肝豆状核变性动物模型的研究进展
DOI: 10.3969/j.issn.1001-5256.2022.05.041
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摘要: 肝豆状核变性(WD)是一种罕见的常染色体隐性遗传病,其发病机制复杂,涉及多系统多脏器及体内复杂的铜稳态调节系统,其中肝脏是铜离子最常沉积的器官,肝损伤也是WD最早和最常见的表现,因此寻找一种理想的动物模型在WD研究中非常重要。本文通过对目前国际上常用的WD动物模型进行综述,系统地归纳了不同模型的背景,肝脏、神经等系统表现以及模型应用,并对不同动物模型的特点进行了比较,为各类WD动物模型的应用提供借鉴。Abstract: Wilson's disease (WD) is a rare autosomal recessive disorder with a complex pathogenesis involving multiple systems, multiple visceral organs, and the complex copper homeostasis regulation system within the body. The liver is the most common organ for copper deposition, and liver injury is the earliest and most common manifestation of WD; therefore, it is important to find an ideal animal model for WD research. By summarizing the animal models of WD commonly used in the world, this article systematically summarizes the background, liver and nervous manifestations, and application of different models and compares the characteristics of different animal models, so as to provide a reference for the application of various animal models of WD.
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Key words:
- Hepatolenticular Degeneration /
- Liver Diseases /
- Disease Models, Animal
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急性胰腺炎(acute pamcreatitis,AP)是临床常见消化系统急腹症之一[1],近年来,其发病率不断上升[2]。Yokoe等[3]研究显示,15%~20%的AP进展为重症急性胰腺炎(severe acute pancreatic, SAP)。脓毒症是病原微生物侵入血液引起的全身感染性疾病,据Sagana等[4]报道美国每年约有0.6%的人发生脓毒症。SAP病情凶险极易引发脓毒症,SAP一旦发生脓毒症不仅加重医疗费用负担、延长住院时间,还可能并发脓毒性休克,多器官功能障碍,病情进展甚至会引起死亡[5],临床诊治极为困难。本研究回顾性分析SAP患者的临床资料,分析SAP患者并发脓毒症的相关因素,旨在为临床防治提供参考。
1. 资料与方法
1.1 研究对象
收集2007年1月—2020年3月贵州医科大学第三附属医院与黔南州人民医院收治的SAP患者临床资料。SAP诊断标准参考中华医学会制定的《急性胰腺炎诊治指南(2014)》[6]。脓毒症诊断标准参照国家卫生健康委颁发的《医院感染诊断标准(试行)》[7]。纳入标准:(1)年龄≥16周岁;(2)符合SAP诊断。剔除标准:(1)病历记录不全;(2)伴有恶性肿瘤晚期或使用糖皮质激素患者;(3)入院手术前已合并脓毒症者;(4)伴有其他部位原发性感染者。
1.2 研究方法
根据SAP是否发生脓毒症分为脓毒症与非脓毒症,记录每例患者年龄、性别、APACHEⅡ评分、血糖、血钙、血清总胆固醇、血清甘油三酯、血尿素氮、血清白蛋白、血清肌酐、胰腺坏死范围所占比例,以及入住ICU、低氧血症、深静脉置管、机械通气、预防性使用抗生素、血液净化、手术病灶坏死组织清除方式、留置导尿情况,血培养检出病原菌种类等临床资料。本研究所纳入SAP患者采取急诊手术清除病灶坏死组织,手术方式分为开腹与腹腔镜两种方式。
1.3 伦理学审查
本研究通过贵州医科大学第三附属医院伦理委员会审批,批号:2020-002,并经患者及家属知情同意。
1.4 统计学方法
