雾化吸入柠檬酸对大鼠灌注难溶性贫铀促溶和解毒作用研究

发布时间：2018-05-01 05:20

本文选题：贫铀 + 雾化吸入　；参考：《安徽医科大学》2012年硕士论文

【摘要】：研究背景军事及恐怖袭击事件等大量使用贫铀（Depleted Uranium，DU）武器，包括DU弹、燃烧弹和含DU的脏弹等。DU弹体在爆炸时形成的放射性气溶胶可导致大规模人群受到长期低剂量放射性内污染的伤害，吸入是造成内污染的最主要途径。吸入的DU气溶胶，特别是难溶性DU气溶胶，长期滞留于肺组织和附近淋巴结内，可造成肺组织严重损伤（肺气肿和肺纤维化等），甚至诱导肺癌。加速肺内难溶性DU气溶胶的清除，缩短DU气溶胶在肺组织的滞留时间及浓度，是减轻DU气溶胶吸入后引起机体损伤的最根本措施，临床上对经呼吸道吸入滞留肺部的难溶性DU气溶胶，除物理方法洗肺外，目前国内外仍未找到有效的医学救治措施，有必要开发新的药物促溶肺内难溶性DU气溶胶颗粒物，减少吸入性DU气溶胶的损伤。目的探讨雾化吸入柠檬酸对大鼠染毒难溶性DU气溶胶促溶和解毒作用及其可能的机制，为进一步研究吸入难溶性DU气溶胶肺内的促溶救治奠定理论和实验基础。方法选用清洁级Wistar大鼠作为实验对象，应用肉眼直视下经口气管插管灌注难溶性DU颗粒物悬浊液的方法，建立难溶性DU气溶胶吸入染毒动物模型。在染毒后30min，给予雾化吸入给予20%（w v~(-1)）柠檬酸溶液，流量为1.44mL min~(-1)，1天1次，每次20min，连续给药7d，观察其对难溶性DU颗粒物的促溶和解毒效果。实验大鼠随机分为生理盐水对照组（对照组）、DU模型组、柠檬酸吸入组，分别在第一次染毒后7d、15d、30d大鼠股动脉放血剖杀，采用湿消化法检测双肺和单肾铀含量，取股动脉血进行血象分析，检测血清生化、胸腺T细胞亚群，HE染色观察肺、肾病理学改变，Masson染色观察肺间质胶原沉积，免疫组化法分析肺间质基质金属蛋白酶-9（MMP-9）和组织金属蛋白酶抑制物-1（TIMP-1）的表达等。结果1）与对照组比较，在15d至30d柠檬酸吸入组大鼠周体重增长正常，DU模型组大鼠周增重也未受到抑制，各组脏器系数变化趋势不明显；2）柠檬酸吸入组和DU模型组大鼠7d、15d WBC有增高的趋势，但30d各组WBC已恢复到正常水平，RBC、HGB和PLT变化不明显；3）血清生化检测发现柠檬酸吸入组在早期（7d）GOT、ALB、UA较DU模型组明显降低，7d、15d和30d柠檬酸吸入组较DU模型组CRE降低，血清镁离子升高；4）7d和15d，与DU模型组比较，柠檬酸吸入组大鼠外周血中CD3~+CD4~+、CD3~+CD4~+/CD3~+CD8~+明显增高，较对照组，无统计学差异性；30d增高的趋势不明显。雾化吸入柠檬酸可减轻DU染毒对大鼠外周血CD3~+CD4~+、CD3~+CD4~+/CD3~+CD8~+抑制作用，使其接近对照组比例；5）柠檬酸吸入组检测的肺U含量低于同时间点DU模型组，且随着染毒时间的延长，肺、肾铀含量均呈现逐渐减低的趋势；6）DU模型组，肺组织出现成纤维增生性改变，支气管上皮细胞脱落，淋巴细胞浸润，柠檬酸吸入组较DU模型组病变相对减轻；肾组织病变，柠檬酸吸入组和DU模型组主要表现为肾小管上皮细胞变性坏死等；7）Masson染色观察发现15d、30d柠檬酸吸入组肺胶原蛋白沉积量低于DU模型组；8）免疫组化分析表明DU模型组肺间质MMP-9和TIMP-1表达逐渐增强，在15d和30d较柠檬酸吸入组较DU模型组表达明显降低。结论1）肉眼指示下经口气管插管染毒DU颗粒悬浊液造模成功；2）雾化吸入柠檬酸能明显减轻肺内难溶性DU颗粒物吸入所致的大鼠肺损伤，其机制可能是改善肺内酸碱微环境，明显降低肺内U含量，减轻DU颗粒物对肺泡壁破坏，降低成纤维细胞增生，，从而调节MMP-9和TIMP-1表达量，使细胞外基质处于动态平衡，发挥对肺组织的保护作用。
[Abstract]:In order to reduce the accumulation time and concentration of DU aerosol in lung tissues , it is necessary to develop new drug - promoting intra - lung insoluble DU aerosol particles and reduce the damage of inhalation DU aerosol .

