本文選題：腹腔高壓癥 + 失血性休克��； 參考：《第三軍醫(yī)大學(xué)》2016年博士論文

【摘要】：研究背景嚴(yán)重創(chuàng)傷性患者在失血性休克、燒傷、腹部創(chuàng)傷等,在救治過程中常發(fā)生腹腔高壓癥(intra-abdominal hypertension,IAH),甚至進(jìn)展為腹腔間隙綜合征(abdominal compartment syndrome,ACS),累及多種腹腔內(nèi)臟器(腸道、胃、肝和腎)及腹腔外器官(腦、心及肺)等。IAH/ACS包括:原發(fā)性、繼發(fā)性和復(fù)發(fā)性3類。原發(fā)性IAH/ACS是由腹腔/盆腔疾病或損傷所引起;繼發(fā)性IAH/ACS并不由腹腔/盆腔疾病或損傷引起,如全身炎癥反應(yīng)綜合征、缺血休克和大面積燒傷等;復(fù)發(fā)性IAH/ACS是指前期IAH/ACS經(jīng)手術(shù)或藥物治療緩解后再次發(fā)生。IAH發(fā)生的危險(xiǎn)因素包括:創(chuàng)傷后大量輸液、復(fù)蘇后毛細(xì)血管滲漏、腹腔內(nèi)容物增加和腹壁順應(yīng)性下降等,而其中創(chuàng)傷后大量輸液是主要原因。IAH的發(fā)病機(jī)制和病理進(jìn)展過程目前尚不完全明確。目前治療IAH的方法依然集中在剖腹減壓等外科技術(shù)的應(yīng)用上,但依然存在如減壓后綜合征造成的再灌注損傷等問題。由于腸道水腫等損傷是腹內(nèi)壓升高的重要因素,本研究以如何減緩腸道水腫等損傷的發(fā)生,以及如何緩解腹內(nèi)高壓影響的重要腹腔外器官—腦部的損傷為主要內(nèi)容。目前越來越受到人們關(guān)注的黑色素皮質(zhì)激素(melanocortin,MC),MC通過其不同受體在多器官中發(fā)揮調(diào)節(jié)色素沉著,能量穩(wěn)態(tài),炎癥控制和免疫調(diào)節(jié)等功能,有研究發(fā)現(xiàn)MC4受體(melanocortin 4 receptor,MC4R)激動(dòng)劑和其人工合成類似物可以在失血性休克、缺血性卒中和創(chuàng)傷性顱腦損傷中發(fā)揮保護(hù)作用,并通過膽堿能抗炎通路發(fā)揮快速抗炎的作用,但具體機(jī)制尚不清楚。本課題旨在探尋MC是否可以起到緩解繼發(fā)性IAH中腸和腦功能障礙的作用,并進(jìn)一步探尋其機(jī)制,以期為臨床腹腔高壓癥患者的治療提供新的策略。為了檢驗(yàn)上述假設(shè),本研究首先建立繼發(fā)性IAH大鼠模型,該模型應(yīng)便于操作、可重復(fù)性高并可在一定程度上較好的模擬IAH的發(fā)病過程。其次,觀察給予RO27-3225(MC4R激動(dòng)劑)后可否減輕IAH誘導(dǎo)的腸道損傷,該保護(hù)作用通過何種機(jī)制發(fā)揮效果。最后探討RO27-3225是否對(duì)于IAH誘發(fā)的腹腔外器官損害--腦損傷的具有保護(hù)效果,并判斷膽堿能信號(hào)通路在其中的作用。研究方法1.采用股動(dòng)脈插管后放血法,誘導(dǎo)平均動(dòng)脈壓(mean arterial pressure,MAP)分別達(dá)到:40mm Hg(維持120 min);30mm Hg(維持90min)和25mm Hg(維持60min),而后均合并IAP=20mm Hg(維持4 h)以建立大鼠繼發(fā)性IAH模型,利用干濕比法檢測腸道和腦組織含水量,利用HE染色法在光鏡下觀察大鼠腸道組織形態(tài)學(xué)和分析不同組間生存率,從中選擇一種既可造成明顯損傷又可保證生存率以供后續(xù)試驗(yàn)可順利進(jìn)行的大鼠休克后IAH模型進(jìn)行下述觀察。2.在繼發(fā)性IAH大鼠模型(30mm Hg維持90min合并IAP=20mm Hg維持4h)中,通過觀察大鼠MAP的變化程度;采用real-time PCR法檢測腸壁全層炎癥因子(TNF-α和IL-1β)變化;使用干濕比法檢測腸道含水量變化;利用HE染色法在光鏡下觀察大鼠腸道組織形態(tài)學(xué)組織變化;利用酶聯(lián)免疫吸附方法檢測血漿內(nèi)腸脂肪酸結(jié)合蛋白變化;通過檢測異硫氰酸熒光素以反映腸道滲透性變化和使用免疫印跡法檢測影響腸道滲透性的關(guān)鍵因子ROCK1及肌球蛋白輕鏈磷酸化水平以及檢測腸道內(nèi)超氧化物歧化酶變化等指標(biāo)探討IAH對(duì)腸道的損傷效果。并在此基礎(chǔ)上進(jìn)一步觀察RO27-3225是否可以發(fā)揮保護(hù)腸道的作用。3.在繼發(fā)性IAH大鼠模型中,利用干濕比法檢測腦含水量變化;通過檢測伊文思藍(lán)外滲法反映血腦屏障滲透性、使用real-time PCR法和酶聯(lián)免疫吸附方法檢測腦內(nèi)炎癥因子(TNF-α和IL-1β)變化、采用酶聯(lián)免疫吸附方法及免疫印跡法檢測水通道蛋白4及金屬基質(zhì)蛋白酶9表達(dá)變化,以及利用免疫組化法檢測神經(jīng)膠質(zhì)細(xì)胞表達(dá)的變化等指標(biāo)探討IAH對(duì)腦的損傷效果,進(jìn)一步觀察RO27-3225是否可以發(fā)揮保護(hù)腦組織的作用。研究結(jié)果1.選取MAP為30mm Hg持續(xù)90 min合并IAP=20 mm Hg持續(xù)4 h這一條件可誘導(dǎo)大鼠腸道出現(xiàn)明顯組織學(xué)損傷,導(dǎo)致腸道含水量明顯上升,并可保證其生存率以確保后續(xù)試驗(yàn)可以進(jìn)行;2.RO27-3225可在一定程度上穩(wěn)定MAP變化,降低IAH所誘發(fā)的腸道內(nèi)炎癥因子(TNF-α和IL-1β)升高,緩解IAH導(dǎo)致的腸道內(nèi)ROCK 1蛋白表達(dá)和肌球蛋白輕鏈磷酸化水平下降,降低血漿內(nèi)腸脂肪酸結(jié)合蛋白水平,減輕腸水腫、腸道滲透性和腸道組織形態(tài)學(xué)等結(jié)果的異常變化,從而起到緩解IAH導(dǎo)致的腸道損傷的作用。而該保護(hù)作用可被其特異性阻滯劑(HS024)和煙堿型乙酰膽堿受體拮抗劑(氯異桑大明)所阻止。3.RO27-3225可減輕IAH導(dǎo)致的腦水腫,降低炎癥因子、水通道蛋白4及金屬基質(zhì)蛋白酶9的表達(dá),從而發(fā)揮緩解IAH中腦損傷的作用。而該保護(hù)作用可被其特異性阻滯劑(HS024)和煙堿型乙酰膽堿受體拮抗劑(氯異桑大明)所阻止。但對(duì)IAH誘導(dǎo)的神經(jīng)膠質(zhì)細(xì)胞表達(dá)增多并無影響。