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1.
目的:检测细胞外基质(ECM)中各蛋白酶在视神经损伤后的变化,分析ECM蛋白酶活性的变化与小鼠视神经损伤和损伤后再生之间的关系。方法:本实验采用建立小鼠视神经钳夹伤的动物模型,用WesternBlot方法检测小鼠视神经损伤后不同时间点神经丝(NF)、金属基质蛋白酶-9(MMP-9)、IgG的表达变化。同时采用原位酶谱分析法检测纤溶酶原激活剂(PA)活性在视神经损伤后各阶段的变化,并分析这种变化与纤维蛋白(原)沉积、髓鞘碎片清除等影响神经再生的因素之间的关系。结果:小鼠视神经损伤后发生进行性Wallerian变性,血-神经屏障(BNB)修复迟缓,沉积的纤维蛋白(原)于损伤后第2d清除。MMP-9在损伤后2d达到高峰,以后仍呈现高水平的表达,且均以前体形式出现。PA活性在损伤后第7d达到高峰,并持续至第28d。结论:视神经损伤后,损伤部位BNB重建、PA激活、纤维蛋白(原)的清除以及MMP-9的表达与周围神经截然不同,正是由于微环境的迥然差异,导致了中枢神经系统(CNS)髓鞘碎片清除不利、轴突再生障碍。 相似文献
2.
L. J. Lawson L. Frost J. Risbridger S. Fearn V. H. Perry 《Journal of neurocytology》1994,23(12):729-744
Summary We investigated the numbers, origin and phenotype of mononuclear phagocytes (macrophages/microglia) responding to Wallerian degeneration of the mouse optic nerve in order to compare it with the response to Wallerian degeneration in the PNS, already described. We found macrophage/microglial numbers elevated nearly four fold in the distal segments of crushed optic nerves and their projection areas in the contralateral superior colliculus 1 week after unilateral optic nerve crush. This relative increase in mononuclear phagocyte numbers compared well with the four-to five-fold increases reported in the distal segments of transected saphenous or sciatic nerves. Moreover, maximum numbers are reached at 3, 5 and 7 days in the saphenous, sciatic and optic nerves respectively, suggesting that the very slow clearance of axonal debris and myelin in CNS undergoing Wallerian degeneration is not simply due to a slow or small mononuclear phagocyte response. The apparent delay in the response in the CNS occurs because the mononuclear phagocytes respond to the Wallerian degeneration of axons, which is slightly slower in the CNS than the PNS, rather than to events associated with the crush itself, such as the abolition of normal electrical activity in the distal segment. This was demonstrated by the protracted time course of the mononuclear phagocyte response in the distal segment following optic nerve crush in mice carrying theWld
smutation which dramatically slows the rate at which the axons undergo Wallerian degeneration. By3H-Thymidine labelling or by blocking microglial proliferation by X-irradiation of the head prior to optic nerve crush, we showed that the majority of macrophages/microglia initiating the response to Wallerian degeneration were of local, CNS origin but these cells rapidly (from 3 days post crush) upregulate endocytic and phagocytic functional markers although they do not resemble rounded myelin-phagocytosing macrophages observed in degenerating peripheral nerves. We speculate that the poor clearance of myelin in CNS fibre tracts undergoing Wallerian degeneration compared to the PNS, in the face of a mononuclear phagocyte response which is similar in relative magnitude and time course, is because Schwann cells in degenerating peripheral nerves promptly modify their myelin sheaths such that they can be recognized and phagocytosed by macrophages, whilst in the CNS oligodendrocytes do not. 相似文献
3.
To investigate the involvement of blood-born factors and extracellular proteases in axonal degeneration and regeneration in both PNS and CNS, we directly compared the differences of blood-nerve barrier (BNB) disruption and matrix metalloprotease-9 (MMP-9) induction between the sciatic nerve and optic nerve after crush injury in the same animal. In sciatic nerve, BNB disruption, fibrin(ogen) deposition and MMP-9 expression were observed only in the first week following injury. Neurofilament (NF) immunoreactivity dramatically decreased in the first 2 days, gradually recovered to the normal levels by day 28. In contrast, the immunoglobulin G deposits spanned from 4 h to 28 days in crushed optic nerves. Fibrin(ogen) deposition was only observed in the first 2 days, while MMP-9 induction did not occur until a week after injury but lasted for 3 weeks in the crushed optic nerves. The NF immunoreactivity did not change much until day 7 and almost completely disappeared on day 28. The decrease of NF immunoreactivity coincided with the induction of MMP-9 after optic nerve crush. These results show that BNB disruption and MMP-9 induction are differentially regulated in the PNS and CNS after injuries, and they may contribute to the different regeneration capacities of the two systems. 相似文献
4.
