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The Establishment of Experimental Aneurysmal Animal Model and the Investigation on Pathogenesis of Intracranial Aneurysm

Author: ZhuWenHuan
Tutor: ZhouZuo
School: Suzhou University
Course: Neurosurgery
Keywords: Intracranial aneurysm Animal model Experitmental animal PathogenesisCerebral aneurysm Pathogenesis Caspase-3 Growth factorPathogenesis Endothelia cell Fluid shear stress Transcription factor PDGF-b c-Jun
CLC: R743
Type: PhD thesis
Year: 2012
Downloads: 178
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Abstract


Part1Investigation on the ways of building intracranial aneurysmanimal modelobjective: To investigate the ways of building ideal intracranial aneurysm animalmodel. mean-while, the forming mechanism of intracranial aneurysm were furtherelucidated by the establishment of aneurysm model in rabbit.Methods:48New Zealand rabbits were randomly divided into A、B、C、D、E5groups.A group:8rabbits were ligated contralateral common carotid artery(CCA) and feeded2%salt water. B group:8rabbits were transluminally damaged the intima at the bifurcation ofcommon carotid artery(CCA) and the ways of A group added. C group:10rabbits wereperformed with elastase soaking in adventitial and the ways of A group added. D group:12rabbits were performed with the ways of B group and and the ways of C group added. Egroup:10rabbits were performed with elastase soaking in adventitial and translu-minallydamaged the intima at the bifurcation of common carotid artery(CCA).The blood pressurewas measured the rabbits of A、D、E groups at preoperation,postoperation,4weeks afteroperation. The rabbits of all groups were given the carotid artery angiography withCT(CTA) at4weeks; and then vivisection at the bifurcation of common carotidartery(CCA), measuring and recording the size of experimental rabbit aneurysmal models.All animals were put to death and recipe the aneurysm models, specimen of aneurysmswere stained with the way of HE and light microscope observed pathologic appearance.Results: The blood pressure was measured the rabbits of A、D、E groups which showed postoperation and4weeks after operation in A、D groups were significant heightencompared with preoperation. The blood pressure in postoperation and4weeks afteroperation in A、D groups were significant heighten compared with postoperation and4weeks after operation in E groups.The blood pressure in postoperation were no significantcompared with preoperation and4weeks after operation in E groups. The ratio of formingexperimental rabbit aneurysmal models in C、D、E groups was no significant; The ratio offorming aneurysmal models in C、D、E groups was significant increasing compared withA、B groups. The size of experimental rabbit aneurysmal models in D groups wassignificant in width and height compared with E groups. D groups was significant in lengthwidth and height compared with C groups. Pathological alterations from induced aneurysmbecome thinning and samples show that internal elastic lamina disrupt or even disappear,arrangement in disorder of the elastic fiber raritas, vacuolus, degeneration of endothelialcell or shedding, the number of vascular smooth muscle cell decreased.Conclusion: The intima damage and elastase soaking at the bifurcation of CCA withligating the contralateral CCA could establish the experimental rabbit aneurysmalmodels.The models were similar to human intracranial aneurysm in size and pathology.Itwere stable、convenient、shortly period.It could act on model for clinical experidmentaltherapy and thrombosis material study.Meanwhile,The formation of aneurysm is a resultwhich many factor operate. Part2The significance of PDGF-bc-JunCaspase-3expression inhuman cerebral aneurysms and experimental rabbit aneurysmal modelsobjective: To explore the expression of PDGF-b、c-Jun、Caspase-3in human cerebralaneurysms and experimental rabbit aneurysmal models and further discover the latentforming mechanism of human cerebral aneurysm.Methods: The immuno-reactivity expression of PDGF-b、c-Jun、 and caspase-3weremeasured in22human cerebral aneurysm、8experimental rabbit aneurysmal models and6 normal cerebral arteries and rabbit common carotid arteries each groups byimmunohistochemical Envision method; The value of mean density expression onPDGF-b、c-Jun、 and caspase-3were obtained by the imagine analysis system of Laserpixand