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. 2014 Sep 15;31(18):1561-9.
doi: 10.1089/neu.2014.3405. Epub 2014 Jul 8.

Cerebrospinal fluid inflammatory cytokines and chemokines in naturally occurring canine spinal cord injury

Amanda R Taylor  1 , C Jane Welsh, Colin Young, Erich Spoor, Sharon C Kerwin, John F Griffin, Gwendolyn J Levine, Noah D Cohen, Jonathan M Levine
Affiliations

Cerebrospinal fluid inflammatory cytokines and chemokines in naturally occurring canine spinal cord injury

Amanda R Taylor et al. J Neurotrauma. .

Abstract

Canine intervertebral disk herniation (IVDH) is a common, naturally occurring form of spinal cord injury (SCI) that is increasingly being used in pre-clinical evaluation of therapies. Although IVDH bears critical similarities to human SCI with respect to lesion morphology, imaging features, and post-SCI treatment, limited data are available concerning secondary injury mechanisms. Here, we characterized cerebrospinal fluid (CSF) cytokines, and chemokines in dogs with acute, surgically treated, thoracolumbar IVDH (n=39) and healthy control dogs (n=21) to investigate early inflammatory events after SCI. A bioplex system was used to measure interleukin (IL)-2, -6, -7, -8, -10, -15, and -18, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-γ), keratinocyte chemoattractant (KC)-like protein, IFN-γ-inducible protein-10, monocyte chemotactic protein 1 (MCP-1), and tumor necrosis factor alpha. Cytokine and chemokine concentrations in the CSF of healthy and SCI dogs were compared and, in SCI dogs, were correlated to the duration of SCI, behavioral measures of injury severity at the time of sampling, and neurological outcome 42 days post-SCI as determined by a validated ordinal score. IL-8 concentration was significantly higher in SCI cases than healthy controls (p=0.0013) and was negatively correlated with the duration of SCI (p=0.042). CSF MCP-1 and KC-like protein were positively correlated with CSF microprotein concentration in dogs with SCI (p<0.0001 and p=0.004). CSF MCP-1 concentration was negatively associated with 42-day postinjury outcome (p<0.0001). Taken together, these data indicate that cytokines and chemokines present after SCI in humans and rodent models are associated with SCI pathogenesis in canine IVDH.

Keywords: inflammation; models of injury; neural injury.

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Figures

<b>FIG. 1.</b>
FIG. 1.
Box-and-whiskers plots summarizing IL-8 (A), IL-18 (B), and IP-10 (C) concentrations in the cerebrospinal fluid of 39 dogs with SCI and 21 healthy control dogs. IL-8 concentration was significantly higher (p=0.0013) in dogs with SCI, compared to healthy dogs. IL-18 and IP-10 concentrations were both significantly lower in dogs with SCI, compared to healthy dogs (p=0.0066 for both). Comparisons were made using Wilcoxon's rank-sum tests with adjustments for multiple comparisons using the method of Hochberg. IL, interleukin; IP-10, interferon-gamma-inducible protein-10; SCI, spinal cord injury.
<b>FIG. 2.</b>
FIG. 2.
Scatter plot of cerebrospinal fluid concentration of IL-8 among 39 dogs with spinal cord injury, demonstrating a significant (p=0.042; regression coefficient=−0.0040; R2=0.144 by generalized linear model) negative association of IL-8 concentration with duration of injury at the time of sample acquisition. IL, interleukin.
<b>FIG. 3.</b>
FIG. 3.
Scatter plots of log10-transformed cerebrospinal fluid (CSF) concentrations of KC-like protein (A) and MCP-1 (B) versus CSF microprotein concentration in 39 dogs with spinal cord injury. The concentration of CSF microprotein was significantly and positively correlated (p=0.0044; regression coefficient=1.012; R2=0.27) with CSF KC-like protein concentration by generalized linear modeling. CSF microprotein concentration was also positively correlated with CSF MCP-1 concentration (p<0.0001; regression coefficient=1.537; R2=l 0.46), using a generalized linear model. MCP-1, monocyte chemotactic protein 1; KC, keratinocyte chemoattractant.
<b>FIG. 4.</b>
FIG. 4.
Scatter plot of log10-transformed cerebrospinal fluid (CSF) MCP-1 concentration versus CSF red blood cell (RBC) concentration in 39 dogs with spinal cord injury. The CSF RBC was significantly and positively correlated with CSF MCP-1 concentration (p<0.0001; regression coefficient=0.292; R2=0.37) using generalized linear modeling. MCP-1, monocyte chemotactic protein 1.
<b>FIG. 5.</b>
FIG. 5.
Scatter plot of log10-transformed values of MCP-1 concentrations in the cerebrospinal fluid (CSF) versus TSCIS (a validated behavioral measure of spinal cord injury severity) on day 42 postinjury in 39 dogs with intervertebral disk herniation. There was a significant negative association between CSF MCP-1 concentration at admission and TSCIS on day 42 (p<0.0001; R2=0.36) using generalized linear modeling. The slope of the solid line is the regression coefficient estimated from the generalized linear model, and dotted lines are the 95% confidence intervals. TSCIS, The Texas Spinal Cord Injury Score; MCP-1, monocyte chemotactic protein 1.
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