The cellular inflammatory response in human spinal cords after injury.
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 alpha-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 (gp91(phox)), 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 gp91(phox) immunoreactivity, was primarily associated with neutrophils and activated microglia. Phagocytic macrophages had weak or no expression of MPO or gp91(phox). 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.
Fleming
Jennifer C
JC
BioTherapeutics Research Group, Robarts Research Institute, London, Ontario, Canada.
Norenberg
Michael D
MD
Ramsay
David A
DA
Dekaban
Gregory A
GA
Marcillo
Alexander E
AE
Saenz
Alvaro D
AD
Pasquale-Styles
Melissa
M
Dietrich
W Dalton
WD
Weaver
Lynne C
LC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D002648:Child; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D017628:Microglia / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000032:analysis; D009336:Necrosis; D009504:Neutrophils / Q000276:immunology; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000032:analysis; D013116:Spinal Cord / Q000276:immunology* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D020780:Matrix Metalloproteinase 9; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D009195:Peroxidase; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C056558:CYBB protein, human