采用SPSS 24.0软件进行数据分析。计量资料以x±s表示,两组间比较采用t检验,计数资料两组间比较采用χ2检验。多因素分析采用logistic回归分析。P < 0.05为差异有统计学意义。
2. 结果
2.1 一般资料
研究共纳入SAP患者178例,其中男106例、女72例, 年龄16~77岁,平均(49.69±14.77) 岁。发生脓毒症56例(31.46%),其中男36例、女20例,平均(51.29±13.92)岁。
2.2 脓毒症菌种分布
在56例SAP并发脓毒症患者血培养中共分离出61株病原菌,其中革兰阳性菌14株,占22.95%,革兰阴性菌39株,占63.93%,真菌8株,占13.11%(表 1)。
表 1 SAP合并脓毒症患者的菌种构成比病原菌 株数(n=61) 构成比(%) 革兰阳性菌 14 22.95 表皮葡萄球菌 8 13.11 溶血葡萄球菌 4 6.56 粪肠球菌 2 3.28 革兰阴性菌 39 63.93 肺炎克雷伯菌 11 18.03 鲍曼不动杆菌 9 14.75 铜绿假单胞菌 9 14.75 大肠埃希菌 7 11.48 嗜麦芽窄食假单胞菌 2 3.28 阴沟肠杆菌 1 1.64 真菌 8 13.11 白色假丝酵母菌 5 8.20 光滑假丝酵母菌 2 3.28 热带假丝酵母菌 1 1.64 2.2 单因素分析
单因素分析显示,APACHEⅡ评分、血糖、血钙、血清总胆固醇、血清甘油三酯、血尿素氮、血清肌酐、血清白蛋白,以及入住ICU、低氧血症、深静脉置管、机械通气、手术方式、血液净化、留置导尿、胰腺坏死范围在脓毒症和非脓毒症患者间差异均有统计学意义(P值均 < 0.05)(表 2)。
表 2 SAP并发脓毒症的单因素分析因素 非脓毒症(n=122) 脓毒症(n=56) 统计值 P值 年龄(岁) 48.95±15.14 51.29±13.92 t=1.011 0.314 男/女(例) 70/52 36/20 χ2=0.761 0.383 APACHEⅡ评分(分) 24.35±5.86 27.71±5.56 t=3.683 < 0.001 入住ICU(例) 41 31 χ2=7.538 0.006 低氧血症(例) 36 31 χ2=10.926 0.001 深静脉置管(例) 82 46 χ2=4.235 0.040 机械通气(例) 44 30 χ2=4.842 0.028 血糖(mmol/L) 11.37±3.80 13.13±4.34 t=2.596 0.011 预防性使用抗生素(例) 51 21 χ2=0.295 0.587 手术方式(例) χ2=8.249 0.004 腹腔镜 43 8 开腹 79 48 血液净化(例) 83 29 χ2=4.343 0.037 留置导尿(例) 34 34 χ2=17.539 < 0.001 胰腺坏死范围(例) χ2=13.386 0.001 >50% 9 12 30%~50% 39 25 < 30% 74 19 血钙(mmol/L) 2.26±0.32 2.14±0.33 t=-2.144 0.034 血清总胆固醇(mmol/L) 6.13±2.26 7.03±2.20 t=2.498 0.014 血清甘油三酯(mmol/L) 2.02±1.12 2.59±1.23 t=2.946 0.004 血尿素氮(mmol/L) 7.13±2.52 9.05±4.56 t=2.951 0.004 血清肌酐(μmol/L) 116.46±46.78 147.87±67.31 t=3.160 0.002 血清白蛋白(g/L) 36.08±7.95 32.62±10.22 t=-2.246 0.027 2.3 多因素分析
将单因素分析中有统计学意义的指标纳入logistic多因素回归分析,结果显示,APACHEⅡ评分、低氧血症、血糖、胰腺坏死范围、血清肌酐是SAP并发脓毒症的独立危险因素,采用腹腔镜清除病灶坏死组织为SAP并发脓毒症的独立保护因素(P值均 < 0.05)(表 3)。
表 3 SAP并发脓毒症的多因素分析变量 B SE Wald P值 OR 95%CI APACHEⅡ评分(分) 1.909 0.574 11.063 0.001 6.748 2.191~20.788 入住ICU 0.994 0.652 2.321 0.128 2.701 0.752~9.700 低氧血症 1.219 0.568 4.607 0.032 3.383 1.112~10.293 深静脉置管 0.577 0.677 0.728 0.394 1.781 0.473~6.710 机械通气 0.750 0.560 1.794 0.180 2.118 0.706~6.350 血糖(mmol/L) 1.665 0.767 4.714 0.030 5.288 1.176~23.781 手术方式(腹腔镜) -1.387 0.682 4.133 0.042 0.250 0.066~0.951 血液净化 -0.185 0.554 