結(jié)論1.IAH可導(dǎo)致腹腔內(nèi)臟器-腸道產(chǎn)生明顯水腫及炎癥反應(yīng),并出現(xiàn)明顯組織學(xué)損傷,此外IAH也可誘導(dǎo)腹腔外器官-腦組織產(chǎn)生明顯炎癥、水腫并導(dǎo)致血腦屏障完整性損害;2.選擇性MC4R激動(dòng)劑(RO27-3225)可以穩(wěn)定機(jī)體血流動(dòng)力學(xué),并通過調(diào)節(jié)ROCK1表達(dá)和肌球蛋白輕鏈磷酸化水平以緩解腸道滲透性增高,并可降低炎癥反應(yīng)程度,而有效緩解IAH誘導(dǎo)的腸道損傷。該保護(hù)作用可能是通過膽堿能通路發(fā)揮效果;3.選擇性MC4R激動(dòng)劑可以通過降低金屬基質(zhì)蛋白酶9表達(dá)以緩解血腦屏障破壞,通過作用水通道蛋白4以降低腦水腫程度,并可減輕腦組織炎癥反應(yīng)有效改善IAH導(dǎo)致的腦組織損傷,該保護(hù)作用可能是通過膽堿能通路發(fā)揮效果。但其在急性期內(nèi)對(duì)神經(jīng)膠質(zhì)細(xì)胞數(shù)量無明顯影響。
[Abstract]:The research background of severe traumatic patients in hemorrhagic shock, burns, abdominal trauma, and so on. In the course of treatment, intra-abdominal hypertension (IAH) often occurs, and even abdominal compartment syndrome (ACS), involving a variety of abdominal viscera (intestine, stomach, liver and kidney) and external organs of the abdomen (brain, .IAH/ACS includes 3 types: primary, secondary and recurrent. Primary IAH/ACS is caused by abdominal / pelvic diseases or injuries; secondary IAH/ACS is not caused by abdominal / pelvic diseases or injuries, such as systemic inflammatory response syndrome, ischemic shock and large area burn, and recurrent IAH/ACS refers to prophase IAH/ACS through surgery or medicine The risk factors for the recurrence of.IAH after the treatment of remission include: massive infusion after trauma, capillary leakage after resuscitation, increase of intraperitoneal content and decrease of abdominal wall compliance, and the pathogenesis and pathological progress of.IAH are not completely clear at present. At present, the methods for the treatment of IAH However, it is focused on the application of surgical techniques such as laparotomy, but there are still problems such as reperfusion injury caused by post decompression syndrome. Because of intestinal edema, such as intestinal edema is an important factor in intraperitoneal pressure increase, this study can reduce the occurrence of intestinal edema and other injuries, as well as the important external organs such as how to relieve the effect of intraabdominal hypertension. The damage of the brain is the main content. Melanocortin (MC) is becoming more and more concerned. MC plays the functions of regulating pigmentation, energy homeostasis, inflammatory control and immunoregulation through its different receptors in multiple organs. The research has found that the MC4 receptor (melanocortin 4 receptor, MC4R) agonists and their artificial agents have been found. Synthetic analogues can play a protective role in hemorrhagic shock, ischemic stroke and traumatic brain injury, and play a rapid and anti inflammatory role through the cholinergic anti-inflammatory pathway, but the specific mechanism is not clear. The purpose of this study is to explore whether MC can play a role in alleviating intestinal and brain dysfunction in secondary IAH and further explore. The mechanism is expected to provide a new strategy for the treatment