Abstract
The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68+/CD163- macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163- macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-alpha, IL-1beta, IFN-gamma and other pro-inflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation.
Highlights
Spinal cord injury (SCI) is a leading cause of long term morbidity after motor vehicle accidents or trauma in combat, with no clinically standardized or substantially effective treatment
In this systematic study on the progression of SCI in the rat model we determined that a localized neurotrauma initiates two types of severe, destructive inflammatory response; the cavity of injury (COI) that progresses to a syrinx deep in the spinal cord and arachnoiditis at the Inflammation in spinal cord injury surface that becomes a scar
Since arachnoiditis progresses from a granulomatous infiltration to a mature scar and does not contain astrocytes or other glial cells, we identify this as a distinct pathology different from the commonly described “glial scar” [39]
Summary
Spinal cord injury (SCI) is a leading cause of long term morbidity after motor vehicle accidents or trauma in combat, with no clinically standardized or substantially effective treatment. In a previous long term, systematic study addressing inflammation after SCI [1] the role of invasive inflammatory cells and astrogliosis in the ongoing damage after SCI is not well defined in SCI damage [2,3] as well as a proposed potential protective role for astrocytes [4]. Pro-inflammatory cytokines such as interleukins 1beta (IL1beta) and 6 (IL6) as well as tumor necrosis factor alpha (TNF-alpha) and interferon gamma (IFN-gamma) [7,8,9], CC, CXC and CX3C chemokines [10] and matrix metalloproteinase 8 [11] are reported to be elevated after SCI, actively promoting severe inflammation. In a recent systematic study up to 8 weeks post-SCI, plasma levels of VEGF, leptin, IP10, IL18, GCSF, and fractalkine were measured and their changing levels reported [12] but the relevance of these changes to the pathogenesis of SCI remains unclear
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