Longitudinal measurements of syrinx size in a rat model of posttraumatic syringomyelia

Najafi, Elmira; Bilston, Lynne E.; Song, Xin; Bongers, André; Stoodley, Marcus A.; Hemley, Sarah J.

doi:10.3171/2015.10.spine15538

Cited by 16 publications

(13 citation statements)

References 20 publications

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“…Remarkable elevation of TNF-alpha and IL-1beta was associated with increased activity of astrocytes and microglia and infiltrating leukocytes [9]. Pro-inflammatory cytokines secreted by reactive astrocytes, microglia and infiltrating macrophages have been shown to injure myelin sheaths and axons in the spinal cord surrounding the trauma [32,55]. In notable exceptions; CX3CL1 (fractalkine), CD86, and IL-13 show consistent gradual increase in levels of the course of the SCI in the present study, and may have been related to tissue anti-inflammatory/neuroprotective activity.…”

Section: Discussionmentioning

confidence: 99%

“…Astrocytes are immunocompetent [26,27] secreting pro-inflammatory cytokines [28] and chemokines [29], complicating their role in SCI neuropathology [4]. Astrocytes have been proposed as mediators of SCI inflammation and scarring [4] but have also conversely been proposed as having a protective role in walling off the expanding cystic areas after SCI [4,16,[30][31][32][33]. Interestingly, increases in reactive astrocytes parallel the rise of anti-inflammatory activity in rat SCI models [18].…”

Section: Introductionmentioning

confidence: 99%

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Prolonged inflammation leads to ongoing damage after spinal cord injury

et al. 2020

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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 + /CD163macrophages 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+/CD163macrophage 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 proinflammatory 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prolonged inflammation leads to ongoing damage after spinal cord injury

et al. 2020

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“…Macrophages continue to phagocytize myelin, persisting for more than 8 weeks post-spinal cord injury (SCI) [21]. As this inflammatory, phagocytic macrophage infiltrate persists, the cavity of injury (COI) increases in volume [18,35,40] creating a barrier for axonal regeneration [20], while the surrounding spinal cord tissue is irreversibly destroyed. Based on these histopathological findings we have postulated that a reduction in the numbers of macrophages in the COI by pharmacological treatments has the potential to protect the nervous system, a therapy designed to limit tissue destruction and potentially reduce neurological deficits.…”

Section: Introductionmentioning

confidence: 99%

Myxoma virus derived immune modulating proteins, M-T7 and Serp-1, reduce early inflammation after spinal cord injury in the rat model

Kwiecień

Dąbrowski

Marzec-Kotarska

et al. 2019

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Spinal cord injury (SCI)-initiated inflammation was treated with anti-inflammatory reagents. We compared local spinal cord or intraperitoneal infusion of two Myxoma virus derived immune modulating proteins, Serp-1 and M-T7, with dexamethasone (DEX). Hemorrhage and necrosis after SCI initiate a complex pathogenesis dominated by early, severe and highly destructive inflammatory macrophage infiltration. We examined sustained, 7-day, subdural infusion of either M-T7, a chemokine modulator or Serp-1, a plasminogen activator and factor inhibitor. Mature male rats had epidural balloon crush SCI and sustained subdural infusion of Serp-1, M-T7, DEX or saline for 7 days via the osmotic pump. A separate group of rats with SCI had intra-peritoneal infusion. Clinical evaluation included endpoint monitoring with body weight, hemorrhagic cystitis and bilateral toe pinch response. Sections of the spinal cord were analyzed histologically and macrophage numbers counted by standardized protocol in the cavity of injury (COI). While the rats administered DEX demonstrated substantial body weight loss, dehydration and dermal atrophy consistent with steroid toxicity, rats infused with Serp-1 and M-T7 had no toxicity. Serp-1 improved withdrawal responses. Subdural infusion of Serp-1, M-T7 and DEX significantly reduced numbers of phagocytic, CD68-positive macrophages. With intraperitoneal infusion only M-T7 reduced macrophage counts, Serp-1 showed only a trend. Local infusion of highly active immune modulating proteins; Serp-1 and M-T7, targeting serine protease and chemokine pathways demonstrated excellent potential for neuroprotection after severe SCI in a rat model, without adverse side effects. Sustained subdural infusion offers an alternative route of administration for treatment of SCI.

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“…Remarkable elevation of TNF-alpha and IL-1beta was associated with increased activity of astrocytes and microglia and infiltrating leukocytes [8]. Pro-inflammatory cytokines secreted by reactive astrocytes, microglia and infiltrating macrophages have been shown to injure myelin sheaths and axons in the spinal cord surrounding the trauma [31, 53]. In notable exceptions; CX3CL1 (fractalkine), CD86, and IL-13 show consistent gradual increase in levels of the course of the SCI in the present study, and may have been related to tissue anti-inflammatory/neuroprotective activity.…”

Section: Discussionmentioning

confidence: 99%

Prolonged inflammation leads to ongoing damage after spinal cord injury

Kwiecień

Dąbrowski

Dąbrowska–Bouta³

et al. 2019

Preprint

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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,...

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Longitudinal measurements of syrinx size in a rat model of posttraumatic syringomyelia

Cited by 16 publications

References 20 publications

Prolonged inflammation leads to ongoing damage after spinal cord injury

Prolonged inflammation leads to ongoing damage after spinal cord injury

Myxoma virus derived immune modulating proteins, M-T7 and Serp-1, reduce early inflammation after spinal cord injury in the rat model

Prolonged inflammation leads to ongoing damage after spinal cord injury

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