| With the development of imaging technologies and deepening of the understanding of children cerebrovascular disease, cerebrovascular hemorrhagic disease in children, especially the bleeding of spontaneous subarachnoid hemorrhage (SAH) caused by ruptured cerebral aneurysm is gradually being recognized. However, due to the lower incidence of children cerebrovascular disease, there are few researches performed on this subject.SAH in children is mainly caused by intracranial aneurysms and cerebral arteriovenous malformations. Cerebral vasospasm (CVS) can be easily induced by the catabolites of SAH. Although people can treat ruptured aneurysm occlusion by surgical clipping or embolization, due to intracisternal hematocele of SAH can not be completely clear, the incidence of CVS still exist.The chance of CVS after SAH is about70%. There will be varying degrees of cerebral vascular stenosis after CVS, which could lead to changes in cerebral blood flow,or brain ischemic changes and neurological dysfunctionin severe cases.The quality of life of the SAH children could be serverely affected. Understanding of the pathogenesis and the process of development of CVS after SAH would help the prevention and treatment of CVS.Study the pathogenesis of CVS has been going on for a long time, but there still was no clear answer for this question. Immune and inflammatory response is considered to play an important role in the pathogenesis of CVS in recent years.Therefore, people now pay attention to the theory that CVS was triggered by secondly inflammation caused by spasm of the blood vessel wall of the bloody fluid stimulation and a series of intercellular signaling cascade.The occurrence of the inflammatory response bounds to the aggregation of inflammatory factors. The role of intercellular adhesion molecule-1(ICAM-1) is gathering inflammation factors to inflammatory tissue and mediating the adhesion and migration of leukocyte in the spasm of the blood vessel wall, thus causing the inflammatory response of the vessel wall. Inflammatory response can activate nuclear transcription factor-KB (NF-κB) which plays the role as gene regulatory protein and the complete the regulation of the ICAM-1transcriptional activity. Mitogen-activated protein kinase (MAPK) is a cellular messenger, and it passes cell signals from surface to the nucleus through the regulation of nuclear transcription factor activity to perfom its function. Mitogen-activated protein kinase p38(p38MAPK) pathway plays an important role in the MAPK pathway.There were studies reported respectively for the above three factors, but there is no three-factor common research reports. The young rabbits arterial blood was collected and injected into the cisterna magna through the atlanto-occipital fascia, and confirmed the success of CVS after SAH model after different time periods of DSA. On this basis,we explore the expression of p38MAPK, NF-κB, ICAM-1in the spasm of the blood vessel wall and in hippocampal nerve cells after CVS, while observe the metabolism changes of nerve cells in the hippocampus after cerebral blood flow changes. Confirm the abnormal expression of the three factors of p38MAPK, NF-κB, ICAM-1in spasm of the blood vessel wall and the hippocampus and the relationship between the abnormal expression and cerebral vasospasm, suggesting that in the the spastic vessel wall and hippocampal nerve cells may exist cascade reactions started by p38MAPK, regulated by NF-κB, and mediated by ICAM-1. In addition, the changes leaded by CVS in cerebral blood flow also caused changes in brain metabolism. Then we seperately block the expression of the3factors to observe the role they play in the immune and inflammatory response of cerebral vasospasm, as well as their role in the immune and inflammatory response in the brain cells to confirm the immune and inflammatory response of cerebral vasospasm indeed existence of this cascade.Block any link of the cascade could prevent and control the occurrence of CVS, and thus effectively improve cerebral blood flow and cerebral metabolism.Part1The Research of p38MAPK, NF-κB, and ICAM-1in Secondary CVS for SAH in the basilar artery and hippocampus region of Young RabbitsObjectTo research the expression of p38mitogen-activated protein kinase (p38MAPK), nuclear transcription factor-κB (NF-κB), intercellular adhesion molecule-1(ICAM-1) in young rabbits subarachnoid hemorrhage (SAH) to secondary cerebral vasospasm (cerebral vasospasm, CVS) in the basilar artery and hippocampus, as well as the changes