Stoll G Schroeter M Jander S Siebert H Wollrath A Kleinschnitz C Brück W 《Brain pathology (Zurich, Switzerland)》2004,14(1):51-58
The mechanisms that control the phagocytic activities of microglia and macrophages during disorders of the nervous system are largely unknown. In the present investigation, we assessed the functional role of transforming growth factor (TGF)beta2 in vitro and studied TGFbeta-2mRNA and protein expression in two CNS lesion paradigms in vivo characterized by fundamental differences in microglia/macrophage behaviour: optic nerve crush exhibiting slow, and focal cerebral ischemia exhibiting rapid phagocytic transformation. Furthermore, we used sciatic nerve crush injury as a PNS lesion paradigm comparable to brain ischemia in its rapid phagocyte response. In normal and degenerating optic nerves, astrocytes strongly and continuously expressed TGF-beta2 immunoreactivity. In contrast, TGF-beta2 was downregulated in Schwann cells of degenerating sciatic nerves, and was not expressed by reactive astrocytes in the vicinity of focal ischemic brain lesions during the acute phagocytic phase. In line with its differential lesion-associated expression pattern, exogenous TGF-beta2 suppressed spontaneous myelin phagocytosis by microglia/macrophages in a mouse ex vivo assay of CNS and PNS Wallerian degeneration. In conclusion, we have identified TGF-beta2 as a nervous system intrinsic cytokine that could account for the differential regulation of phagocytic activities of microglia and macrophages during injury. 相似文献
5.
Multiple sclerosis: elevated expression of matrix metalloproteinases in blood monocytes 总被引:4,自引:0,他引:4
Mathilde Kouwenhoven Volkan
zenci Andreia Gomes Dmitry Yarilin Vilmantas Giedraitis Rayomand Press Hans Link 《Journal of autoimmunity》2001,16(4):463-470
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by blood-brain barrier (BBB) breakdown. Disruptions of BBB continuity result in an influx of activated T cells and monocytes, and could contribute to lesion formation in the CNS. Matrix metalloproteinases (MMP) are enzymes implicated in BBB disruption, and in degradation of extracellular matrix proteins and myelin components. An imbalance in levels of MMP and tissue inhibitors of MMP (TIMP) has been implicated in the pathogenesis of MS. Since monocytes form a major cell population in acute MS lesions and may facilitate their entrance into the CNS by secretion of MMP, knowledge on MMP expression by blood monocytes could be useful to improve our understanding of the pathogenesis of MS. In the present study, we examined the expression of MMP-1, -3, -7, -9, -14 and TIMP-1 mRNA by blood monocytes in patients with MS using in situ hybridization. Levels of MMP-1, -3, -7, -9 and of TIMP-1 mRNA expressing monocytes were elevated in MS compared to controls, while those of MMP-14 did not differ. We therefore conclude that MS is associated with elevated levels of MMP and TIMP expressing blood monocytes that may contribute to MS pathogenesis. 相似文献
6.
Wallerian degeneration of the rabbit optic nerve was produced by enucleation and the myelin output as well as its lipid composition were studied. In spite of the marked drop in the myelin mass, occurring very soon after enucleation the lipid composition of the corresponding myelin fractions did not change appreciably, phosphatidylcholine being the most resistant lipid species. However, from the very beginning of the degenerating process there appeared in the myelin lipid spectrum marked amounts of cholesteryl esters and phosphatidic acids and in the later period elevated amounts of lysophosphatidylcholine. Enhanced esterification of cholesterol could function as an early primary factor injuring the myelin membrane, the lysocompounds may be involved at a later stage in the pathomechanism of myelin decomposition in the central nervous system. 相似文献
7.