of patients with clinical abdominal hypertension. In order to test the above hypothesis, this study first established the secondary IAH rat model. This model should be easy to operate, can be highly reproducible and can simulate the pathogenesis of IAH to a certain extent. The second, the observation is given RO27-3225 (MC4R agonist) can be reduced. The protective effect of the protective effect of light IAH on the intestinal damage and the effect of the protective effect. Finally, the effect of RO27-3225 on IAH induced intraperitoneal organ damage, brain injury, and the role of cholinergic signal pathway in it were judged. Method 1. the mean arterial pressure (mean AR) was induced by the method of blood release after femoral artery intubation. Terial pressure, MAP), 40mm Hg (maintain 120 min), 30mm Hg (maintain 90min) and 25mm Hg (maintain 60min), and then all merged (maintain 4) to establish a secondary rat model, use the dry wet ratio method to detect the water content of the intestine and brain tissue, and observe the intestinal morphology and analysis of the rat's intestines under the light microscope. The survival rate of the same group was selected from the IAH model of rats after shock, which could both cause obvious damage and guarantee survival rate for subsequent experiments. The following observation was made by.2. in the secondary IAH rat model (30mm Hg maintenance 90min combined with IAP=20mm Hg to maintain 4h), by observing the degree of change of MAP in rats; real-time PCR method was used. The changes in the whole intestinal wall inflammatory factors (TNF- - and IL-1 beta) were detected, the changes in the intestinal water content were detected by the dry wet ratio method, and the changes of the intestinal tissue in the rats were observed by the HE staining method, and the changes in the intestinal fatty acid binding protein were detected by the enzyme linked immunosorbent assay, and the isothiocyanate fluorescent protein was detected to reflect the intestinal tract. The key factors affecting the permeability of the intestinal tract, ROCK1, the level of myosin light chain phosphorylation, and the changes of the superoxide dismutase in the intestinal tract were detected by Western blot, and the effects of IAH on the intestinal damage were investigated. On the basis of this, the effect of RO27-3225 on the protection of intestinal tract was further observed,.3. In the secondary IAH rat model, the changes in the water content of the brain were detected by the dry wet ratio method, and the blood brain barrier permeability was detected by Evans blue exosmosis. The changes of the brain inflammatory factors (TNF- and IL-1 beta) were detected by real-time PCR and ELISA, and the water channel eggs were detected by enzyme linked immunosorbent assay and Western blot. The changes in the expression of white 4 and metal matrix proteinase 9 and the changes of the expression of