Effect of MMP-9, TIMP-1 Expressions on the Brain Edema around Hematoma Intracerebral Hemorrhage
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Aim:To study the effect of MMP-9, TIMP-1 expressions on the brain edema around hematoma intracerebral hemorrhage(ICH). Methods:50 Wistar rats were randomly divided into control group, ICH group. The time (6 h, 24 h, 48 h, 72 h, 120 h) was established in these two groups. Brain water content and Evens blue (EB) content was determined and the expression of MMP-9, TIMP-1 was detected in the rat brain. Results:Brain water content, EB content and the expression of MMP-9, TIMP-1 arrived at the peak at the time 72h,48h and 48h respectively, the ultra-structure of blood-brain barrier(BBB) was damaged all the time. Conclusion:The expression of MMP-9 around hematoma can increase the penetrating ability of BBB, TIMP-1 can decrease the brain edema by inhibiting the expression of MMP-9.Keywords:
Brain Edema
Cerebral edema
Intracerebral hematoma
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Objective: The detailed mechanism of white matter injury after subarachnoid hemorrhage (SAH) remains unclear. We hypothesized that blood-brain barrier (BBB) disruption occurs in white matter after SAH and it leads to consequent injury. In this study, we investigated the potential role of matrix metalloproteinase-9 (MMP9) in SAH-induced white matter injury. Methods: SAH was induced by endovascular perforation in male wild-type (WT) C57BL/6 and MMP9 knockout (MMP9-/-) mice. The following three experiments were devised: 1) to determine BBB disruption and MMP9 activation/expression in white matter, mice underwent MRI at 24 h after SAH. They were then euthanized for immunostaining, transmission electron microscopy and MMP zymography; 2) to investigate the role of MMP9 in BBB disruption, lesion volumes on MRI were compared between WT and MMP9-/- mice at 24 h after SAH; 3) WT and MMP9-/- mice underwent MRI at 1 and 8 days after SAH induction to detect time-dependent changes, and were euthanized at 8 days after SAH. Removed brains were used to investigate myelin integrity and axonal damage in the white matter. Results: In WT mice with SAH, albumin leakage along the white matter was increased (p<0.05; vs. sham) and was consistent with T2-hyperintensity on MRI (r=0.97, p<0.01). In microvessels, tight junction detachment and swollen astrocyte endfeet were demonstrated by electron microscopy. MMP9 activity was elevated in white matter at 24 h after SAH (vs. sham; p<0.05), and MMP9 was mainly expressed in astrocytes and oligodendrocyte precursors. The volume of T2-hyperintensity in the white matter in WT mice with SAH was 6.2 ± 3.0 mm3 (p<0.001; vs. WT sham), while that in MMP9-/- mice with SAH was significantly smaller (1.0 ± 1.4 mm3; p<0.01). At 8 days after SAH, decreased myelin integrity and an increased density of damaged axons were observed in WT with SAH mice compared to normal control mice (p<0.05; for each), while T2-hyperintensity on MRI in the white matter almost disappeared. MMP9-/- mice developed less of those injuries than WT mice at 8 days after SAH (p<0.05; for each). Conclusions: SAH causes BBB disruption and consequent injury in the white matter, and MMP9 plays an important role for those pathologies. MMP9 could be a therapeutic target for SAH-induced white matter injury.
MMP9
Immunostaining
Perforation
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Objective To study the effect of dynamic expression at different time points of metallo proteinase-9 on brain edema after cerebral hemorrhage. Methods Serum levels of MMP-9 in 90 patients with brain hemorrhage and 80 normal patients were detected by radioimmunoassay on 24 h、72 h、7 d and 14 d.The relationship between levels of MMP-9 and brain edema after cerebral hemorrhage.Results Brain edema went up to the peak at 72 h and slowly decline after it. At 24 h, the serum level of MMP-9 were significantly higher, and reached the peak at 72 h according to the peak of cerebral edema, and then decreased significantly after 7 d. Cerebral hemorrhage group compared with the control group were significantly higher(P＜0.01). The level of MMP-9 close to normal levels on 14 d. MMP-9 was positive correlated with edema volume and edema ratioat 24 h and 72 h (P=0.01).Conclusions Serum MMP-9 dynamic changes over time after cerebral hemorrhage. The level of MMP-9 was correlated with the brain edema volume and had more stronger correlation with relative size of brain edema. MMP-9 was correlated with inflammation after cerebral hemorrhage.
