Level-Specific Differences in Systemic Expression of Pro- and Anti-Inflammatory Cytokines and Chemokines after Spinal Cord Injury.

James Hong,Yang Liu,Michael Fehlings,Jian Wang,Alex Chang,Mohammad-Masoud Zavvarian

doi:10.3390/ijms19082167

Abstract

While over half of all spinal cord injuries (SCIs) occur in the cervical region, the majority of preclinical studies have focused on models of thoracic injury. However, these two levels are anatomically distinct—with the cervical region possessing a greater vascular supply, grey-white matter ratio and sympathetic outflow relative to the thoracic region. As such, there exists a significant knowledge gap in the secondary pathology at these levels following SCI. In this study, we characterized the systemic plasma markers of inflammation over time (1, 3, 7, 14, 56 days post-SCI) after moderate-severe, clip-compression cervical and thoracic SCI in a rat model. Using high-throughput ELISA panels, we observed a clear level-specific difference in plasma levels of VEGF, leptin, IP10, IL18, GCSF, and fractalkine. Overall, cervical SCI had reduced expression of both pro- and anti-inflammatory proteins relative to thoracic SCI, likely due to sympathetic dysregulation associated with higher level SCIs. However, contrary to the literature, we did not observe level-dependent splenic atrophy with our incomplete SCI model. This is the first study to compare the systemic plasma-level changes following cervical and thoracic SCI using level-matched and time-matched controls. The results of this study provide the first evidence in support of level-targeted intervention and also challenge the phenomenon of high SCI-induced splenic atrophy in incomplete SCI models.

Highlights

Traumatic spinal cord injury (SCI)—despite breakthroughs in pre-operative, surgical and post-operative care—continues to be a life-threatening injury, both acutely and chronically [1]
While it is difficult to determine the causative mechanism of secondary injury, several mechanisms including vascular disruption [4], glutamate excitoxicity [5,6], lipid peroxidation [7,8,9], blood-spinal-cord-barrier disruption [10,11,12] and ionic imbalance [13,14] have been the focus of therapeutic targeting
To investigate whether there were baseline differences in the expression of any of these proteins after cervical and thoracic laminectomy, heat-mapping and statistical analyses of protein concentrations were carried out with naïve plasma shown as a reference

Summary

Introduction

Traumatic spinal cord injury (SCI)—despite breakthroughs in pre-operative, surgical and post-operative care—continues to be a life-threatening injury, both acutely and chronically [1]. A central rationale for investigating cSCI models is the appreciation that critical anatomical differences exist between the cervical and thoracic spinal cord resulting in different pathophysiological responses to injury and treatment [16]. In high-thoracic transection models of SCI, removal of spinal sympathetic preganglionic neurons from supraspinal control results in autonomic dysreflexia [17]. This in turn has been shown to instigate immunosuppressive effects—known as SCI-induced immune depression syndrome (SCI-IDS)—that stem directly from early splenocyte death and splenic atrophy due to acute and repeated chronic exposure to glucocorticoids and intrasplenic norepinephrine [18]

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