Stokes Jennifer A, Arbogast Tara E, Moya Esteban A, Fu Zhenxing, Powell Frank L
Division of Physiology, Department of Medicine; University of California, San Diego, La Jolla, California
Division of Physiology, Department of Medicine; University of California, San Diego, La Jolla, California.
J Neurophysiol. 2017 Apr 1;117(4):1625-1635. doi: 10.1152/jn.00525.2016. Epub 2017 Jan 18.
Ventilatory acclimatization to hypoxia (VAH) is the time-dependent increase in ventilation, which persists upon return to normoxia and involves plasticity in both central nervous system respiratory centers and peripheral chemoreceptors. We investigated the role of glial cells in VAH in male Sprague-Dawley rats using minocycline, an antibiotic that inhibits microglia activation and has anti-inflammatory properties, and barometric pressure plethysmography to measure ventilation. Rats received either minocycline (45mg/kg ip daily) or saline beginning 1 day before and during 7 days of chronic hypoxia (CH, Pi = 70 Torr). Minocycline had no effect on normoxic control rats or the hypercapnic ventilatory response in CH rats, but minocycline significantly ( < 0.001) decreased ventilation during acute hypoxia in CH rats. However, minocycline administration during only the last 3 days of CH did not reverse VAH. Microglia and astrocyte activation in the nucleus tractus solitarius was quantified from 30 min to 7 days of CH. Microglia showed an active morphology (shorter and fewer branches) after 1 h of hypoxia and returned to the control state (longer filaments and extensive branching) after 4 h of CH. Astrocytes increased glial fibrillary acidic protein antibody immunofluorescent intensity, indicating activation, at both 4 and 24 h of CH. Minocycline had no effect on glia in normoxia but significantly decreased microglia activation at 1 h of CH and astrocyte activation at 24 h of CH. These results support a role for glial cells, providing an early signal for the induction but not maintenance of neural plasticity underlying ventilatory acclimatization to hypoxia. The signals for neural plasticity in medullary respiratory centers underlying ventilatory acclimatization to chronic hypoxia are unknown. We show that chronic hypoxia activates microglia and subsequently astrocytes. Minocycline, an antibiotic that blocks microglial activation and has anti-inflammatory properties, also blocks astrocyte activation in respiratory centers during chronic hypoxia and ventilatory acclimatization. However, minocycline cannot reverse ventilatory acclimatization after it is established. Hence, glial cells may provide signals that initiate but do not sustain ventilatory acclimatization.
低氧通气适应（VAH）是指通气随时间增加，在恢复常氧后仍持续存在，且涉及中枢神经系统呼吸中枢和外周化学感受器的可塑性。我们使用米诺环素（一种抑制小胶质细胞活化且具有抗炎特性的抗生素）和气压容积描记法来测量通气，研究了雄性Sprague-Dawley大鼠中胶质细胞在VAH中的作用。大鼠在慢性低氧（CH，Pi = 70 Torr）的前1天及7天期间，每天腹腔注射米诺环素（45mg/kg）或生理盐水。米诺环素对常氧对照大鼠或CH大鼠的高碳酸通气反应没有影响，但米诺环素显著（<0.001）降低了CH大鼠急性低氧期间的通气。然而，仅在CH的最后3天给予米诺环素并不能逆转VAH。在CH的30分钟至7天内，对孤束核中的小胶质细胞和星形胶质细胞活化进行了定量。低氧1小时后，小胶质细胞呈现活跃形态（分支更短且更少），CH 4小时后恢复到对照状态（细丝更长且分支广泛）。在CH的4小时和24小时，星形胶质细胞的胶质纤维酸性蛋白抗体免疫荧光强度增加，表明活化。米诺环素在常氧条件下对胶质细胞没有影响，但在CH 1小时时显著降低小胶质细胞活化，在CH 24小时时显著降低星形胶质细胞活化。这些结果支持胶质细胞的作用，为低氧通气适应潜在的神经可塑性诱导而非维持提供早期信号。慢性低氧通气适应潜在的延髓呼吸中枢神经可塑性信号尚不清楚。我们表明慢性低氧激活小胶质细胞，随后激活星形胶质细胞。米诺环素是一种阻断小胶质细胞活化且具有抗炎特性的抗生素，在慢性低氧和通气适应期间，它也能阻断呼吸中枢中的星形胶质细胞活化。然而，米诺环素在通气适应建立后无法逆转它。因此，胶质细胞可能提供启动但不维持通气适应的信号。