Key words:
Cerebral hemorrhage; Brain edema; Matrix metallo proteinases-9
Brain Edema
Cerebral edema
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Terminal deoxynucleotidyl transferase
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Objective: To study the expression of aquaporin4(AQP4) protein in perihematomal tissue after intracerebral hemorrhage(ICH) in rats. Methods: The experimental ICH m odel was established in rats by injecting quantitative collagenase into the left caudate nuclei of the rats. The changes of brain water content(BWC) were measur e d by the wet and dry weight methods. Immunohistochemistry was used to determine the change of expression of AQP4 protein during different periods after ICH. Results: BWC and AQP4 protein expression in perihematomal tissue were increased at 6 ho urs after ICH and reached peak at 72 hours. In one week following ICH, it was st il l higher than normal level. In addition, the expression of AQP4 was positively c orrelated with BWC(r=0 985 7,P0 01). Conclusion: AQP4 has a relevant relationship with the formation of brain edema after ICH.
Brain Edema
Brain tissue
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Objective To investigate the effect of hemoglobin on structure and function of blood-brain barrier (BBB) in rat models after intracerebral hemorrhage.Methods One hundred and eight male SD rats were randomized into normal control group (n=12),intracerebral hemoglobin injection group (Hb group,n=48) and sham-operated group (n=48); according to the different observation time points,rats in the Hb group and sham-operated group were divided into 4 subgroups (6 and 24 h,3 and 7 d after the injection,n=1 2).Histological changes and iron deposition of the brain tissues were examined with HE staining and iron staining,respectively.BBB permeability was evaluated by the permeation of Evens blue.The expressions of claudin-5 and ZO-1 in perihematomal brain tissues were detected by immunofluorescence staining and real-time fluorescence quantitative PCR.Results Evident edema and necrosis were observed in the perihematomal zone of Hb group,and iron deposition was found 3 and 7 days after the injection.The permeation of Evens blue in Hb group was significantly increased as compared with that in sham-operated group (P＜0.05).Immunofluorescence staining indicated that expressions ofclaudin-5 and ZO-1 were low and discontinuous in Hb group; the mRNA expression levels of claudin-5 and ZO-1 in Hb group were significantly lower than those in the sham-operated group (P＜0.05).Conclusion After intracerebral hemorrhage,Hb may induce the damage of BBB and participate in the course of brain edema.
Key words:
Hemoglobin; Blood-brain barrier; Tight junction; Brain edema
Immunofluorescence
Evans Blue
Brain Edema
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Objective To observe the expression of aquaporin-4 (AQP-4) mRNA and study the relationship between AQP-4,brain edema,pathological changes and uhrastructure of perihematoma tissue in intracerebral hemorrhage (ICH) patients.Methods Intracranial operation was performed via nonfunctional area with a funnel-like approach on 30 ICH patients.The brain tissue which must be removed 1 cm away the hematoma was removed within 12 hours for observation as normal brain tissue and taken as the control group (7 patients),and which of the brain tissue within 1 cm around hematoma was taken as the study specimens.The experimental group was subdivided into five groups according to the time interval after ICH;＜6 hours (6 cases),6-12 hours (7 cases),12-24 hours (5 cases),24-72 hours (6 cases),and＞72 hours (6 cases).Expression of the AQP-4 mRNA,brain edema,pathological and ultrastructural changes were observed with reverse transcription-polymerase chain reaction (RT-PCR),light microscope and electron microscope. Results The expression of the AQP-4 mRNA was not remarkable,the morphology and construction were basically normal in control group.The expression of AQP-4 mRNA was mild (1.17±0.41 ) and there was edema of neuroglia in the ＜6 hours group.After 6 hours,besides neuroglial edema,the expression of the AQP-4 mRNA was gradually obvious,capillary endothelial cells began to swell too,and tight junctions gradually began to loosen.In the 12 - 72 hours group the expression of the AQP-4 mRNA reached its peak (3.50 ± 0.55,3.60±0.55,both P＜ 0.01 ),and brain edema was most prominent,and electron microscopy showed that neurons,neuroglia,and capillary endothelial cells were markedly deformed.After 72 hours,the expression of AQP-4 mRNA gradually recovered,and brain cells showed less damage.On the 5th day the damage began to repair,and on the 8th day,the damage was basically repaired.The correlation analysis showed that there was a remarkable positive correlation between the expression of the AQP-4 mRNA and the degree of brain edema and the size of hematoma (r1=0.67,P＜0.01;r2=0.44,P＜0.05). Conclusion Secondary edema and brain damage may correlate with the expression of the AQP-4 mRNA in the perihematoma brain edema area. Removal of hematoma will help decrease the AQP-4 mRNA expression and brain edema damage in the early stage.
