Brain Advance Access originally published online on October 28, 2006
Brain 2006 129(12):3249-3269; doi:10.1093/brain/awl296
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The cellular inflammatory response in human spinal cords after injury
1 BioTherapeutics Research Group, Robarts Research Institute London, Ontario, Canada 2 Graduate Program in Neuroscience, London Health Sciences Centre and University of Western Ontario London, Ontario, Canada 3 Departments of Pathology and Clinical Neurological Sciences, London Health Sciences Centre and University of Western Ontario London, Ontario, Canada 4 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine and Miami Veterans Affairs Medical Center Miami, FL, USA 5 Department of Pathology, The University of Miami Miller School of Medicine and Miami Veterans Affairs Medical Center Miami, FL, USA
Correspondence to: Dr Lynne C. Weaver, Spinal Cord Injury Laboratory, BioTherapeutics Research Group, Robarts Research Institute, 100 Perth Drive, PO Box 5015, London, Ontario, Canada N6A 5K8 E-mail: lcweaver{at}robarts.ca
Spinal cord injury (SCI) provokes an inflammatory response that generates substantial secondary damage within the cord but also may contribute to its repair. Anti-inflammatory treatment of human SCI and its timing must be based on knowledge of the types of cells participating in the inflammatory response, the time after injury when they appear and then decrease in number, and the nature of their actions. Using post-mortem spinal cords, we evaluated the time course and distribution of pathological change, infiltrating neutrophils, monocytes/macrophages and lymphocytes, and microglial activation in injured spinal cords from patients who were ‘dead at the scene’ or who survived for intervals up to 1 year after SCI. SCI caused zones of pathological change, including areas of inflammation and necrosis in the acute cases, and cystic cavities with longer survival (Zone 1), mantles of less severe change, including axonal swellings, inflammation and Wallerian degeneration (Zone 2) and histologically intact areas (Zone 3). Zone 1 areas increased in size with time after injury whereas the overall injury (size of the Zones 1 and 2 combined) remained relatively constant from the time (1–3 days) when damage was first visible. The distribution of inflammatory cells correlated well with the location of Zone 1, and sometimes of Zone 2. Neutrophils, visualized by their expression of human neutrophil 
-defensins (defensin), entered the spinal cord by haemorrhage or extravasation, were most numerous 1–3 days after SCI, and were detectable for up to 10 days after SCI. Significant numbers of activated CD68-immunoreactive ramified microglia and a few monocytes/macrophages were in injured tissue within 1–3 days of SCI. Activated microglia, a few monocytes/macrophages and numerous phagocytic macrophages were present for weeks to months after SCI. A few CD8+ lymphocytes were in the injured cords throughout the sampling intervals. Expression by the inflammatory cells of the oxidative enzymes myeloperoxidase (MPO) and nicotinamide adenine dinucleotide phosphate oxidase (gp91phox), and of the pro-inflammatory matrix metalloproteinase (MMP)-9, was analysed to determine their potential to cause oxidative and proteolytic damage. Oxidative activity, inferred from MPO and gp91phox immunoreactivity, was primarily associated with neutrophils and activated microglia. Phagocytic macrophages had weak or no expression of MPO or gp91phox. Only neutrophils expressed MMP-9. These data indicate that potentially destructive neutrophils and activated microglia, replete with oxidative and proteolytic enzymes, appear within the first few days of SCI, suggesting that anti-inflammatory ‘neuroprotective’ strategies should be directed at preventing early neutrophil influx and modifying microglial activation.
Key Words: inflammation; macrophage; neutrophil; oxidative activity; SCI
Abbreviations: ß-APP, ß-amyloid precursor protein; H & E, haematoxylin and eosin; H & E/LFB, combined H & E and Luxol fast blue; MMP, matrix metalloproteinase; MPO, myeloperoxidase; NADPH, nicotinamide adenine dinucleotide phosphate; SCI, spinal cord injury
Received January 9, 2006. Revised September 15, 2006. Accepted September 19, 2006.
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