本文選題：繼發(fā)性淋巴水腫 + 獼猴�。� 參考：《山東大學(xué)》2017年博士論文

【摘要】：目的:繼發(fā)性上肢淋巴水腫(Secondary upper limb lymphedema,SULL)是乳腺癌術(shù)后常見并發(fā)癥之一,是腋窩淋巴結(jié)清掃術(shù)和電離放射治療后區(qū)域淋巴管損傷形成的慢性進行性淋巴系統(tǒng)病變,嚴(yán)重影響患者身心健康。雖然近些年乳腺癌患者中淋巴水腫的診斷和治療已取得重要進展,但淋巴水腫仍是影響該疾病患者生活質(zhì)量和身心健康的重要因素。目前許多研究者致力于乳腺癌患者術(shù)后SULL的研究,以期改善術(shù)后生活質(zhì)量。SULL治療研究的一個重要方面就是動物模型的建立。迄今,據(jù)報道已成功建立多種淋巴水腫的動物模型,包括嚙齒動物和食肉動物。雖然在非靈長類動物模型中關(guān)于淋巴水腫的發(fā)病機制和治療的研究取得了鼓舞人心的成果,但是非靈長類淋巴水腫動物模型建模成功率相對較低,而且更重要的是其與人類的肢體在生理、解剖和功能上存在著很大差異,并不能正確反映人類的生理和病理狀態(tài)�；谏鲜鲈�,這些傳統(tǒng)的動物模型并不能很好的復(fù)制人類上肢淋巴水腫的病理生理過程。本研究擬使用與人類生理、解剖和遺傳極其接近的獼猴作為研究對象,探索建立SULL模型的可行性,以及建模評價指標(biāo)。方法:健康雌性獼猴,年齡4-5歲,模擬實施標(biāo)準(zhǔn)的人類腋窩淋巴結(jié)清掃術(shù),分別于術(shù)前2 周和術(shù)后4周聯(lián)合使用放射技術(shù)對動物腋窩區(qū)域進行電離放射,作用于獼猴上肢,以破壞殘存淋巴管。超聲成像檢查腋窩血管血流通暢情況,以排除血管因素所致水腫;分段測量前臂中部、肘不和上臂中部的周徑變化;高分辨率核磁共振成像(magnetic resonance imaging,MRI)淋巴管造影觀察上肢淋巴系統(tǒng)影像學(xué)改變;生物電阻抗分析(bioelectrical impedance analysis,BIA)監(jiān)測上肢細胞外液體改變;常規(guī)病理觀察淋巴管形態(tài)學(xué)改變;免疫組織化學(xué)染色檢測淋巴上皮標(biāo)志物表達以進一步確認淋巴管形態(tài)學(xué)變化。結(jié)果:1.上肢周徑:干預(yù)側(cè)肢體呈進行性水腫,并持續(xù)存在,24個月內(nèi),干預(yù)側(cè)上肢/對側(cè)上肢周徑比率為100%-137%,手掌厚度增加約15%-40%,表現(xiàn)為典型的淋巴水腫特征;2.MRI淋巴造影:手術(shù)3個月后MRI顯示上肢淋巴管出現(xiàn)明顯變化。與對側(cè)正常上肢相比,干預(yù)測上肢的淋巴干消失,淋巴管結(jié)構(gòu)被霧狀背景襯托下明亮的點狀樣式所取代。在所有動物中,淋巴水腫顯示為筋膜外分布,并在T2加權(quán)像上呈高信號強度。正面3D擾相梯度回波高分辨率MRI和數(shù)字減影血管造影(digital subtraction angiography,DSA)淋巴管造影顯像中,觀察到網(wǎng)狀分布的擴張淋巴管,其淋巴回流延遲,提示存在與梗阻相關(guān)的新血管生成;3.B1A顯示:上肢細胞外液水分容量增加,與淋巴水腫的病理學(xué)改變呈線性相關(guān);4.病理切片和免疫組化染色顯示了動物模型淋巴管數(shù)量增多,管腔明顯擴張,淋巴管的變化曲率呈淋巴水腫的典型病理學(xué)改變。結(jié)論:1.獼猴SULL模型的建立過程簡單,容易成模。2.獼猴SULL動物模型以與人類更相似的遺傳背景復(fù)制了該病的病理生理學(xué)特點。3.評價方法簡便易行,該新型動物模型有助于增加我們對上肢獲得性淋巴水腫的認識,并可促進新治療方法的開發(fā)。
[Abstract]:Objective: secondary upper limb lymphedema (Secondary upper limb lymphedema, SULL) is one of the common complications after breast cancer surgery. It is a chronic progressive lymphatic disease caused by axillary lymph node dissection and ionizing radiation therapy, which seriously affects the physical and mental health of the patients. Although in recent years, the lymph nodes in the breast cancer patients are lymphatic. An important progress has been made in the diagnosis and treatment of edema, but lymphedema is still an important factor affecting the quality of life and physical and mental health of the patients. Many researchers are currently working on the study of postoperative SULL in patients with breast cancer, in order to improve the research of.SULL treatment for postoperative life quality is the establishment of animal models. It is reported that many animal models of lymphedema have been successfully established, including rodents and carnivorous animals. Although there are encouraging results in the study of the pathogenesis and treatment of lymphedema in the non primate model, the success rate of non primate lymphoedema animal model modeling is relatively low and more important. It is different from the human body in physiology, anatomy and function, and does not correctly reflect the physiological and pathological state of human beings. Based on the above reasons, these traditional animal models do not reproduce well the pathophysiological process of the human upper limb lymphedema. This research is intended to be used with human physiology, anatomy