Key words:
intracerebral hemorrhage; brain edema; aquaporin; pathology; ultrastructure
Brain tissue
Aquaporin 1
Cerebral edema
Brain Edema
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Background Endothelin-1 (ET-1) has deleterious effects on water homeostasis, cerebral edema, and blood-brain barrier (BBB) integrity. Highly expressed ET-1 was observed after intracerebral hemorrhage (ICH); however, ET-1 changes and their relationship with BBB disruption within 24 hours of ICH have not been thoroughly investigated. The aim of the present study was to observe the changes in perihematomal ET-1 levels in various phases of ICH and their correlation with the BBB integrity in a rabbit model of ICH. Methods Twenty-five rabbits (3.2–4.3 kg body weight) were randomly divided into a normal control group (five rabbits) and a model group (20 rabbits). Animals in the model group were equally divided into four subgroups (five rabbits each to be sacrificed at 6, 12, 18, and 24 hours following ICH establishment). An ICH model was prepared in the model group by infusing autologous arterial blood into the rabbit brain. ET-1 expression in perihematomal brain tissues was determined using immunohistochemistry and color image analysis, and the permeability of the BBB was assayed using the Evan's Blue (EB) method. A repeated measures analysis of variance was used to make comparisons of the ET-1 and EB content across the entire time series. Results The number of perihematomal endothelial cells with ET-1 positive expressions following 6, 12, 18, and 24 hours ICH model establishment was 9.32, 13.05, 15.90, and 20.44, respectively, but as low as 6.67 in the control group. The average transmittance of ET-1-positive cell bodies at 6, 12, 18, and 24 hours after ICH was 99.10, 97.40, 85.70, and 80.80, respectively, but 100.12 in the control group. These data reveal that the expression of ET-1 was significantly increased at 6, 12, 18, and 24 hours after ICH compared with the control group, and a marked decrease in the average transmittance of ET-1-positive cell bodies was noted ( P <0.05). Similarly, the perihematomal EB content at 6, 12, 18, and 24 hours after ICH was 29.39±1.16, 32.20±0.73, 33.63±1.08, and 35.26±1.12, respectively, in the model group and 28.06±0.80 in the control group. The results indicate that a significant increase in the EB content in the model group was observed compared with that of the control group ( P <0.05). Moreover, a positive correlation between the number of ET-1-positive endothelial cells and BBB permeability was observed ( r =0.883, P <0.05). Conclusions High levels of ET-1 are closely associated with BBB disruption. ET-1 may play an important role in the pathogenesis of secondary brain injury after ICH.
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Objective To observe the effects of the expressions of matrix metalloproteinase-9 （MMP-9）, intracerebral hemorrhage volume and blood-brain barrier permeability after embolic cerebral ischemia and thrombolysis with urokinase （UK） and to investigate the relationship between MMP-9 and blood-brain barrier permeability and intracerebral hemorrhage after thrombolysis. Methods A rat model of middle cerebral artery occlusion was established by intracarotid injection of autologous blood clots. UK was given intravenously at 6 hours after ischemia. After 24 hours, the expressions of MMP-9 in brain tissue, blood-brain barrier permeability, cerebral infarct volume, and intracerebral hemorrhage volume were detected by the immunohistochemical method, Evans blue extravasation method, TTC staining method, and spectrophotometric method, respectively. Results The expressions of MMP-9 in a cerebral ischemic group were significantly higher than those in a sham-operation group （P 〈 0.01 ）, and in the UK group they were significantly higher than those in the cerebral ischemic group （P 〈 0. 01）. The Evens blue content in the cerebral ischemic group was 5774.00 ＋ 1659. 70 ng/g, which was significantly higher than 643.33 ± 151.34 ng/g in the sham-operation group （P 〈 0.01 ）, and in the UK group was 6283.83 ± 1099. 28 ng/g, there was a tendency higher than in the cerebral ischemic group. 1he intracerebral hemorrhage volumes in the UK and cerebral ischemic groups were 3.16 ±8.84 μl （median ± quartile） and 0. 00 ± 1.48 μl, respectively, and the incidences of intracerebral hemorrhage were 25.00% % and 4. 17%, respectively. Conclusions UK thrombolysis may upregulate the expressions of MMP-9, and its expressions are associated with the increased blood-brain barrier permeability and intracerebral hemorrhage after thrombolysis.
