Prolonged inflammation leads to ongoing damage after spinal cord injury

Abstract

27The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains 28 limited. Emerging evidence indicates the severity of post-SCI inflammation and an ongoing 29 controversy in the roles of astrocytes with studies identifying astrocytes as associated both with 30 ongoing inflammation and damage as well as potentially having a protective role. We have 31 completed an extensive systematic study with MRI, histopathology, proteomics and ELISA 32 analyses designed to further define the severe protracted and damaging inflammation after SCI in 33 a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting 34 day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68 + /CD163 -35 macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) 36 when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous 37 tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163macrophage 38 numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present 39 at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by 40 a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord 41 edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around 42 the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. 43Acutely increased levels of TNF-, IL-1, IFN- and other pro-inflammatory cytokines, 44 chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In 45 this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have 46 demonstrated a close association between progressive astrogliosis and reduction in the severity of 47 inflammation. 48 4 49 50 KEYWORDS 51 Neurotrauma inflammation, cavity of injury, arachnoiditis, M1 macrophage, astrogliosis. 5 52 53Spinal cord injury (SCI) is a leading cause of long term morbidity after motor vehicle 54 accidents or trauma in combat, with no clinically standardized or substantially effective treatment. 55Effective therapeutics have remained limited due to an incomplete understanding of the 56 pathogenesis of SCI and thus identified effective therapeutic targets while the underlying and 57 persistent inflammatory damage after SCI remains poorly characterized. The role of invasive 58 inflammatory cells and specifically astrogliosis in the ongoing damage after SCI is not fully 59 defined with studies supporting both a role in SCI damage [1,2] as well as a proposed potential 60 protective role for astrocytes [3]. We have completed an extensive analysis with MRI, 61 histochemistry, proteomics and ELISA in a rat model of SCI in order to further define the 62 pathological changes that occur after SCI. 63 SCI initiates hemorrhage and ischemia, free radical release, severe inflammation,...

Early decompression promotes motor recovery after cervical spinal cord injury in rats with chronic cervical spinal cord compression

“…It has been reported that prolonged in ammation leads to ongoing damage after spinal cord injury. [12] In a comparison of the three groups, although the immediate decompression group showed the most rapid functional improvement, there was no signi cant difference between the subacute decompression group and the immediate decompression group by four weeks. Clinically, in patients with mild to moderate spinal cord injury, the results suggest that decompression itself may lead to improvement in motor function, regardless of the timing of decompression surgery.…”

AC-YVAD-CMK Inhibits Caspase-1-mediated Imflammatory Response to Improve Bone Marrow Stromal Cells on Neuroprotection After Sci in Rats

“…As we all know, it has been reported that the mechanism of SCI is very complex, including in ammation reaction, the less nurotrophic factors and neurons lost within the lesion site, which may inhibit axonal regrowth [29]. In ammation is one of the main mechanisms after the acute SCI [30,31]. Meanwhile, previous studies have revealed that caspase-1 appeared to play a role in tissue injury by participating in the in ammatory pathways [32].…”

Escalate and De-Escalate Therapies for Intracranial Pressure Control in Traumatic Brain Injury

“…Three main paths for evacuation of excess fluid from acute cerebral edema have been identified in animal models: (1) via the glia limitans externa to the subarachnoid space, (2) via the glia limitans interna and ependyma to the ventricles/central canal, and (3) via the BBB into the lumen of blood vessels ( 26 ). Fluid is also lost into the site of injury, which is converted into a “cavity of injury” ( 27 ). Recent research has confirmed that excess edema fluid leaves the brain through an integrated system of astrocytes which overexpress acquaporin-4 (AQP4) ( 28 – 30 ).…”