and heredity. The feasibility of establishing SULL model and modeling evaluation index were explored. Methods: healthy female rhesus monkeys, aged 4-5 years old, simulated the implementation of standard human axillary lymph node dissection, were used to ionize radiation in the axillary region of animals at 2 weeks before and 4 weeks after operation respectively. The upper limb was used to destroy the remaining lymphatic vessels. Ultrasound imaging examined the patency of the axillary vascular blood flow to exclude the edema caused by vascular factors; measure the middle of the forearm and the circumference of the middle of the upper arm in the middle of the forearm; the high-resolution magnetic resonance imaging (magnetic resonance imaging, MRI) lymphangiogram observed the imaging changes of the upper limb lymphatic system; Bioelectrical impedance analysis (BIA) was used to monitor the changes in the outer fluid of the upper extremity; the morphological changes of the lymphatics were observed by routine pathology; the expression of lymphoepithelial markers was detected by immunohistochemical staining to further confirm the morphological changes of the lymphatics. Results: 1. the circumferential diameter of the upper limb: the intervention side limbs were progressive edema and continued. Within 24 months, the ratio of the circumferential diameter of the upper limb / contralateral upper limb of the intervention side was 100%-137% and the palmar thickness increased by about 15%-40%, which showed typical lymphedema characteristics; 2.MRI lymphography: 3 months after the operation, the MRI showed obvious changes in the upper limb lymphatic vessels. Compared with the normal upper limbs, the lymphatic trunk of the upper limb disappeared and the lymphatic structure was foggy compared with the normal upper limb. In all animals, lymphedema is displayed outside the fascia and shows high signal intensity on the T2 weighted image in all animals. The reticular distribution of the positive 3D phase gradient echo high resolution MRI and the digital subtraction angiography (DSA) angiography (digital subtraction angiography, DSA) lymphangiography Dilated lymphatic vessels, with delayed lymphatic reflux, suggested the existence of new angiogenesis associated with obstruction; 3.B1A showed an increase in water capacity in the outer fluid of the upper limb and a linear correlation with the pathological changes of lymphedema; 4. pathological sections and immunohistochemical staining showed the increase in the number of lymphatics in the animal model, the obvious dilatation of the lumen and the change of lymphatic vessels. Typical pathological changes in the curvature of lymphedema. Conclusion: 1. the establishment of SULL model in rhesus monkeys is simple and easy to model.2. macaque SULL animal model to replicate the pathophysiological characteristics of the disease with the more similar genetic background of human beings. The.3. evaluation method is simple and easy. This new animal model helps to increase our upper limb acquired lymph nodes. The understanding of edema can promote the development of new treatment methods.

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R737.9;R-332

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