of nerve cell metabolism of hippocampus after CVS.MethodEstablish young rabbits CVS model after SAH by injecting autologous arterial blood through atlanto-occipital fascia into magnum pool twice. Examine the effectiveness of this model by digital subtraction angiography (DSA). Explore p38MAPK, NF-κB, ICAM-1expression changes detected in1,3,5,7,9,11days in the basilar artery, and the hippocampus after SAH, while in the same time period to detect changes in the hippocampal nerve cell metabolism, observe the relationship between the above indicators and CVS process.ResultsThe DSA results showed that the control group and the NS group basilar artery was smooth and straight with no obvious narrowing of changes. In SAH group, the vessel wall increased thickening, endothelial cells swelled, the cells of inner wall shrinked, the medial smooth muscle cells twisted, thus the basilar artery became cramped from1-7d, and the narrowest spot was on the7th day. The situation was relieved on the9th day and was back to normal on11th day. P38MAPK, NF-κB, ICAM-1expression level in the basilar artery and hippocampus also changed as different degrees with vessel spasms. ICAM-1expression gradually increased from1st to7th day after SAH and reached the highest spot at the7th day, which consistent with the development process of CVS. The expression level of p38MAPK and NF-κB expression went up earlier and reached the highest spot at the5th day, p38MAPK expression was more strongly. The expression of p38MAPK, NF-κB, ICAM-1intensity has time phase. The SOD quantity in hippocampal neurons was in a decreasing trend while MDA was gradually increased. With the reduction of spasticity, these changes gradually relieved.ConclusionIn the CVS secondary to SAH, there is possibly immune inflammatory reaction existing at the basilar artery and hippocampal nerve cells mediated by p38MAPK, NF-κ B, controled by ICAM-1. This cascade reaction affected the hippocampal neuronal metabolic function as well.Part2The research of treatment of CVS by p38MAPK, NF-κB, ICAM-1antagonistsObjectTo identify immune inflammatory reaction mediated by p38MAPK, NF-κB and ICAM-1in the basilar artery and hippocampal neural cell in the CVS secondary to SAH. Explore the change of CVS development after blocking this cascade reaction and the metabolic function of hippocampus neural cells.MethodWhen establish young rabbits CVS model after SAH by injecting autologous arterial blood through atlanto-occipital fascia into magnum pool, inject antagonists of p38MAPK, NF-κB, ICAM-1into magnum pool for3days. Perform DSA after5days from SAH, observe the situation of CVS and keep specimens.Exam the expression level of p38MAPK, NF-κB, ICAM-1in the endothelial cells of basilar artery and hippocampal neural cells, while check the hippocampal neuronal metabolic changes at the same time.ResultsAfter p38MAPK inhibitor therapy in basilar artery endothelial cells, p38MAPK, NF-κB, ICAM-1expression limited mainly to the endometrium with low expression level. After NF-κB antagonist treatment, NF-κB, ICAM-1weakly expressed in the endometrium, while p38MAPK expression also appears in the tunicae media. After treatment of ICAM-1monoclonal antibody, p38MAPK and NF-κB expressed both in endometrium and tunicae media, but ICAM-1only express weakly in endometrium. In control group,there is strong expression of p38MAPK, NF-κB, ICAM-1in endometrium and tunicae media. The expression of p38MAPK, NF-κB, ICAM-1was significantly inhibited in nerve cells in the hippocampus after p38MAPK inhibitor treatment. After the treatment of NF-κB antagonist, the expression of NF-κB, ICAM-1was significantly inhibited while p38MAPK still expressed strongly; the expression of p38MAPK, NF-κB remains high level while ICAM-1was weakly positive after treatment of ICAM-1monoclonal antibody; in control group, p38MAPK, NF-κB, ICAM-1was strongly positive in the nerve cells of the hippocampus. In the treatment group of p38MAPK, NF-κB, ICAM-1, SOD content in the hippocampal tissue was significantly higher than the control group,while MDA decreased significantly. The the effect was more obvious in p38MAPK, NF-κB treatment group.ConclusionIn the CVS secondary to SAH, there is definitly immune inflammatory reaction exist at the basilar artery and hippocampal nerve cells mediated by p38MAPK, NF-κB, controlled by ICAM-1. Block any link of the cascade could prevent and control the occurrence of CVS, and thus effectively improve cerebral metabolism... |
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