Wallerian degeneration in the severed newt's (Triturus viridescens) optic nerve is complete between the 10–14th post operative day (p.o.d.). Consequently, the newt optic nerve displays one of the most rapid degenerative responses yet reported for the central nervous system of vertebrates. In most cases it also exhibits the speed of degenerative phenomena in the vertebrate peripheral nervous system. The degeneration of unmyelinated axons is most rapid and is completed by 2–3 p.o.d., compared to myelinated axons, most of which degenerate between 2–10 p.o.d. Myelin ring formation (vesicular transformation) is the principal form of lamellar breakdown and occurs in a highly organized manner which can be clearly staged. The glial cell response to Wallerian degeneration is two-fold: cytoplasmic hypertrophy and myelin-lytic. Glial hypertrophy subsides by the 10–14 p.o.d. with the ingrowth of numerous regenerating nerve fibers. The myelin-lytic response accounts for most of the myelin destruction. Leukocyte-like and microglialike cells also participate in myelin breakdown but to a lesser degree. 相似文献
8.
V. I. Vougioukas S. Roeske U. Michel W. Brück 《The American journal of pathology》1998,152(1):241-249
Wallerian degeneration of the peripheral nervous system was studied in ICAM-1-deficient mice and compared with the phenomena observed in C57BL wild-type animals. There was a decrease in myelin density in both mice strains 4 and 6 days after transection of the sciatic nerve. The degenerating nerves were invaded by Mac-1-, LFA-1-, and F4/80-positive macrophages; significantly lower numbers of macrophages were present in ICAM-1-deficient nerves. Myelin loss decreased after nerve transection with a more prominent loss in ICAM-1-deficient animals. Schwann cells revealed a much higher myelin load in these animals when compared with wild-type nerves, and there was an increased proliferation of endoneurial cells in ICAM-1-deficient mice. These data indicate that ICAM-1 is involved in macrophage recruitment to injured peripheral nerves as well as in the proliferative and phagocytic response of Schwann cells after peripheral nerve transection. 相似文献
9.
Central and peripheral nerve regeneration by transplantation of Schwann cells and transdifferentiated bone marrow stromal cells 总被引:1,自引:0,他引:1
In contrast to the peripheral nervous system (PNS), little structural and functional regeneration of the central nervous system
(CNS) occurs spontaneously following injury in adult mammals. The inability of the CNS to regenerate is mainly attributed
to its own inhibitorial environment such as glial scar formation and the myelin sheath of oligodendrocytes. Therefore, one
of the strategies to promote axonal regeneration of the CNS is to experimentally modify the environment to be similar to that
of the PNS. Schwann cells are the myelinating glial cells in the PNS, and are known to play a key role in Wallerian degeneration
and subsequent regeneration. Central nervous system regeneration can be elicited by Schwann cell transplantation, which provides
a suitable environment for regeneration. The underlying cellular mechanism of regeneration is based upon the cooperative interactions
between axons and Schwann cells involving the production of neurotrophic factors and other related molecules. Furthermore,
tight and gap junctional contact between the axon and Schwann cell also mediates the molecular interaction and linking. In
this review, the role of the Schwann cell during the regeneration of the sciatic (representing the PNS) and optic (representing
the CNS) nerves is explained. In addition, the possibility of optic nerve reconstruction by an artificial graft of Schwann
cells is also described. Finally, the application of cells not of neuronal lineage, such as bone marrow stromal cells (MSCs),
in nerve regeneration is proposed. Marrow stromal cells are known as multipotential stem cells that, under specific conditions,
differentiate into several kinds of cells. The strategy to transdifferentiate MSCs into the cells with a Schwann cell phenotype
and the induction of sciatic and optic nerve regeneration are described. 相似文献
10.
The Role of Macrophages in Wallerian Degeneration 总被引:5,自引:0,他引:5
Wolfgang Brück M.D. 《Brain pathology (Zurich, Switzerland)》1997,7(2):741-752
The present review focuses on macrophage properties in Wallerian degeneration. The identification of hematogenous phagocytes, the involvement of cell surface receptors and soluble factors, the state of activation during myelin removal and the signals and factors leading to macrophage recruitment into degenerating peripheral nerves after nerve transection are reviewed. The main effector cells in Wallerian degeneration are hematogenous phagocytes. Resident macrophages and Schwann cells play a minor role in myelin removal. The macrophage complement receptor type 3 is the main surface receptor involved in myelin recognition and uptake. The signals leading to macrophage recruitment are heterogenous and not yet defined in detail. Degenerating myelin and axons are suggested to participate. The relevance of these findings for immune-mediated demyelination are discussed since the definition of the role of macrophages might lead to a better understanding of the pathogenesis of demyelination. 相似文献
11.
