Daily Acute Intermittent Hypoxia Improves Breathing Function with Acute and Chronic Spinal Injury Via Distinct Mechanisms

Overview

Journal Respir Physiol Neurobiol

Specialty Pulmonary Medicine

Date 2017 May 28

PMID 28549897

Citations 25

Authors

B J Dougherty

J Terada

S R Springborn

S Vinit

P M MacFarlane

G S Mitchell

Affiliations

Soon will be listed here.

Abstract

Daily acute intermittent hypoxia (dAIH) elicits respiratory plasticity, enhancing respiratory motor output and restoring breathing capacity after incomplete cervical spinal injuries (cSCI). We hypothesized that dAIH-induced functional recovery of breathing capacity would occur after both acute (2 weeks) and chronic (8 weeks) cSCI, but through distinct cellular mechanisms. Specifically, we hypothesized that dAIH-induced breathing recovery would occur through serotonin-independent mechanisms 2wks post C2 cervical hemisection (C2Hs), versus serotonin-dependent mechanisms 8wks post C2Hs. In two independent studies, dAIH or sham (normoxia) was initiated 1 week (Study 1) or 7 weeks (Study 2) post-C2Hs to test our hypothesis. Rats were pre-treated with intra-peritoneal vehicle or methysergide, a broad-spectrum serotonin receptor antagonist, to determine the role of serotonin signaling in dAIH-induced functional recovery. Our data support the hypothesis that dAIH-induced recovery of breathing capacity transitions from a serotonin-independent mechanism with acute C2Hs to a serotonin-dependent mechanism with chronic C2Hs. An understanding of shifting mechanisms giving rise to dAIH-induced respiratory motor plasticity is vital for clinical translation of dAIH as a therapeutic modality.

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References

Zhou S, Goshgarian H . 5-Hydroxytryptophan-induced respiratory recovery after cervical spinal cord hemisection in rats. J Appl Physiol (1985). 2000; 89(4):1528-36. DOI: 10.1152/jappl.2000.89.4.1528. View

Saruhashi Y, Young W, Perkins R . The recovery of 5-HT immunoreactivity in lumbosacral spinal cord and locomotor function after thoracic hemisection. Exp Neurol. 1996; 139(2):203-13. DOI: 10.1006/exnr.1996.0094. View

Fuller D, Zabka A, Baker T, Mitchell G . Phrenic long-term facilitation requires 5-HT receptor activation during but not following episodic hypoxia. J Appl Physiol (1985). 2001; 90(5):2001-6; discussion 2000. DOI: 10.1152/jappl.2001.90.5.2001. View

Zimmer M, Goshgarian H . Spinal activation of serotonin 1A receptors enhances latent respiratory activity after spinal cord injury. J Spinal Cord Med. 2006; 29(2):147-55. PMC: 1864797. DOI: 10.1080/10790268.2006.11753868. View

Fuller D, Doperalski N, Dougherty B, Sandhu M, Bolser D, Reier P . Modest spontaneous recovery of ventilation following chronic high cervical hemisection in rats. Exp Neurol. 2008; 211(1):97-106. PMC: 2613014. DOI: 10.1016/j.expneurol.2008.01.013. View

Hoffman M, Mitchell G . Spinal 5-HT7 receptors and protein kinase A constrain intermittent hypoxia-induced phrenic long-term facilitation. Neuroscience. 2013; 250:632-43. PMC: 3833466. DOI: 10.1016/j.neuroscience.2013.06.068. View

Baker-Herman T, Mitchell G . Phrenic long-term facilitation requires spinal serotonin receptor activation and protein synthesis. J Neurosci. 2002; 22(14):6239-46. PMC: 6757927. DOI: 20026595. View

Lovett-Barr M, Satriotomo I, Muir G, Wilkerson J, Hoffman M, Vinit S . Repetitive intermittent hypoxia induces respiratory and somatic motor recovery after chronic cervical spinal injury. J Neurosci. 2012; 32(11):3591-600. PMC: 3349282. DOI: 10.1523/JNEUROSCI.2908-11.2012. View

Zhou S, Goshgarian H . Effects of serotonin on crossed phrenic nerve activity in cervical spinal cord hemisected rats. Exp Neurol. 2000; 160(2):446-53. DOI: 10.1006/exnr.1999.7213. View

10.

Hayes H, Jayaraman A, Herrmann M, Mitchell G, Rymer W, Trumbower R . Daily intermittent hypoxia enhances walking after chronic spinal cord injury: a randomized trial. Neurology. 2013; 82(2):104-13. PMC: 3897437. DOI: 10.1212/01.WNL.0000437416.34298.43. View

11.

Sandhu M, Dougherty B, Lane M, Bolser D, Kirkwood P, Reier P . Respiratory recovery following high cervical hemisection. Respir Physiol Neurobiol. 2009; 169(2):94-101. PMC: 2783827. DOI: 10.1016/j.resp.2009.06.014. View

12.

Hsu S, Lee K . Effects of serotonergic agents on respiratory recovery after cervical spinal injury. J Appl Physiol (1985). 2015; 119(10):1075-87. DOI: 10.1152/japplphysiol.00329.2015. View

13.

Dale E, Ben Mabrouk F, Mitchell G . Unexpected benefits of intermittent hypoxia: enhanced respiratory and nonrespiratory motor function. Physiology (Bethesda). 2014; 29(1):39-48. PMC: 4073945. DOI: 10.1152/physiol.00012.2013. View

14.

Devinney M, Huxtable A, Nichols N, Mitchell G . Hypoxia-induced phrenic long-term facilitation: emergent properties. Ann N Y Acad Sci. 2013; 1279:143-53. PMC: 3880582. DOI: 10.1111/nyas.12085. View

15.

Huxtable A, Vinit S, Windelborn J, Crader S, Guenther C, Watters J . Systemic inflammation impairs respiratory chemoreflexes and plasticity. Respir Physiol Neurobiol. 2011; 178(3):482-9. PMC: 3172820. DOI: 10.1016/j.resp.2011.06.017. View

16.

Devinney M, Fields D, Huxtable A, Peterson T, Dale E, Mitchell G . Phrenic long-term facilitation requires PKCθ activity within phrenic motor neurons. J Neurosci. 2015; 35(21):8107-17. PMC: 4444536. DOI: 10.1523/JNEUROSCI.5086-14.2015. View

17.

Baker-Herman T, Bavis R, Dahlberg J, Mitchell A, Wilkerson J, Golder F . Differential expression of respiratory long-term facilitation among inbred rat strains. Respir Physiol Neurobiol. 2009; 170(3):260-7. PMC: 2844459. DOI: 10.1016/j.resp.2009.12.008. View

18.

Fuller D, Baker T, Behan M, Mitchell G . Expression of hypoglossal long-term facilitation differs between substrains of Sprague-Dawley rat. Physiol Genomics. 2001; 4(3):175-81. DOI: 10.1152/physiolgenomics.2001.4.3.175. View

19.

Hoffman M, Nichols N, MacFarlane P, Mitchell G . Phrenic long-term facilitation after acute intermittent hypoxia requires spinal ERK activation but not TrkB synthesis. J Appl Physiol (1985). 2012; 113(8):1184-93. PMC: 3472488. DOI: 10.1152/japplphysiol.00098.2012. View

20.

Doperalski N, Sandhu M, Bavis R, Reier P, Fuller D . Ventilation and phrenic output following high cervical spinal hemisection in male vs. female rats. Respir Physiol Neurobiol. 2008; 162(2):160-7. PMC: 2605649. DOI: 10.1016/j.resp.2008.06.005. View