title: Dominance of chemokine ligand 2 and matrix metalloproteinase-2 and -9 and suppression of pro-inflammatory cytokines in the epidural compartment after intervertebral disc extrusion in a canine model.
abstract: BACKGROUND
  In canine intervertebral disc (IVD) disease, a useful animal model, only little is known about the inflammatory response in the epidural space.
  
  
  OBJECTIVE
  To determine messenger RNA (mRNA) expressions of selected cytokines, chemokines, and matrix metalloproteinases (MMPs) qualitatively and semiquantitatively over the course of the disease and to correlate results to neurologic status and outcome.
  
  
  METHODS
  Prospective study using extruded IVD material of dogs with thoracolumbar IVD extrusion.
  
  
  METHODS
  Seventy affected and 13 control (24 samples) dogs.
  
  
  METHODS
  Duration of neurologic signs, pretreatment, neurologic grade, severity of pain, and outcome were recorded. After diagnostic imaging, decompressive surgery was performed.
  
  
  METHODS
  Messenger RNA expressions of interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor (TNF), interferon (IFN)γ, MMP-2, MMP-9, chemokine ligand (CCL)2, CCL3, and three housekeeping genes was determined in the collected epidural material by Panomics 2.0 QuantiGene Plex technology. Relative mRNA expression and fold changes were calculated. Relative mRNA expression was correlated statistically to clinical parameters.
  
  
  RESULTS
  Fold changes of TNF, IL-1β, IL-2, IL-4, IL-6, IL-10, IFNγ, and CCL3 were clearly downregulated in all stages of the disease. MMP-9 was downregulated in the acute stage and upregulated in the subacute and chronic phase. Interleukin-8 was upregulated in acute cases. MMP-2 showed mild and CCL2 strong upregulation over the whole course of the disease. In dogs with severe pain, CCL3 and IFNγ were significantly higher compared with dogs without pain (p=.017/.020). Dogs pretreated with nonsteroidal anti-inflammatory drugs revealed significantly lower mRNA expression of IL-8 (p=.017).
  
  
  CONCLUSIONS
  The high CCL2 levels and upregulated MMPs combined with downregulated T-cell cytokines and suppressed pro-inflammatory genes in extruded canine disc material indicate that the epidural reaction is dominated by infiltrating monocytes differentiating into macrophages with tissue remodeling functions. These results will help to understand the pathogenic processes representing the basis for novel therapeutic approaches. The canine IVD disease model will be rewarding in this process.
authors.affiliation: Division of Neurological Sciences, Department of Clinical Veterinary Neurology, Vetsuisse Faculty, University of Bern, Länggassstrasse 128, Bern CH-3001, Switzerland. Electronic address: philemon.karli@vetsuisse.unibe.ch.
authors.forename: Philemon
authors.initials: P
authors.lastname: Karli
authors.affiliation: Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
authors.forename: Valentine
authors.initials: V
authors.lastname: Martlé
authors.affiliation: Department of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium.
authors.forename: Kenny
authors.initials: K
authors.lastname: Bossens
authors.affiliation: Research Department, Institute of Virology and Immunoprophylaxis (IVI), Sensemattstrasse 293, 3147 Mittelhäusern, Switzerland.
authors.forename: Artur
authors.initials: A
authors.lastname: Summerfield
authors.affiliation: Department of Clinical Research and Veterinary Public Health, Vetsuisse Faculty, University of Bern, Länggassstrasse 128, Bern CH-3001, Switzerland.
authors.forename: Marcus G
authors.initials: MG
authors.lastname: Doherr
authors.affiliation: Affymetrix UK Ltd, Voyager, Mercury Park, Wycombe Lane, Wooburn Green, High Wycombe HP10 0HH, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Turner
authors.affiliation: Division of Neurological Sciences, Department of Clinical Veterinary Neurology, Vetsuisse Faculty, University of Bern, Länggassstrasse 128, Bern CH-3001, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Vandevelde
authors.affiliation: Division of Clinical Surgery, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Länggassstrasse 128, Bern CH-3001, Switzerland.
authors.forename: Franck
authors.initials: F
authors.lastname: Forterre
authors.affiliation: Division of Neurological Sciences, Department of Clinical Veterinary Neurology, Vetsuisse Faculty, University of Bern, Länggassstrasse 128, Bern CH-3001, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Henke
mesh_terms: D000818:Animals; D054426:Chemokine CXCL2 / Q000134:cerebrospinal fluid*; D019299:Decompression, Surgical; D004195:Disease Models, Animal; D004285:Dogs; D004824:Epidural Space / Q000378:metabolism; D005260:Female; D053583:Interleukin-1beta / Q000134:cerebrospinal fluid; D016209:Interleukin-8 / Q000134:cerebrospinal fluid; D055959:Intervertebral Disc Degeneration / Q000134:cerebrospinal fluid* / Q000601:surgery*; D007405:Intervertebral Disc Displacement / Q000134:cerebrospinal fluid* / Q000601:surgery*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000134:cerebrospinal fluid*; D020780:Matrix Metalloproteinase 9 / Q000134:cerebrospinal fluid*; D012333:RNA, Messenger / Q000134:cerebrospinal fluid; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid
chemical_list: D054426:Chemokine CXCL2; D053583:Interleukin-1beta; D016209:Interleukin-8; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: CCL2; Epidural space; IL-8; MCP-1; MMP; Microarray