Objective To study the effect and possible mechanism of aerosol inhalation of citric acid on the dissolution and detoxification of hard - soluble DU aerosol in rats .

Methods The experimental rats were randomly divided into physiological saline control group ( control group ) , DU model group and citric acid inhalation group . The rats were randomly divided into physiological saline control group ( control group ) , DU model group and citric acid inhalation group . The rats were randomly divided into physiological saline control group ( control group ) , DU model group and citric acid inhalation group . The rats were randomly divided into physiological saline control group ( control group ) , DU model group and citric acid inhalation group .

Results 1 ) Compared with the control group , the peripheral weight of the rats in the group of 15 days to 30 days was normal , and the peripheral weight gain of DU model group was not inhibited , and the change trend of organ coefficients in each group was not obvious ;
2 ) There was an increasing trend of WBC in the group of citric acid inhalation group and DU model group at 7 days and 15 days , but the WBC recovered to normal level in 30d group , RBC , HGB and PLT changes were not obvious ;
3 ) The serum biochemical test showed that the concentration of GOT , ALB and UA in the early stage ( 7 d ) of the citrate inhalation group were significantly lower than those in DU model group , and the level of CRE in the treated group was lower than that in DU model group at 7 d , 15d and 30d , and the serum magnesium ions increased ;
4 ) Compared with DU model group , CD3 ~ + CD4 ~ + , CD3 ~ + CD4 ~ + / CD3 ~ + CD8 ~ + in peripheral blood of rats were significantly higher than those in DU model group .
The increase of CD3 ~ + CD4 ~ + , CD3 ~ + CD4 ~ + / CD3 ~ + CD8 ~ + in peripheral blood of rats was inhibited by atomization inhalation of citric acid , which was close to the control group .
5 ) The lung U content detected by the citric acid inhalation group was lower than that of DU model group in the same time , and the contents of lung and kidney were gradually decreased with the increase of the time of exposure .
6 ) Compared with DU model group , DU model group , lung tissue appeared fibroproliferative change , bronchial epithelial cell shedding , lymphocyte infiltration , and citric acid inhalation group compared with DU model group ;
Renal tissue lesion , citric acid inhalation group and DU model group were mainly characterized by degeneration and necrosis of tubular epithelial cells .
7 ) The deposition of pulmonary collagen was lower than that of DU model group after 15d and 30d of citric acid inhalation group .
8 ) Immunohistochemical analysis showed that the expression of MMP - 9 and TIMP - 1 was gradually increased in DU model group , and the expression of MMP - 9 and TIMP - 1 in DU model group was significantly lower than that in DU model group at 15 days and 30 days . Conclusion 1 ) The success of DU granule suspension was successful under the visual indication .
2 ) atomizing inhalation of citric acid can obviously reduce the lung injury of rats caused by inhalation of insoluble DU particles in the lung , and the mechanism may be to improve the acid - base microenvironment in the lung , reduce the U content in the lung , reduce the damage of DU particles to the alveolar wall , reduce the fibroblast proliferation , regulate the expression amount of MMP - 9 and TIMP - 1 , and make the extracellular matrix in a dynamic balance and play a role in protecting the lung tissue .

【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R114

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