Wallerian degeneration in the peripheral nervous system: participation of both Schwann cells and macrophages in myelin degradation 总被引:12,自引:0,他引:12
Summary This study examined the role of Schwann cells and hematogenous macrophages in myelin degradation and Ia antigen expression during Wallerian degeneration of rodent sciatic nerve. To identify and distinguish between macrophages and Schwann cells we used, in addition to electron microscopy, immunocytochemical staining of teased nerve fibres and 1 m thick cryosections. Before the appearance of adherent macrophages the myelin sheath fragmented into ovoids, small whorls of myelin debris appeared within Schwann cell cytoplasm and the Schwann cell displayed numerous lipid droplets. However, at least in large fibres most myelin degradation and removal was accomplished or assisted by macrophages, identified by their expression of the ED1 marker. These cells began entering the nerve from blood vessels by day 2, migrated to degenerating nerve fibres and adhered to nerve fibres in the regions of the ovoids. There they penetrated the Schwann cell basal lamina to occupy an intratubal position and phagocytose myelin.During Wallerian degeneration a subpopulation of ED1-positive monocytes/macrophages expressed Ia antigen; Schwann cells were Ia-negative. Ia expression by monocytes/macrophages appeared to be a transient event and was not seen in post-phagocytic macrophages, as indicated by the fact that ED1-positive phagocytes with large vacuoles were Ia-negative.Our data show that both Schwann cells and macrophages play important roles in degrading and removing myelin during Wallerian degeneration. The expression of Ia antigen during Wallerian degeneration indicates that Ia expression need not necessarily reflect specific immune events but in some instances can represent a nonspecific response to PNS damage. 相似文献
12.
Developmental and lesion-induced changes in the distribution of the glucose transporter Glut-1 in the central and peripheral nervous system 总被引:1,自引:0,他引:1
Stark B Carlstedt T Cullheim S Risling M 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》2000,131(1):74-84
The active transport of D-glucose from the vascular to the neural compartment requires the presence of a carrier molecule at the blood-brain and the blood-nerve barrier. The glucose transporter 1 (Glut-1) seems to be the main carrier in blood-tissue barriers of endothelial and perineurial type. The distribution of Glut-1 was assessed in the normal central and peripheral nervous system of young and adult animals and compared with changes after nerve injury. Immuno-histochemistry, in situ hybridization, and perfusions with Evans Blue were carried out. Glut- I was not expressed in the perineurium of peripheral nerves at birth, but appeared in the perineurium of peripheral nerves, spinal roots, in the capsule of dorsal-root ganglia, and in the pia mater of adult animals. The perineurium of peripheral nerves subjected to Wallerian degeneration presented a faint Glut-1 immunoreaction, which was restored after regeneration. Glut-1 was expressed in capillaries of the gray substance of the spinal cord. Perineurial-derived lamellar cells of Pacinian corpuscles exhibited a strong Glut-1-like immunoreactivity in response to denervation and during development. Merkel cells and Meissner corpuscles were found to be Glut-1 negative. Glut-1 seems to reflect the quality of an adult, mature perineurial and blood-nerve barrier. 相似文献
13.
