Activated Macrophages and the Blood–Brain Barrier: Inflammation after CNS Injury Leads to Increases in Putative Inhibitory Molecules

Fitch, Michael T.; Silver, Jerry

doi:10.1006/exnr.1997.6701

Cited by 242 publications

(147 citation statements)

References 118 publications

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“…Traditionally, thought to be a simple mechanical barrier (Windle and Chambers, 1950), later studies suggested that regeneration still fails even when a dense glial scar does not form (Guth et al, 1986). Multiple models have now demonstrated that the molecular composition of the scar and the production of inhibitory molecules by astrocytes are contributing factors for regenerative failure (Busch and Silver, 2007;Fawcett, 2006;Fitch and Silver, 1997a;Fitch and Silver, 2000;Liu et al, 2006;McGraw et al, 2001;Silver and Miller, 2004;Yiu and He, 2006;Zhang et al, 2006). Reactive astrocytes within the glial scar have been shown to upregulate molecules such as tenascin (Apostolova et al, 2006;Brodkey et al, 1995;McKeon et al, 1995), Semaphorin 3 (Pasterkamp et al, 2001), ephrin-B2 (Bundesen et al, 2003), slit proteins (Hagino et al, 2003), and a host of chondroitin sulfate proteoglycans (Jones et al, 2003a;McKeon, et al, 1995;Rhodes and Fawcett, 2004).…”

Section: Molecules Within the Glial Scar Contribute To Regenerative Fmentioning

confidence: 99%

“…The NG2 proteoglycan is increased after CNS injury by oligodendrocyte precursor cells (Levine, 1994;Rhodes et al, 2006), phosphacan is upregulated within glial scars (McKeon, et al, 1995), and phosphacan, brevican, versican, and neurocan are all produced within the injured spinal cord (Jones, et al, 2003a). Chondroitin sulfate proteoglycans are found in the brain after stab wound (Fitch and Silver, 1997a), in the spinal cord after injury to the dorsal root (Pindzola et al, 1993), and in the spinal cord following injury (Fitch and Silver, 1997a;Jones, et al, 2003a;Jones et al, 2003b). The rapid and long lasting upregulation of proteoglycans within the vicinity of the glial scar has implicated them in the creation of nonpermissive growth environments in the CNS, similar to their role in boundary formation within the CNS during development (Fitch and Silver, 1997b;Grimpe and Silver, 2004;Silver, 1994;Snow et al, 1990).…”

Section: Molecules Within the Glial Scar Contribute To Regenerative Fmentioning

confidence: 99%

“…They are typically enhanced in regions of BBB breakdown (Fitch and Silver, 1997a;Rhodes, et al, 2006), but new evidence also suggests they are upregulated in the perineuronal net in areas distant from the lesion in synaptic centers denervated by the injury (Massey, et al, 2006). In order to appropriately manipulate the extracellular matrix, we must first consider those triggers that initiate the increased production of inhibitory molecules.…”

Section: Triggers For the Production Of Inhibitory Extracellular Matrixmentioning

confidence: 99%

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CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Fitch

Silver

2008

Experimental Neurology

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877

657

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Spinal cord and brain injuries lead to complex cellular and molecular interactions within the central nervous system in an attempt to repair the initial tissue damage. Many studies have illustrated the importance of the glial cell response to injury, and the influences of inflammation and wound healing processes on the overall morbidity and permanent disability that result. The abortive attempts of neuronal regeneration after spinal cord injury are influenced by inflammatory cell activation, reactive astrogliosis and the production of both growth promoting and inhibitory extracellular molecules. Despite the historical perspective that the glial scar was a mechanical barrier to regeneration, inhibitory molecules in the forming scar and methods to overcome them have suggested molecular modification strategies to allow neuronal growth and functional regeneration. Unlike myelin associated inhibitory molecules, which remain at largely static levels before and after central nervous system trauma, inhibitory extracellular matrix molecules are dramatically upregulated during the inflammatory stages after injury providing a window of opportunity for the delivery of candidate therapeutic interventions. While high dose methylprednisolone steroid therapy alone has not proved to be the solution to this difficult clinical problem, other strategies for modulating inflammation and changing the make up of inhibitory molecules in the extracellular matrix are providing robust evidence that rehabilitation after spinal cord and brain injury has the potential to significantly change the outcome for what was once thought to be permanent disability.