0.112 0.738 0.831 0.280~2.463 留置导尿 0.636 0.559 1.293 0.256 1.889 0.631~5.651 胰腺坏死范围 1.709 0.640 7.130 0.008 5.523 1.575~19.360 血钙(mmol/L) -0.964 0.586 2.710 0.100 0.381 0.121~1.202 血清总胆固醇(mmol/L) 0.498 0.593 0.703 0.402 1.645 0.514~5.263 血清甘油三酯(mmol/L) 0.740 0.840 0.777 0.378 2.097 0.404~10.880 血尿素氮(mmol/L) 1.066 0.630 2.862 0.091 2.903 0.845~9.977 血清肌酐(μmol/L) 1.612 0.671 5.771 0.016 5.012 1.345~18.672 血清白蛋白(g/L) -0.719 0.705 1.041 0.308 0.487 0.122~1.939 3. 讨论
SAP是常见消化系统急症,后期继发感染性胰腺坏死的概率较高[8-9]。脓毒症是SAP的严重并发症之一,也是患者后期死亡的重要原因。本研究显示,在178例SAP患者中发生脓毒症56例(31.46%),与陈莎燕等[10]报道结果相近,提示SAP患者并发脓毒症的概率较高,直接影响治疗的预后,临床应予以注意。本研究在56例SAP并发脓毒症患者血培养中共分离出61株病原菌,其中革兰阳性球菌14株,占22.95%,革兰阴性杆菌39株,占63.93%,真菌8株,占13.11%,与廖全凤等[11]研究结果相似,临床应根据其感染病原菌特点选用抗菌药物。
APACHE-Ⅱ评分是判断SAP严重程度与预后的重要评分系统,评分越高提示病情越严重,免疫功能越差,病原菌越易进入血液形成脓毒症[12];SAP胰腺组织灌注不足,此时合并低氧血症可增加胰腺组织缺氧程度与坏死范围,导致胰腺感染增加并侵入血流[13],同时SAP常伴发肺部感染等胰腺外感染,后者又可加重SAP患者的感染严重程度,严重者引起低氧血症与呼吸功能衰竭,甚至发生多器官功能衰竭风险[14];胰腺的内分泌部分泌的胰岛素是调节血糖的重要激素,SAP胰腺坏死损伤胰岛导致胰岛素分泌不足,糖代谢紊乱,血糖升高,有利于病原菌入侵,同时其免疫功能下降,更利于病原菌入侵血流,增加脓毒症的发生[15]。肌酐是肌肉代谢产物, 肌肉中肌酸通过非酶脱水反应产生,再释放进入血液中,随尿排出体外。因此血清肌酐与人体肌肉总量密切相关,而不易受饮食等影响;再加上肌酐为小分子物质,通过肾小球滤过,很少被肾小管吸收,每日体内产生量几乎均随尿排出,不受尿量影响,因此,临床上将血清肌酐作为肾功能重要指标之一,血清肌酐升高提示肾功能受损[16];本研究显示,血清肌酐与脓毒症密切相关,可能原因为肾功能不全时白细胞趋化性功能受损,淋巴细胞功能障碍,体内免疫球蛋白降低,免疫功能下降,容易发生脓毒症[17-18]。手术病灶清除引流是治疗感染性胰腺坏死的重要手段[19];感染性胰腺坏死病灶清除引流手术的方式有开腹与微创手术两种,手术可清除炎性病灶减少感染,但是开放手术创伤大,可引起坏死炎性胰腺组织扩散,感染病原菌侵入血流,同时开腹手术破坏人体自然屏障,外界环境中的病原菌也易通过切口侵入引起脓毒症[20],而微创手术方式既可清除炎性坏死组织,又可减少外界病原菌侵入,可减少脓毒症[21]。胰腺坏死程度越高提示感染性胰腺坏死病灶越大,产生的炎性坏死组织越多,对周围组织破坏也越大,病原菌越易侵入血流产生胰外感染[22]。多因素分析显示,APACHEⅡ评分、低氧血症、血糖、胰腺坏死程度高、血清肌酐等因素是SAP并发脓毒症的独立危险因素,采用微创手术方式清除病灶坏死组织为SAP并发脓毒症的独立保护因素。
总之,SAP并发脓毒症与多因素相关。控制血糖,保护肺肾等重器官功能,采用微创手术方式清除病灶坏死组织,注意重症、胰腺坏死程度高患者的救治是减少SAP并发脓毒症的重要措施。
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表 1 常见WD动物模型特点
Table 1. Characteristics of common WD animal models
模型种类 肝损伤
症状神经系统症状
(无/轻微/明显)K-F环
(有/无)母乳中是否含
有铜(有/无)应用特点 TX小鼠 有 无 无 无 肝损伤出现较早且表现突出,应用较广泛 TX-J小鼠 有 轻微 无 无 铜沉积出现较早,适合进行铜代谢等方面研究,应用较广 ATP7B-/-小鼠 有 无 无 无 肝铜沉积较早且含量较高,适用于疗效评估,但价格昂贵,目前应用尚不广泛 LEC大鼠 有 轻微 无 有 肝病进展迅速,适合用于进行干预研究,但大鼠病死率较高 -
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