McPhail LT Borisoff JF Tsang B Hwi LP Kwiecien JM Ramer MS 《Neuroscience letters》2007,411(3):206-211
Regeneration within or into the CNS is thwarted by glial inhibition at the site of a spinal cord injury and at the dorsal root entry zone (DREZ), respectively. At the DREZ, injured axons and their distal targets are separated by degenerating myelin and an astrocytic glia limitans. The different glial barriers to regeneration following dorsal rhizotomy are temporally and spatially distinct. The more peripheral astrocytic barrier develops first, and is surmountable by neurotrophin-3 (NT-3) treatment; the more central myelin-derived barrier, which prevents dorsal horn re-innervation by NT-3-treated axons, becomes significant only after the onset of myelin degeneration. Here we test the hypothesis that in the presence of NT-3, axonal regeneration is hindered by myelin degeneration products. To do so, we used the Long Evans Shaker (LES) rat, in which oligodendrocytes do not make CNS myelin, but do produce myelin-derived inhibitory proteins. We show that delaying NT-3 treatment for 1 week in normal (LE) rats, while allowing axonal penetration of the glia limitans and growth within degenerating myelin, results in misdirected regeneration with axons curling around presumptive degenerating myelin ovoids within the CNS compartment of the dorsal root. In contrast, delaying NT-3 treatment in LES rats resulted in straighter, centrally-directed regenerating axons. These results indicate that regeneration may be best optimized through a combination of neurotrophin treatment plus complete clearance of myelin debris. 相似文献
14.
Henrik Toft-Hansen Alicia A Babcock Jason M Millward Trevor Owens 《Journal of neuroinflammation》2007,4(1):24
Background
Matrix metalloproteinases (MMPs) are thought to mediate cellular infiltration in central nervous system (CNS) inflammation by cleaving extracellular matrix proteins associated with the blood-brain barrier. The family of MMPs includes 23 proteinases, including six membrane type-MMPs (MT-MMPs). Leukocyte infiltration is an integral part of the pathogenesis of autoimmune inflammation in the CNS, as occurs in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), as well as in the response to brain trauma and injury. We have previously shown that gene expression of the majority of MMPs was upregulated in the spinal cord of SJL mice with severe EAE induced by adoptive transfer of myelin basic protein-reactive T cells, whereas four of the six MT-MMPs (MMP-15, 16, 17 and 24) were downregulated. The two remaining MT-MMPs (MMP-14 and 25) were upregulated in whole tissue. 相似文献15.
Characterisation of matrix metalloproteinases and the effects of a broad-spectrum inhibitor (BB-1101) in peripheral nerve regeneration 总被引:1,自引:0,他引:1
Demestre M Wells GM Miller KM Smith KJ Hughes RA Gearing AJ Gregson NA 《Neuroscience》2004,124(4):767-779
The effect of treatment with a broad-spectrum inhibitor (BB1101) of the matrix metalloproteinases (MMPs) on nerve regeneration and functional recovery after nerve crush was examined. Drug treatment had no effect on latency but from 63 days the compound muscle action potential was significantly increased and was no different to that in the sham-operated controls at 72 days. Levels of MMP mRNA expression, and the localisation and activity of MMP proteins, were examined in rats for a 2 month period following a nerve crush injury, and compared with sham-operated controls. The mRNA of all the MMPs studied was up-regulated by 5-10 days after nerve crush, and they remained up-regulated for 40-63 days, except for MMP-9 which was down-regulated by 10 days. MMP immunoreactivity was localised to Schwann cells, macrophages and endothelial cells, and with the exception of membrane type 1-MMP (MT1-MMP), it was more intense after nerve crush compared with sham-operated controls. Regenerating axons showed immunoreactivity for MMP-2 and MMP-3. In situ zymography confirmed that the activity of MMPs in the nerve was increased following crush but that the activity was greatly reduced in rats treated with BB-1101. Thus despite the inhibition of MMPs by BB-1101, the drug did not appear to essentially affect nerve degeneration or regeneration following nerve crush but that it could be beneficial in promoting the more effective reinnervation of muscles possibly by actions at the level of the muscles. 相似文献
16.