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Section: Molecules Within the Glial Scar Contribute To Regenerative Fmentioning

confidence: 99%

Section: Molecules Within the Glial Scar Contribute To Regenerative Fmentioning

confidence: 99%

Section: Triggers For the Production Of Inhibitory Extracellular Matrixmentioning

confidence: 99%

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CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Fitch

Silver

2008

Experimental Neurology

Self Cite

877

657

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“…Specifically, reactive astrogliosis is denoted by increased immunoreactivity of glial fibrillary acid protein (GFAP), which is a distinct cellular marker of astrocytes. 14,48,[71][72][73][74]111 It has been demonstrated that reactive adult astrocytes upregulate the production of laminin and neurotrophin C. 75,76 In addition to the endogenously present myelinassociated neurite growth inhibitory constitutents, reactive astrocytes form an astroglial scar that acts as a physical and/or chemical barrier to axonal regeneration. 8,35,72,77,78 Proximity to the lesion epicentre determines whether the reactive glial environment will be growth supportive or inhibitory.…”

Section: Experimental Modelsmentioning

confidence: 99%

Post-traumatic inflammation following spinal cord injury

2003

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“…Recent studies have shown that activated monocytes release the excitotoxic substance quinolinic acid, 7,8 and there is also evidence that infiltrating monocytes are involved in the production of chondroitin sulphate proteoglycans that are known to inhibit axonal outgrowth. 9,10 Taken together, monocyte recruitment and activation contribute to secondary damage of neurons and a delayed loss of axons.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of monocyte/endothelial cell interactions and monocyte adhesion molecule expression by the immunosuppressant mycophenolate mofetil

2003

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Study design: In vitro study on the effects of mycophenolate mofetil (MMF) on isolated human monocytes and endothelial cells. Objectives: Haematogenous macrophages play an essential role in the development of secondary damage following spinal cord injury (SCI), and there is evidence that the use of immunosuppressants such as MMF can reduce monocyte invasion and neuronal damage. Setting: University Hospital for Orthopaedic Surgery, Frankfurt am Main, Germany. Methods: The effects of MMF on the adhesion of human monocytes to human umbilical vein endothelial cells (HUVEC), monocyte binding to immobilised E-selectin, and monocyte expression of intercellular adhesion molecule (ICAM)-1, sialyl Lewis X (sLeX) and major histocompatibility complex (MHC)-II were studied. The binding of monocytes to E-selectin was examined by using purified and immobilised E-selectin fusion protein. Adhesion molecule expression was investigated by flow cytometry. Results: The binding of monocytes to HUVEC was significantly reduced by 30.1% after treatment of monocytes with MMF (10 mg/ml), whereas the pretreatment of HUVEC with MMF did not result in significant changes in monocyte adhesion. MMF forcefully inhibited monocyte binding to immobilised E-selectin by 55.7%. Furthermore, MMF significantly inhibited the upregulation of ICAM-1-and MHC-II-expression on monocytes stimulated with either lipopolysaccharide or interferon-g, whereas the expression of sLeX was not impaired. Toxic effects were excluded by propidium-iodide staining and measurement of fluoresceindiacetate metabolism. Conclusion: MMF can downregulate important monocytic adhesion molecules and inhibits monocyte adhesion to endothelial cells, thus indicating that treatment with MMF could be beneficial after SCI. Sponsorship: This study was supported by the DFG (Ha 2721/1-3), the Paul und Ursula KleinStiftung and the Stiftung Friedrichsheim.

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Activated Macrophages and the Blood–Brain Barrier: Inflammation after CNS Injury Leads to Increases in Putative Inhibitory Molecules

Cited by 242 publications

References 118 publications

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Post-traumatic inflammation following spinal cord injury

Inhibition of monocyte/endothelial cell interactions and monocyte adhesion molecule expression by the immunosuppressant mycophenolate mofetil

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