Key words:
urokinase; intracranial embolism and thrombosis; matrix metalloproteinase 9; thrombolytic therapy; blood-brain barrier; rats
Evans Blue
Extravasation
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To examined the effect of local mild hypothermia on the expression of aquaporin-4 (AQP-4) following intracerebral hemorrhage (ICH) in rats and clarified the mechanism of hypothermia on brain edema formation following ICH.Two hundreds and forty male Wistar rats were randomly divided into two groups: the intracerebral hemorrhage (ICH) group, in which autologous arterial blood were stereotaxically injected into right caudate nucleus; the local mild hypothermia (ICH + H) group, in which the rats were given 4 h local mild hypothermia after the injection of blood. Each group was divided into 6 subgroups: control, 6 h, 24 h, 72 h, 5 d and 7 d after operation; Brain water content was determined by dry-wet weight method and the permeability of BBB was measured by Evans-Blue extravasation. RT-PCR and Western blot were respectively used to evaluate AQP-4 mRNA and protein expression.In ICH group, compared with control, ICH significantly increased BWC, the permeability of BBB and the expression of AQP-4 mRNA, all began at 6 h and peaked at 72 h (P < 0.01), the increased protein expression of AQP-4 began at 24 h and also peaked at 72 h (P < 0.01). AQP-4 expression positively correlated, both at the mRNA and the protein level, with the permeability of BBB (r = 0.78 and r = 0.76 respectively). In ICH + H group, compared with ICH group, the elevation of BWC, BBB permeability and AQP-4 protein expression were strongly attenuated at all time point by hypothermia treatment (P < 0.01), while AQP-4 mRNA levels demonstrated a modest attenuation from 48 h. At 72 h, AQP-4 mRNA optical density (A) decreased from 1.25 +/- 0.03 (ICH group) to 1.04 +/- 0.02 (P < 0.01), AQP-4 protein expression (A) decreased from 0.77 +/- 0.08 (ICH group) to 0.25 +/- 0.04 (P < 0.01).This study indicates that BBB breakdown can increase the expression of AQP-4; local mild hypothermia can significantly reduce brain edema formation after ICH by suppressing the elevation of AQP-4 protein expression; Inhibition of BBB breakdown and the elevation of AQP-4 protein expression with local mild hypothermia appear to contribute to brain protection in this model.
Extravasation
Evans Blue
Cerebral edema
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Objective To clear the cerebral hemorrhage perifocal brain tissue at different time points of MMP-9 protein expression pattern the possible role of the occurrence and development of cerebral edema correlation and its clinical significance. Methods The cerebral hemorrhage foci were taken during the craniotomy operation for patients with cerebral hemorrhage at different time points. The patients were divided into 3 d groups according to the time of onset. To operative cranial path away from the hematoma at a little damage of brain tissue do as the samples in the control group by dry wet weighing method in measuring the brain water content,and immunohistochemical staining and RT-PCR methods observe changes of brain tissue around the MMP-9 expression in each group at different time points lesions. Results(1) The water content of brain tissue changeds,cerebral hemorrhage cerebral edema with bleeding time increased,in 6 h containing water hemorrhage increased significantly,after 24 h significantly increased,peaked in about three days,then reduced( P < 0. 05).(2) In the human brain hemorrhage perifocal MMP-9 shall have expression expressed,as compared with the control group,hemorrhage group were significant( P < 0. 05) compared to and bleeding between groups comparison showed a significant difference( P < 0. 05). The number of immune positive cells increased after bleeding 6 h,and the cell numbers of 24 h ~ 3 d cells was the most,then decreased gradually. MMP-9 was positively related to cerebral edema. Conclusion (1) The expression of MMP-9 in the human brain was significantly higher which was closely related to cerebral edema.(2) Abnormal expression of MMP-9 plays an important role in cerebral edema after hypertensive intracerebral hemorrhage and promotes the occurrence of cerebral edema and provides a new target for the treatment of cerebral hemorrhage.
Cerebral edema
Brain Edema
Brain tissue
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