Post-traumatic inflammation following spinal cord injury

Hausmann, Oliver

doi:10.1038/sj.sc.3101483

Cited by 552 publications

(414 citation statements)

References 114 publications

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“…The mechanical forces imparted to the spinal cord cause tissue disruption, with axonal injury, inducing death of neurons that is very unlikely to be regenerated (DeVivo et al, 1987;Tator, 1995). Moreover, neuronal death continues for hours after SCI, because of multiple mechanisms including excitotoxicity, vascular abnormalities, and inflammation (Liu et al, 1999;Tator and Koyanagi, 1997;Hausmann, 2003). The clinical outcome of SCI depends, in part, on the extent of secondary damage, which evolves with contribution of apoptosis (Lu et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Neutralization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Reduces Spinal Cord Injury Damage in Mice

Cantarella

Benedetto

Scollo

et al. 2010

Neuropsychopharmacol

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Spinal cord injury (SCI) is a major cause of disability, its clinical outcome depending mostly on the extent of damage in which proapoptotic cytokines have a crucial function. In particular, the inducers of apoptosis belonging to TNF receptor superfamily and their respective ligands are upregulated after SCI. In this study, the function of the proapoptotic cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in SCI-induced damage was investigated in the mouse. SCI resulted in severe trauma, characterized by prominent inflammation-related damage and apoptosis. Immunostaining for TRAIL and its receptor DR5 was found in the white and gray matter of the perilesional area, as also confirmed by western blotting experiments. Immunoneutralization of TRAIL resulted in improved functional recovery, reduced apoptotic cell number, modulation of molecules involved in the inflammatory response (FasL, TNF-a, IL-1b, and MPO), and the corresponding signaling (caspase-8 and -3 activation, JNK phosphorylation, Bax, and Bcl-2 expression). As glucocorticoid-induced TNF receptor superfamily-related protein (GITR) activated by its ligand (GITRL) contributes to SCI-related inflammation, interactions between TRAIL and GITRL were investigated. SCI was associated with upregulated GITR and GITRL expression, a phenomenon prevented by anti-TRAIL treatment. Moreover, the expression of both TRAIL and DR5 was reduced in tissues from mice lacking the GITR gene (GITR À/À ) in comparison with wild-type mice suggesting that TRAIL-and GITRL-activated pathways synergise in the development of SCI-related inflammatory damage. Characterization of new targets within such molecular systems may constitute a platform for innovative treatment of SCI.

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Section: Introductionmentioning

confidence: 99%

Neutralization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Reduces Spinal Cord Injury Damage in Mice

Cantarella

Benedetto

Scollo

et al. 2010

Neuropsychopharmacol

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“…The early inflammatory cascade is at least partially responsible for secondary tissue destruction and additional loss of function. 1 The early phase of secondary parenchymal damage is followed by the removal of tissue debris. Finally, severe lesions become dominated by the deposition of scar tissue composed of connective tissue and fluid-filled cysts, surrounded by a dense astroglial scar.…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 and TGF-β2 expression after traumatic human spinal cord injury

et al. 2007

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Study design: Immunohistochemical investigation in control and lesioned human spinal cords. Objectives: To assess the spatial and temporal expression patterns of transforming growth factor-b1 and -b2 (TGF-b1 and TGF-b2) in the human spinal cord after traumatic injury. Setting: Germany, Aachen, Aachen University Hospital. Methods: Sections from human spinal cords from 4 control patients and from 14 patients who died at different time points after traumatic spinal cord injury (SCI) were investigated immunohistochemically. Results: In control cases, TGF-b1 was confined to occasional blood vessels, intravascular monocytes and some motoneurons, whereas TGF-b2 was only found in intravascular monocytes. After traumatic SCI, TGF-b1 immunoreactivity was dramatically upregulated by 2 days after injury (the earliest survival time investigated) and was detected within neurons, astrocytes and invading macrophages. The staining was most intense over the first weeks after injury but gradually declined by 1 year. TGF-b2 immunoreactivity was first detected 24 days after injury. It was located in macrophages and astrocytes and remained elevated for up to 1 year. In white matter tracts undergoing Wallerian degeneration, there was no induction of either isoform. Conclusion: The early induction of TGF-b1 at the point of SCI suggests a role in the acute inflammatory response and formation of the glial scar, while the later induction of TGF-b2 may indicate a role in the maintenance of the scar. Neither of these TGF-b isoforms appears to contribute to the astrocytic scar formation in nerve fibre tracts undergoing Wallerian degeneration.

