Vascular Events After Spinal Cord Injury: Contribution to Secondary Pathogenesis

Mautes, A.; Weinzierl, Martin; Donovan, Frances; Noble, Linda

doi:10.1093/ptj/80.7.673

Cited by 347 publications

(218 citation statements)

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“…Primary injury deforms neuronal cell bodies, axons and oligodendrocytes. Disruption of vascular elements and structures within injured tissue leads to petechial hemorrhage, the release of vasoactive molecules and loss of autoregulation by the vascular system (Anderson and Hall 1993;Amar and Levy 1999;Mautes et al 2000). The primary injury also initiates a cascade of pathochemical and pathophysiological events, collectively known as the secondary injury.…”

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Cathepsin B mRNA and protein expression following contusion spinal cord injury in rats

Ellis¹,

Earnhardt²,

Hayes

et al. 2003

Journal of Neurochemistry

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We provide the first data that cathepsin B (Cath B), a lysosomal cysteine protease, is up-regulated following contusionspinal cord injury (SCI). Following T12 laminectomy and moderate contusion, Cath B mRNA and protein expression profiles were examined from 2 to 168 h post-injury in rats using real-time PCR and immunoblots, respectively. Contusion injury significantly increased [mRNA] Cath B in the injury site and adjacent segments over sham injury levels. While the largest [mRNA] Cath B induction (20-fold over naive) was seen in the injury site, the caudal segment routinely yielded [mRNA] Cath B levels greater than 10-fold over naive. Interestingly, sham injury animals also experienced mRNA induction at several time points at the injury site and in segments rostral and caudal to the injury site. Contusion injury also significantly elevated levels of Cath B proenzyme protein (37 kDa) over sham injury in the injury site (48, 72 and 168 h post-injury). Furthermore, significant protein increases of single and double chain Cath B (both active forms) occurred at the injury site at 72 and 168 h post-injury. Similar significant increases in Cath B protein levels were seen in areas adjacent to the injury site. The induction of Cath B mRNA and protein expression following contusion injury is previously undescribed and suggests that Cath B may potentially be involved in the secondary injury cascade, perhaps for as long as 1 week post-injury. Injury to the spinal cord is typically the result of some type of mechanical insult. This primary injury can be contusive, shearing, stretching or concussive in nature. Primary injury deforms neuronal cell bodies, axons and oligodendrocytes. Disruption of vascular elements and structures within injured tissue leads to petechial hemorrhage, the release of vasoactive molecules and loss of autoregulation by the vascular system (Anderson and Hall 1993; Amar and Levy 1999; Mautes et al. 2000). The primary injury also initiates a cascade of pathochemical and pathophysiological events, collectively known as the secondary injury. These events include but are not limited to lipid hydrolysis, eicosanoid production, lipid peroxidation, loss of mitchondrial function and ionic homeostasis, invasion of neutrophils and macrophages, cytokine production, loss of the blood-spinal cord barrier integrity and excitotoxicity (Velardo et al. 1999;Demediuk et al. 1985Demediuk et al. , 1987Anderson and Hall 1993;Amar and Levy 1999;McGrath 1999;Lu et al. 2000). Ultimately there is significant loss of neural tissue via apoptotic and necrotic cell death, which frequently results in cavitation around the injury site. As a result, there is a loss of function and sensation distal to the injury site and the prognosis for substantial functional recovery is usually poor.There has been significant interest in understanding the activation and involvement of enzymatic cascades in the secondary injury response associated with trauma to the spinal cord. Several phospholipases, kinases, endonucleases and proteases a...

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confidence: 99%

Cathepsin B mRNA and protein expression following contusion spinal cord injury in rats

Ellis¹,

Earnhardt²,

Hayes

et al. 2003

Journal of Neurochemistry

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“…Early cell death occurs due to cell permeabilization, ischemia, and an overwhelming increase in pro-apoptotic signaling. This is compounded by disruption of the sensitive blood-spinal cord barrier leading to a marked influx of peripheral inflammatory cells, pro-inflammatory cytokines, and fluid shifts causing spinal cord swelling (Mautes et al, 2000; Whetstone et al, 2003). Over the following hours, by-products of cell necrosis (DNA, ATP, glutamate) are released into the microenvironment leading to further cell death and activation of pro-inflammatory microglia.…”

Section: Pathophysiologymentioning

confidence: 99%

Induced Pluripotent Stem Cells for Traumatic Spinal Cord Injury

Khazaei

Ahuja

Fehlings

2017

Front. Cell Dev. Biol.