Comley LH Fuller HR Wishart TM Mutsaers CA Thomson D Wright AK Ribchester RR Morris GE Parson SH Horsburgh K Gillingwater TH 《Human molecular genetics》2011,20(12):2406-2421
Apolipoprotein E (apoE) is a 34 kDa glycoprotein with three distinct isoforms in the human population (apoE2, apoE3 and apoE4) known to play a major role in differentially influencing risk to, as well as outcome from, disease and injury in the central nervous system. In general, the apoE4 allele is associated with poorer outcomes after disease or injury, whereas apoE3 is associated with better responses. The extent to which different apoE isoforms influence degenerative and regenerative events in the peripheral nervous system (PNS) is still to be established, and the mechanisms through which apoE exerts its isoform-specific effects remain unclear. Here, we have investigated isoform-specific effects of human apoE on the mouse PNS. Experiments in mice ubiquitously expressing human apoE3 or human apoE4 on a null mouse apoE background revealed that apoE4 expression significantly disrupted peripheral nerve regeneration and subsequent neuromuscular junction re-innervation following nerve injury compared with apoE3, with no observable effects on normal development, maturation or Wallerian degeneration. Proteomic isobaric tag for relative and absolute quantitation (iTRAQ) screens comparing healthy and regenerating peripheral nerves from mice expressing apoE3 or apoE4 revealed significant differences in networks of proteins regulating cellular outgrowth and regeneration (myosin/actin proteins), as well as differences in expression levels of proteins involved in regulating the blood-nerve barrier (including orosomucoid 1). Taken together, these findings have identified isoform-specific roles for apoE in determining the protein composition of peripheral nerve as well as regulating nerve regeneration pathways in vivo. 相似文献
17.
Volkan
zenci Luciano Rinaldi Natalia Teleshova Darius Matusevicius Pia Kiviskk Mathilde Kouwenhoven Hans Link 《Journal of autoimmunity》1999,12(4):297-303
Matrix metalloproteinases (MMPs) comprise a family of proteolytic enzymes. MMPs are capable of disrupting the blood-brain barrier (BBB), mediating the destruction of extracellular matrix and myelin components. MMPs are also involved in the processing of a variety of cell surface molecules, including the proinflammatory cytokine TNF-alpha. Each of these mechanisms are thought to be important in the pathogenesis of multiple sclerosis (MS). We investigated mRNA expression of MMP-3, MMP-9 and two tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in parallel in blood mononuclear cells (MNC) from patients with MS and controls, using in situ hybridization. Numbers of MMP-9 mRNA-expressing cells in blood were higher in patients with MS compared to other neurological diseases (OND), other inflammatory neurological diseases (OIND) and healthy subjects (P<0.0001 for all comparisons). Patients with MS had also higher levels of MMP-3 and TIMP-1 mRNA expressing blood MNC compared to patients with OND and healthy subjects. A positive correlation was observed for MMP-9 and TIMP-1 mRNA expression in MS. These results demonstrate that MMPs and TIMPs are upregulated in MS and may contribute to the pathogenesis of the disease. 相似文献
18.
Beatriz I Gallego Juan J Salazar Rosa de Hoz Blanca Rojas Ana I Ramírez Manuel Salinas-Navarro Arturo Ortín-Martínez Francisco J Valiente-Soriano Marcelino Avilés-Trigueros Maria P Villegas-Perez Manuel Vidal-Sanz Alberto Trivi?o Jose M Ramírez 《Journal of neuroinflammation》2012,9(1):1-18
Background
The myelin sheath provides electrical insulation of mechanosensory A??-afferent fibers. Myelin-degrading matrix metalloproteinases (MMPs) damage the myelin sheath. The resulting electrical instability of A??-fibers is believed to activate the nociceptive circuitry in A??-fibers and initiate pain from innocuous tactile stimulation (mechanical allodynia). The precise molecular mechanisms, responsible for the development of this neuropathic pain state after nerve injury (for example, chronic constriction injury, CCI), are not well understood.Methods and results
Using mass spectrometry of the whole sciatic nerve proteome followed by bioinformatics analyses, we determined that the pathways, which are classified as the Infectious Disease and T-helper cell signaling, are readily activated in the nerves post-CCI. Inhibition of MMP-9/MMP-2 suppressed CCI-induced mechanical allodynia and concomitant TNF-?? and IL-17A expression in nerves. MMP-9 proteolysis of myelin basic protein (MBP) generated the MBP84-104 and MBP68-86 digest peptides, which are prominent immunogenic epitopes. In agreement, the endogenous MBP69-86 epitope co-localized with MHCII and MMP-9 in Schwann cells and along the nodes of Ranvier. Administration of either the MBP84-104 or MBP68-86 peptides into the na?ve nerve rapidly produced robust mechanical allodynia with a concomitant increase in T cells and MHCII-reactive cell populations at the injection site. As shown by the genome-wide expression profiling, a single intraneural MBP84-104 injection stimulated the inflammatory, immune cell trafficking, and antigen presentation pathways in the injected na?ve nerves and the associated spinal cords. Both MBP84-104-induced mechanical allodynia and characteristic pathway activation were remarkably less prominent in the T cell-deficient athymic nude rats.Conclusions
These data implicate MBP as a novel mediator of pain. Furthermore, the action of MMPs expressed within 1?day post-injury is critical to the generation of tactile allodynia, neuroinflammation, and the immunodominant MBP digest peptides in nerve. These MBP peptides initiate mechanical allodynia in both a T cell-dependent and -independent manner. In the course of Wallerian degeneration, the repeated exposure of the cryptic MBP epitopes, which are normally sheltered from immunosurveillance, may induce the MBP-specific T cell clones and a self-sustaining immune reaction, which may together contribute to the transition of acute pain into a chronic neuropathic pain state. 相似文献19.