glial cells by immunohistochemical method were used to investigate the effect of IAH on brain damage, and further to observe the effect of RO27-3225 on the protection of brain tissue. Results 1. the results were selected as the condition of MAP for 30mm Hg holding 90 min with IAP=20 mm Hg continuous 4 h. It can induce obvious histological damage in the intestinal tract of rats, which can lead to an obvious increase in the water content of the intestine, and ensure the survival rate to ensure the follow-up test. 2.RO27-3225 can stabilize the MAP changes to a certain extent, reduce the increase of the intestinal inflammatory factors (TNF- A and IL-1 beta) induced by IAH, and alleviate the ROCK 1 protein table in the intestinal tract caused by IAH. The level of light chain phosphorylation of myosin and myosin decreases, reduces the level of intestinal fatty acid binding protein, reduces the abnormal changes in intestinal edema, intestinal permeability and intestinal histology, and thus plays a role in alleviating the intestinal damage caused by IAH, and the protective effect can be treated by its specific blocker (HS024) and nicotinic acetylcholate. The alkali receptor antagonist (cisisan Daming) prevents.3.RO27-3225 from the brain edema caused by IAH, and reduces the expression of inflammatory factors, aquaporin 4 and metal matrix protease 9, which can play a role in alleviating brain damage in IAH, and this protective effect can be treated by its specific blocker (HS024) and nicotinic acetylcholine receptor antagonist (chloroisoyl). Sang Daming) prevented. But it did not affect the increase of the expression of glial cells induced by IAH. Conclusion 1.IAH can cause obvious edema and inflammatory reaction in the visceral organs of the abdominal cavity, and there is obvious histological damage. In addition, IAH can induce obvious inflammatory disease in the external organ - brain tissue, edema and damage of blood brain barrier integrity; 2. Selective MC4R agonist (RO27-3225) can stabilize the hemodynamics of the body, and by regulating the expression of ROCK1 and the level of myosin light chain phosphorylation to alleviate the increase in intestinal permeability and reduce the degree of inflammation, and effectively alleviate the intestinal damage induced by IAH. The protective effect may be through the cholinergic pathway; 3. Sexual MC4R agonists can reduce the destruction of blood brain barrier by reducing the expression of matrix metalloproteinase 9, reducing the degree of brain edema through the action of aquaporin 4, and alleviating the inflammatory response of brain tissue to effectively improve the brain tissue damage caused by IAH. This protective effect may be achieved through the bile alkali energy pathway. There was no obvious effect on the number of glial cells.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R641

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