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“…In addition to damage from mechanical forces, spinal cord and traumatic brain injuries may result from secondary mechanisms involving ischemia, excitotoxicity, cytokines, and an infiltration of neutrophils at the site of injury (6,7). The inflammatory response results in the generation of reactive oxygen species (ROS), 2 including superoxide and hydrogen peroxide, which can cause oxidative damage to tissues and lead to cell death (8).…”

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confidence: 99%

A Direct Redox Regulation of Protein Kinase C Isoenzymes Mediates Oxidant-induced Neuritogenesis in PC12 Cells

Gopalakrishna

Gundimeda

Schiffman

et al. 2008

Journal of Biological Chemistry

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In this study, we have used the PC12 cell model to elucidate the mechanisms by which sublethal doses of oxidants induce neuritogenesis. The xanthine/xanthine oxidase (X/XO) system was used for the steady state generation of superoxide, and CoCl 2 was used as a representative transition metal redox catalyst. Upon treatment of purified protein kinase C (PKC) with these oxidants, there was an increase in its cofactor-independent activation. Redox-active cobalt competed with the redoxinert zinc present in the zinc-thiolates of the PKC regulatory domain and induced the oxidation of these cysteine-rich regions. Both CoCl 2 and X/XO induced neurite outgrowth in PC12 cells, as determined by an overexpression of neuronal marker genes. Furthermore, these oxidants induced a translocation of PKC from cytosol to membrane and subsequent conversion of PKC to a cofactor-independent form. Isoenzyme-specific PKC inhibitors demonstrated that PKC⑀ plays a crucial role in neuritogenesis. Moreover, oxidant-induced neurite outgrowth was increased with a conditional overexpression of PKC⑀ and decreased with its knock-out by small interfering RNA. Parallel with PKC activation, an increase in phosphorylation of the growth-associated neuronal protein GAP-43 at Ser 41 was observed. Additionally, there was a sustained activation of extracellular signal-regulated kinases 1 and 2, which was correlated with activating phosphorylation (Ser 133 ) of cAMP-responsive element-binding protein. All of these signaling events that are causally linked to neuritogenesis were blocked by antioxidant N-acetylcysteine (both L and D-forms) and by a variety of PKC-specific inhibitors. Taken together, these results strongly suggest that sublethal doses of oxidants induce neuritogenesis via a direct redox activation of PKC⑀.Understanding the signaling mechanisms involved in neuritogenesis resulting from a compensatory response to injury is crucial to the development of therapeutic agents for recovery after spinal cord and traumatic brain injuries (1, 2). The study of neuritogenesis requires the identification of molecular targets using a suitable experimental model. One of the best characterized cellular models for studying the neuronal pathways involved in neuritogenesis is the rat pheochromocytoma cell line PC12 (3). This cell line continues to be an important model system for the study of cell signaling mechanisms induced by a variety of stimuli, including neurotrophins, hormones, and oxidants (4, 5).In addition to damage from mechanical forces, spinal cord and traumatic brain injuries may result from secondary mechanisms involving ischemia, excitotoxicity, cytokines, and an infiltration of neutrophils at the site of injury (6, 7). The inflammatory response results in the generation of reactive oxygen species (ROS), 2 including superoxide and hydrogen peroxide, which can cause oxidative damage to tissues and lead to cell death (8). Paradoxically, sublethal doses of oxidants can also induce a variety of cellular processes, including cell growth, adhesion, inva...

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Post-traumatic inflammation following spinal cord injury

Cited by 552 publications

References 114 publications

Neutralization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Reduces Spinal Cord Injury Damage in Mice

Neutralization of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Reduces Spinal Cord Injury Damage in Mice

TGF-β1 and TGF-β2 expression after traumatic human spinal cord injury

A Direct Redox Regulation of Protein Kinase C Isoenzymes Mediates Oxidant-induced Neuritogenesis in PC12 Cells

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