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Spinal cord injury (SCI) is a common cause of mortality and neurological morbidity. Although progress had been made in the last decades in medical, surgical, and rehabilitation treatments for SCI, the outcomes of these approaches are not yet ideal. The use of cell transplantation as a therapeutic strategy for the treatment of SCI is very promising. Cell therapies for the treatment of SCI are limited by several translational road blocks, including ethical concerns in relation to cell sources. The use of iPSCs is particularly attractive, given that they provide an autologous cell source and avoid the ethical and moral considerations of other stem cell sources. In addition, different cell types, that are applicable to SCI, can be created from iPSCs. Common cell sources used for reprogramming are skin fibroblasts, keratinocytes, melanocytes, CD34+ cells, cord blood cells and adipose stem cells. Different cell types have different genetic and epigenetic considerations that affect their reprogramming efficiencies. Furthermore, in SCI the iPSCs can be differentiated to neural precursor cells, neural crest cells, neurons, oligodendrocytes, astrocytes, and even mesenchymal stromal cells. These can produce functional recovery by replacing lost cells and/or modulating the lesion microenvironment.

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“…8 Several underlying molecular mechanisms have been investigated in this respect experimentally such as overexpression of the Sur1-Trpm4 channel [9][10][11] and of endothelin-1 (ET-1). 12 Among the three ET isoforms, ET-1 is the most abundant and physiologically relevant form, and is expressed in liver, lung, kidneys, brain and spinal cord and binds to either the ET A or ET B receptor. [13][14][15][16] It is a potent vasoconstrictor.…”

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confidence: 99%

“…[21][22][23][24] The formation of ET-1 is stimulated by oxyhemoglobin either derived from the injured tissue itself, or from red blood cells after disruption of blood vessels a frequent complication of SCI. 12,20,25 In experimental SCI in rats, ET-1 synthesis is initially upregulated in neurons and endothelial cells 26,27 and delayed in reactive astrocytes. 24,28 The pathophysiology of ascending/descending myelomalacia (ADMM) after IVD extrusion remains poorly understood.…”

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confidence: 99%

Endothelin‐1 Immunoreactivity and its Association with Intramedullary Hemorrhage and Myelomalacia in Naturally Occurring Disk Extrusion in Dogs

Mayer

Oevermann

Seuberlich

et al. 2016

Veterinary Internal Medicne

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BackgroundThe pathophysiology of ascending/descending myelomalacia (ADMM) after canine intervertebral disk (IVD) extrusion remains poorly understood. Vasoactive molecules might contribute.Hypothesis/ObjectivesTo investigate the immunoreactivity of endothelin‐1 (ET‐1) in the uninjured and injured spinal cord of dogs and its potential association with intramedullary hemorrhage and extension of myelomalacia.AnimalsEleven normal control and 34 dogs with thoracolumbar IVD extrusion.MethodsSpinal cord tissue of dogs retrospectively selected from our histopathologic database was examined histologically at the level of the extrusion (center) and in segments remote from the center. Endothelin‐1 immunoreactivity was examined immunohistochemically and by in situ hybridization. Associations between the immunoreactivity for ET‐1 and the severity of intramedullary hemorrhage or the extension of myelomalacia were examined.ResultsEndothelin‐1 was expressed by astrocytes, macrophages, and neurons and only rarely by endothelial cells in all dogs. At the center, ET‐1 immunoreactivity was significantly higher in astrocytes (median score 4.02) and lower in neurons (3.21) than in control dogs (3.0 and 4.54) (P < .001; P = .004) irrespective of the grade of hemorrhage or myelomalacia. In both astrocytes and neurons, there was a higher ET‐1 immunoreactivity in spinal cord regions remote from the center (4.58 and 4.15) than in the center itself (P = .013; P = .001). ET‐1 mRNA was present in nearly all neurons with variable intensity, but not in astrocytes.Conclusion and Clinical ImportanceEnhanced ET‐1 immunoreactivity over multiple spinal cord segments after IVD extrusion might play a role in the pathogenesis of ADMM. More effective quantitative techniques are required.

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Vascular Events After Spinal Cord Injury: Contribution to Secondary Pathogenesis

Cited by 347 publications

References 128 publications

Cathepsin B mRNA and protein expression following contusion spinal cord injury in rats

Cathepsin B mRNA and protein expression following contusion spinal cord injury in rats

Induced Pluripotent Stem Cells for Traumatic Spinal Cord Injury

Endothelin‐1 Immunoreactivity and its Association with Intramedullary Hemorrhage and Myelomalacia in Naturally Occurring Disk Extrusion in Dogs

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