The optic nerve is often affected in patients with glaucoma and multiple sclerosis. Conventional MRI can detect nerve damage, but it does not accurately assess the underlying pathologies. Mean diffusivity and diffusion anisotropy indices derived from diffusion tensor imaging have been shown to be sensitive to a variety of central nervous system white matter pathologies. Despite being sensitive, the lack of specificity limits the ability of these measures to differentiate the underlying pathology. Directional (axial and radial) diffusivities, measuring water diffusion parallel and perpendicular to the axonal tracts, have been shown to be specific to axonal and myelin damage in mouse models of optic nerve injury, including retinal ischemia and experimental autoimmune encephalomyelitis. The progression of Wallerian degeneration has also been detected using directional diffusivities after retinal ischemia. However, translating these findings to human optic nerve is technically challenging. The current status of diffusion MRI of human optic nerve, including imaging sequences and protocols, is summarized herein. Despite the lack of a consensus among different groups on the optimal sequence or protocol, increased mean diffusivity and decreased diffusion anisotropy have been observed in injured optic nerve from patients with chronic optic neuritis. From different mouse models of optic nerve injuries to the emerging studies on patients with optic neuritis, directional diffusivities show great potential to be specific biomarkers for axonal and myelin injury. 相似文献
20.
Expression and role of matrix metalloproteinases MMP-2 and MMP-9 in human spinal column tumors 总被引:3,自引:0,他引:3
Gokaslan ZL Chintala SK York JE Boyapati V Jasti S Sawaya R Fuller G Wildrick DM Nicolson GL Rao JS 《Clinical & experimental metastasis》1998,16(8):721-728
Matrix metalloproteinases (MMPs) have been implicated in the process of tumor invasion and metastasis formation. Thus, we determined the expression of MMPs in various primary and metastatic spinal tumors in order to assess the role of these enzymes in spinal invasion. MMP expression was examined by immuno-histochemical localization, and quantitative evaluation of MMP protein content was determined by enzyme-linked immunosorbant assay (ELISA) and Western blotting. MMP enzyme activity was determined by gelatin zymography. Lung carcinomas and melanomas metastatic to the spine were shown to have higher levels of MMP-9 activity than those of breast, thyroid, renal metastases and primary spinal tumors. Immunohistochemical analysis revealed similar difference in expression of MMP-9 in tissue samples. When the tissue samples were subjected to gelatin zymography for examination of MMP-2 and MMP-9 activity and to ELISA and Western blotting for quantitative estimation of protein content, the most striking results were obtained for lung carcinomas and melanomas relative to the other tumors. Lung carcinomas and melanomas metastatic to the spine had considerably higher levels of MMP-9 activity than those of primary spinal tumor or breast, thyroid, and renal carcinoma metastases. Within the metastatic tumor category, neoplasms that are known to be associated with the shortest overall survival rates and most aggressive behavior, such as lung carcinomas and melanomas, had the highest levels of MMP-2 and MMP-9 activity compared to those less aggressive metastatic tumors such as breast, renal cell, and thyroid carcinomas. Our results suggest that MMPs may contribute to the metastases to the spinal column, and overexpression of these enzymes may correlate with enhanced invasive properties of both primary and metastatic spinal tumors.© Kluwer Academic Publishers 1998 相似文献