were taken statistics analysis.Results: immunoreactivity activity of PDGF-b、c-Jun and caspase-3in human aneurysmand experimental rabbit aneurysmal models was higher than that of the normal contro(p<0.01),their expression were significantly up-regulated in aneurysm groups comparedwith that of the normal control groups. Especially, there were no PDGF-b、c-Jun andcaspase-3expression on the normal CCA walls, immunoreactivity activity expression ofPDGF-b、c-Jun and caspase-3in experimental rabbit aneurysmal models were moreobviously than that of normal rabbit CCA walls. PDGF-b、c-Jun and caspase-3IOD valueof human intracranial aneurysm slices was more higher than that of the normal controlgroup(p<0.01),which PDGF-b and caspase-3expression couldn’t be detected in normalcontrol group samples. The difference between two groups had statistical significance.PDGF-b、c-Jun and caspase-3IOD value of human intracranial aneurysm slices wereanalysed their correlation that showed PDGF-b and c-Jun was positive correlation,so wasc-Jun and caspase-3. Staining degree of all cases in each group were comprehensiveindication.Conclusion: PDGF-b、c-Jun and caspase-3contributed to the origin、growth、remodeling、rupture and evolvement of human intracranial aneurysm. Nucleus transcription factorc-Jun was probable common ring-joint of PDGF-b、apoptosis factor、a series change ofenzymology in the pathogenesis of human intracranial aneurysm. These findings probablyprovided the theory evidence to develop the new clinical target-inhibitor. Part3Role of fluid shear stress to artery endothelial cell on theexpression of PDGF-b、c-Jun、Caspase-3mRNA Objective: to investigate the effect of high shear stress on the expression of PDGF-b、c-Jun、Caspase-3mRNA in the artery endothelial cells, and analyse the significance ofshear stress in the pathogenesis of human intracranial aneurysms.Methods: Human thoracic aorta endothelial cells selected and conducted the cell origin oncell functional study after culture and passage.(1) The transcription levels of PDGF-b、c-Jun、Caspase-3in the aorta endothelial cells,which were exposed to high shear stress(40dyne/cm2)Oh,1h,4h,6h separately,was detected with real-time RT-PCR quantitativemethod.(2) The transcription of PDGF-b、c-Jun、Caspase-3in the endothelial cellsexposed to normal shear stress level (20dyne/cm2)4h separately,was detected with real-timeRT-PCR quantitative method.(3)the difference of high shear stress and normal shear stessin the transcription levels of PDGF-b、c-Jun、Caspase-3in the endothelial cells.Results: The transcription levels of PDGF-b in the aorta endothelial cells,which wereexposed to high shear stress1h group,was obviously heighten compared with0h、4h、6hgroup (p<0.01);4h、6h group compared with0h group were significant(p<0.01);Thetranscription levels of c-Jun in the endothelial cells,which were exposed to high shearstress0h、1h、4h、6h group, was distinctly step up with time extending, compared with anytwo groups (p<0.01); The transcription levels of Caspase-3in the endothelial cells,whichwere exposed to high shear stress1h group,was obviously heighten compared with0h、4h、6h group (p<0.01);4h group compared with0h group were significant descent (p<0.01);6h group compared with0h group were no significant(p>0.01). The transcription levels ofPDGF-b and c-Jun in the endothelial cells,which were exposed to contrast group、normalshear stress、high shear stres4h, was distinctly step up with time extending (p<0.01);Thetranscription levels of Caspase-3in the endothelial cells,which were exposed to contrastgroup、normal shear stress、high shear stres4h, was descent with time extending p<0.05.Conclusion: The expression of PDGF-b and c-Jun in endothelial cells can be up-regulatedby high shear stress via time-and magnitude-dependent pattern. Shear stress with differentmagnitude (20dyne/cm2,40dyne/cm2)can induce the expression of PDGF-b and c-Jun inendothelial cells. Combining two parts of the present experiment, we proposed that continued high shear stress in the local cerebral artery could induce the development andrupture of the human intracranial aneurysm, via up-regulate the PDGF-b and c-Junexpression in the local vascular endothelial cells. The expression of Caspase-3inendothelial cells in our experitmen need further investigate through more groups andprolonging hours.

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