本文選題：肥胖 + 牙周炎　； 參考：《南方醫(yī)科大學(xué)》2017年博士論文

【摘要】：許多研究都已分別證實肥胖與慢性腎病具有相關(guān)性、牙周炎與慢性腎病具有相關(guān)關(guān)系。但尚缺乏在肥胖這種代謝異常狀態(tài)下牙周病對腎臟影響的直接證據(jù)。本研究使用牙周炎復(fù)合肥胖小鼠模型,旨在探討在肥胖狀態(tài)下,牙周炎是否對腎臟病變的產(chǎn)生存在影響及其可能的機制。為牙周炎是否影響腎臟疾病的發(fā)生尋找直接的證據(jù)。為臨床多學(xué)科聯(lián)合診斷,治療和預(yù)防提供依據(jù)。本文內(nèi)容共分為三部分:一牙周炎對肥胖小鼠腎臟損害的影響目的:建立飲食誘導(dǎo)型肥胖伴實驗性牙周炎的小鼠模型,研究牙周炎對肥胖小鼠腎臟功能及腎臟病損是否存在影響。方法:275只小鼠隨機分為高脂飼料組(HF組)和低脂飼料組(LF組)兩組。飼料誘導(dǎo)時間分為8周、16周、30周三個時間點。每個飼料誘導(dǎo)時間結(jié)束時,再將每個飼料組分為牙周炎組(P組)和非牙周炎組(對照組,C組),P組采用絲線結(jié)扎法誘導(dǎo)實驗性牙周炎,C組做假性結(jié)扎對照處理。處死小鼠取材。取30周小鼠,檢測血清腎功能指標(biāo)血清總蛋白、白蛋白、血尿素氮、肌酐,并對組織切片行HE染色及三種特殊染色(MASSON染色、PAS染色、改良六胺銀染色)。結(jié)果:HF組比LF組血清總蛋白、白蛋白水平均有顯著下降。而HFP和HFC兩組間無明顯差異,同樣,LF組有無牙周炎干預(yù)(LFP和LFC),二者之間也沒有明顯差異。HFP組的血清肌酐明顯高于LFP和LFC,而HFC、LFP和LFC三組之間無明顯差異,HFP和HFC之間也無明顯差異。HF組的血清尿素氮數(shù)值偏高,但四組之間沒有統(tǒng)計學(xué)差異。腎組織病理改變可見LFP組織學(xué)特征與LFC接近,表現(xiàn)為正常腎臟的組織學(xué)特點。HFP和HFC組小鼠可見腎小球局灶性毛細血管袢消失,系膜細胞增生,腎小球基底膜及球周纖維增生。腎小管上皮細胞玻璃樣或空泡變性,管間質(zhì)纖維增生。以上病理特征在HFP組與HFC組小鼠情況近似,但HFP組的腎小管間質(zhì)纖維增生更為嚴(yán)重。結(jié)論:本研究成功建立了不同程度的飲食誘導(dǎo)型肥胖復(fù)合牙周炎的小鼠模型。正常小鼠患單純牙周病并不會導(dǎo)致腎臟損害,肥胖才是腎臟損害的主要因素。在DIO30周這種嚴(yán)重肥胖的情況下,牙周炎可能會加劇腎小管間質(zhì)纖維化的病變。二不同肥胖/牙周炎癥狀態(tài)下對腎臟損害的差異目的:利用DI08周、16周、30周及牙周感染5d、10d小鼠,探索在不同肥胖狀態(tài)下及不同牙周炎癥狀態(tài)下,牙周感染對肥胖小鼠腎臟損害的影響。方法:對所有分組小鼠組織切片行HE染色及三種特殊染色(MASSON染色、PAS染色、改良六胺銀染色)。結(jié)果:從DI08周至16周至30周,肥胖小鼠腎小球均有系膜細胞增生和毛細血管基底膜增厚,嚴(yán)重程度近似,但受累腎小球數(shù)目及范圍增加,腎小管上皮細胞均有空泡變性,范圍逐漸擴大。腎小球周纖維增生逐漸加重,腎小管間質(zhì)纖維化程度加重、范圍加大。DI016周小鼠牙周感染10d與5d腎臟病變無明顯區(qū)別,30周小鼠牙周感染10d比5d腎小管間質(zhì)纖維化程度更加嚴(yán)重。結(jié)論:隨著肥胖狀態(tài)增加,腎臟損害加重。可能在DIO30周這種重度肥胖狀態(tài)下,小鼠牙周感染時間越長,對腎小管間質(zhì)纖維化的影響越大。三牙周炎影響腎臟損害的可能機制目的:檢測各組小鼠腎臟組織中TGF-β1,MMP-2,TIMP-1蛋白和基因轉(zhuǎn)錄水平的表達差異,進而探討肥胖狀態(tài)下時慢性牙周炎影響腎臟損害可能的病理機制。方法:采用免疫組化檢測小鼠腎臟組織中TGF-β1,MMP-2,TIMP-1蛋白的表達,進行半定量分析,另采用實時定量PCR技術(shù)進行TGF-β1,MMP-2,TIMP-1 mRNA基因表達差異分析。結(jié)果:免疫組化顯示,HFP、HFC、LFP、LFC四組腎臟組織中TGF-β1、TIMP1蛋白有統(tǒng)計學(xué)差異,每兩組均差異明顯,HFP組表達量最高。MMP2表達與之相反,LF兩組表達較高。實時定量PCR結(jié)果顯示,肥胖是主要影響因素,HFP、HFC、LFP、LFC 四組之間 TGF-β1、MMP2、TIMP1 mRNA 表達有統(tǒng)計學(xué)差異。結(jié)論:在肥胖狀態(tài)下,牙周干預(yù)促進了腎臟組織TGF-β1、TIMP-1這兩個促進纖維化抑制降解蛋白的表達,同時抑制了降解EDM的主要水解酶MMP-2的表達,這可能是牙周炎影響肥胖小鼠腎臟病變的機制之一。
[Abstract]:Many studies have confirmed the correlation between obesity and chronic kidney disease. Periodontitis is associated with chronic kidney disease. But there is no direct evidence of the impact of periodontitis on the metabolic disorder of obesity. This study uses periodontitis compound obesity mice model to explore whether periodontitis is the kidney in the condition of obesity. The existence of the influence and possible mechanisms of the formation of visceral lesions. It provides a direct evidence for the effect of periodontitis on the occurrence of renal diseases. It provides a basis for clinical multidisciplinary combined diagnosis, treatment and prevention. The content of this article is divided into three parts: the effect of periodontitis on kidney damage in obese mice: the establishment of diet induced obesity with real disease The effect of periodontitis on renal function and renal impairment in obese mice was studied. Methods: 275 mice were randomly divided into high fat diet group (HF group) and low fat diet group (group LF). The feed induction time was divided into 8 weeks, 16 weeks, 30 Wednesday time points. Each feed induction time was over, and each feed was then fed. The material group was divided into periodontitis group (group P) and non periodontitis group (control group, group C). Group P was used to induce experimental periodontitis by wire ligation, and group C was treated with pseudoligature. The mice were sacrificed for 30 weeks. The serum total protein, albumin, blood urea nitrogen and creatinine were detected in the serum kidney function index, and the tissue sections were stained with HE and three special types. Staining (MASSON staining, PAS staining, improved six amine silver staining). Results: the level of serum total protein and albumin decreased significantly in group HF than in group LF, but there was no significant difference between groups of HFP and HFC. Similarly, there was no periodontitis intervention (LFP and LFC) in the LF group (LFP and LFC), and the serum creatinine in the two group was significantly higher than that of LFP and LFC. There was no significant difference between the three groups. There was no significant difference in the serum urea nitrogen between the HFP and the HFC groups, but there was no statistical difference between the four groups. The histopathological changes of the renal tissue showed that the histological features of the LFP were close to LFC, and the histological features of the normal kidneys were found to disappear in the glomerular focal capillary loops in the group.HFP and the HFC group. Mesangial cell proliferation, glomerular basement membrane and peripheral fibrous hyperplasia. Renal tubular epithelial cells were glassy or vacuolar degeneration, tubulointerstitial fibrous hyperplasia. The above pathological features were similar in group HFP to HFC mice, but in group HFP, tubulointerstitial fiber hyperplasia was more serious. Conclusion: This study successfully established a different degree of dietary induced fertilizer. A mouse model of fat complex periodontitis. Normal periodontitis does not cause renal damage in normal mice. Obesity is the main factor in renal damage. Periodontitis may exacerbate renal tubulointerstitial fibrosis in DIO30 weeks. Two different obesity / periodontitis differences in renal damage Using DI08 weeks, 16 weeks, 30 weeks and periodontal infection 5D, 10d mice, to explore the effect of periodontal infection on kidney damage in obese mice under different obesity and periodontitis. Methods: HE staining and three special staining (MASSON staining, PAS staining, improved six amine silver staining) were carried out in all the tissue sections of the group mice. Results: from DI08 From 16 weeks to 30 weeks, the glomeruli of the obese mice had mesangial cell proliferation and capillary basement membrane thickening. The severity of the glomeruli was similar, but the number and scope of the glomeruli were increased. The renal tubular epithelial cells were vacuolated and expanded gradually. The proliferation of peripheral fibrous fibrosis was gradually aggravated and the degree of renal tubulointerstitial fibrosis was aggravated. There was no obvious difference between 10d and 5D in the periodontal infection of mice in the large.DI016 week. The periodontal infection of the mice in 30 weeks was more severe than that of the 5D renal tubule. Conclusion: with the increase of obesity, the renal damage is aggravated. The longer the periodontal infection time is, the longer the periodontal infection of the mice is, the fibrosis of the renal tubules. The possible mechanism of the effect of three periodontitis on renal damage: the difference in the expression of TGF- beta 1, MMP-2, TIMP-1 protein and gene transcription level in kidney tissues of mice was detected, and the possible pathological mechanism of chronic periodontitis in the condition of obesity was explored. Methods: immunohistochemistry was used to detect T in the kidney tissues of mice. GF- beta 1, MMP-2, TIMP-1 protein expression, semi quantitative analysis, and real-time quantitative PCR technology for TGF- beta 1, MMP-2, TIMP-1 mRNA gene expression difference analysis. Results: immunohistochemistry showed that HFP, HFC, LFP, LFC four groups of renal tissue beta 1, every two groups are different, the highest expression of the two groups On the contrary, the expression of LF two groups was higher. Real-time quantitative PCR results showed that obesity was the main influencing factor. The expression of TGF- beta 1, MMP2, TIMP1 mRNA was statistically different between groups of HFP, HFC, LFP and LFC. Conclusion: in the obese state, periodontal intervention promoted the TGF- beta 1 of the kidney tissue, TIMP-1 these two promote the expression of fibrotic inhibition degrading protein. It inhibited the expression of MMP-2, a major hydrolytic enzyme that degrades EDM, which may be one of the mechanisms of periodontitis affecting the kidney of obese mice.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R781.4;R692

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