Abstract
BackgroundSpinal cord injury (SCI) induces secondary tissue damage that is associated with inflammation. We have previously demonstrated that inflammation-related gene expression after SCI occurs in two waves - an initial cluster that is acutely and transiently up-regulated within 24 hours, and a more delayed cluster that peaks between 72 hours and 7 days. Here we extend the microarray analysis of these gene clusters up to 6 months post-SCI.MethodsAdult male rats were subjected to mild, moderate or severe spinal cord contusion injury at T9 using a well-characterized weight-drop model. Tissue from the lesion epicenter was obtained 4 hours, 24 hours, 7 days, 28 days, 3 months or 6 months post-injury and processed for microarray analysis and protein expression.ResultsAnchor gene analysis using C1qB revealed a cluster of genes that showed elevated expression through 6 months post-injury, including galectin-3, p22PHOX, gp91PHOX, CD53 and progranulin. The expression of these genes occurred primarily in microglia/macrophage cells and was confirmed at the protein level using both immunohistochemistry and western blotting. As p22PHOX and gp91PHOX are components of the NADPH oxidase enzyme, enzymatic activity and its role in SCI were assessed and NADPH oxidase activity was found to be significantly up-regulated through 6 months post-injury. Further, treating rats with the nonspecific, irreversible NADPH oxidase inhibitor diphenylene iodinium (DPI) reduced both lesion volume and expression of chronic gene cluster proteins one month after trauma.ConclusionsThese data demonstrate that inflammation-related genes are chronically up-regulated after SCI and may contribute to further tissue loss.
Highlights
Spinal cord injury (SCI) induces secondary tissue damage that is associated with inflammation
We have shown that genes associated with inflammation, including those expressed primarily by microglia/ macrophages, are strongly up-regulated immediately after injury and remain up-regulated for at least 7 days [15]
Popovich et al [16] has demonstrated that areas of blood-spinal cord barrier permeability 14 to 28 days post-injury are associated with OX42 labeling, suggesting extensive monocytic activity at delayed time points post-injury
Summary
Spinal cord injury (SCI) induces secondary tissue damage that is associated with inflammation. Spinal cord injury (SCI) is followed by delayed secondary damage that occurs for days, weeks and even months following the initial insult [1,2]. Inflammation, including the activation and migration of microglia and macrophages, plays a significant role in this secondary injury [3,4,5,6,7,8,9]. We have shown that genes associated with inflammation, including those expressed primarily by microglia/ macrophages, are strongly up-regulated immediately after injury and remain up-regulated for at least 7 days [15]. Popovich et al [16] has demonstrated that areas of blood-spinal cord barrier permeability 14 to 28 days post-injury are associated with OX42 (microglia/ macrophage) labeling, suggesting extensive monocytic activity at delayed time points post-injury
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