Navarrete-Opazo A, Dougherty B J, Mitchell G S
Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA; Teletón Children Rehabilitation Institute, Alameda 4620, Santiago, Chile.
Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA.
Exp Neurol. 2017 Jan;287(Pt 2):93-101. doi: 10.1016/j.expneurol.2016.03.026. Epub 2016 Apr 11.
Daily acute intermittent hypoxia (dAIH) improves breathing capacity after C2 spinal hemisection (C2HS) in rats. Since C2HS disrupts spinal serotonergic innervation below the injury, adenosine-dependent mechanisms underlie dAIH-induced functional recovery 2weeks post-injury. We hypothesized that dAIH-induced functional recovery converts from an adenosine-dependent to a serotonin-dependent, adenosine-constrained mechanism with chronic injury. Eight weeks post-C2HS, rats began dAIH (10, 5-min episodes, 10.5% O; 5-min intervals; 7days) followed by AIH 3× per week (3×wAIH) for 8 additional weeks with/without systemic A receptor inhibition (KW6002) on each AIH exposure day. Tidal volume (V) and bilateral diaphragm (Dia) and T2 external intercostal motor activity were assessed in unanesthetized rats breathing air and during maximum chemoreflex stimulation (MCS: 7% CO, 10.5% O). Nine weeks post-C2HS, dAIH increased V versus time controls (p<0.05), an effect enhanced by KW6002 (p<0.05). dAIH increased bilateral Dia activity (p<0.05), and KW6002 enhanced this effect in contralateral (p<0.05) and ipsilateral Dia activity (p<0.001), but not T inspiratory activity. Functional benefits of combined AIH plus systemic A receptor inhibition were maintained for 4weeks. Thus, in rats with chronic injuries: 1) dAIH improves V and bilateral diaphragm activity; 2) V recovery is enhanced by A receptor inhibition; and 3) functional recovery with A2A receptor inhibition and AIH "reminders" last 4weeks. Combined dAIH and A receptor inhibition may be a simple, safe, and effective strategy to accelerate/enhance functional recovery of breathing capacity in patients with respiratory impairment from chronic spinal injury.
每日急性间歇性低氧（dAIH）可改善大鼠C2脊髓半横断（C2HS）后的呼吸能力。由于C2HS会破坏损伤平面以下的脊髓5-羟色胺能神经支配，损伤后2周，腺苷依赖性机制是dAIH诱导功能恢复的基础。我们推测，随着损伤时间延长，dAIH诱导的功能恢复会从腺苷依赖性机制转变为5-羟色胺依赖性、腺苷受限机制。C2HS术后8周，大鼠开始接受dAIH（10次，每次5分钟，10.5%氧气；间隔5分钟；共7天），随后每周进行3次间歇性低氧（3×wAIH），持续8周，在每次AIH暴露日给予或不给予全身性A2A受体抑制（KW6002）。在未麻醉且呼吸空气的大鼠以及最大化学反射刺激（MCS：7%二氧化碳，10.5%氧气）期间，评估潮气量（V）、双侧膈肌（Dia）和T2肋间外肌运动活性。C2HS术后9周，与时间对照组相比，dAIH增加了V（p<0.05），KW6002增强了这一效应（p<0.05）。dAIH增加了双侧Dia活性（p<0.05），KW6002增强了对侧（p<0.05）和同侧Dia活性（p<0.001）的这一效应，但对T吸气活性无影响。联合AIH加全身性A2A受体抑制的功能益处持续了4周。因此，在慢性损伤大鼠中：1）dAIH改善了V和双侧膈肌活性；2）A2A受体抑制增强了V恢复；3）A2A受体抑制和AIH“强化”的功能恢复持续4周。联合dAIH和A2A受体抑制可能是一种简单、安全且有效的策略，可加速/增强慢性脊髓损伤所致呼吸功能障碍患者呼吸能力的功能恢复。
