposed rats, but immunolabeling was minimal in surrounding microglia; IH-1 had no discernable effect on COX-2 immunoreactivity. We conclude that the inflammatory impairment of pLTF by IH-1 is independent of COX enzyme activity or upregulated COX-2 expression.
尽管炎症在许多影响呼吸的临床疾病中普遍存在，但我们才刚刚开始了解炎症对呼吸控制神经机制的影响。我们最近证明，一种呼吸运动可塑性形式对由单次夜间（8小时）间歇性低氧（IH-1）诱导的轻度炎症极为敏感，这模拟了阻塞性睡眠呼吸暂停的某些方面。具体而言，中度急性间歇性低氧（AIH）后的膈神经长期易化（pLTF）被IH-1消除，但高剂量的非甾体抗炎药酮洛芬可使其恢复。由于酮洛芬的主要靶点是环氧化酶（COX），我们使用选择性COX抑制剂NS-398测试了COX在IH-1对pLTF的抑制中的作用。全身COX抑制（3mg/kg，腹腔注射，AIH前3小时）对常氧处理大鼠的pLTF无影响（相对于基线变化76±40%，n=6），且未恢复IH-1处理大鼠的pLTF（相对于基线-9±7%，n=6）。同样地，脊髓COX抑制（27mM，12μl，鞘内注射）对常氧大鼠的pLTF无影响（相对于基线76±34%，n=7），且在IH-1后未显著恢复pLTF（相对于基线37±18%，n=7）。COX-2蛋白在常氧和暴露于IH-1的大鼠的已鉴定膈运动神经元中均有表达，但在周围小胶质细胞中的免疫标记极少；IH-1对COX-2免疫反应性无明显影响。我们得出结论，IH-1对pLTF的炎症损害与COX酶活性或COX-2表达上调无关。
