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Citation: Zhang YP,Zhang Q,Deng F,et al.Effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its mechanism[J].Chin J Burns Wounds,2022,38(11):1014-1022.DOI: 10.3760/cma.j.cn501225-20220630-00272.

Effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its mechanism

doi: 10.3760/cma.j.cn501225-20220630-00272
Funds:

Youth Science Foundation Project of National Natural Science Foundation of China 82100889

Chongqing Doctor "Through Train" Project CSTB2022BSXM-JCX0022

Science and Technology Ability Promotion Project of Army Medical University XZ-2019-505-018

More Information
  •   Objective  To investigate the effect of P62 on the migration and motility of human epidermal cell line HaCaT in high glucose microenvironment and its possible molecular mechanism, so as to explore the mechanism of refractory diabetic foot wound healing.  Methods  The method of experimental research was used. HaCaT cells in logarithmic growth phase was taken for experiment. The cells were collected and divided into normal control group (culture solution containing glucose with final molarity of 5.5 mmol/L) and high glucose (culture solution containing glucose with final molarity of 30.0 mmol/L) 24 h group, high glucose 48 h group, and high glucose 72 h group according to the random number table (the same grouping method below). The cells in normal control group were routinely cultured for 72 h, cells in high glucose 72 h group were cultured with high glucose for 72 h, cells in high glucose 48 h group were routinely cultured for 24 h then cultured with high glucose for 48 h, cells in high glucose 24 h group were routinely cultured for 48 h then cultured with high glucose for 24 h. Then the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal control group and high glucose group. After being correspondingly cultured for 48 h as before, the protein expression of P62 was detected by immunofluorescence method (indicated as green fluorescence). The cells were collected and divided into negative control small interfering RNA (siRNA) group, P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group, and transfected with the corresponding reagents. At post transfection hour (PTH) 72, the protein expression of P62 was detected by Western blotting. The cells were collected and divided into normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group. After the corresponding treatment, the protein expression of P62 was detected by Western blotting at PTH 72 h, the cell migration rate was detected and calculated at 24 h after scratching by scratch test, with the number of samples being 9; and the range of cell movement was observed and the trajectory velocity was calculated within 3 h under the living cell workstation, with the number of samples being 76, 75, 80, and 79 in normal glucose+negative control siRNA group, normal glucose+P62-siRNA group, high glucose+negative control siRNA group, and high glucose+P62-siRNA group, respectively. The cells were collected and divided into normal glucose+phosphate buffered solution (PBS) group, high glucose+PBS group, and high glucose+N-acetylcysteine (NAC) group. After the corresponding treatment, the protein expression of P62 at 48 h of culture was detected by Western blotting and immunofluorescence method, respectively. Except for scratch test and cell motility experiment, the number of samples was all 3 in the rest experiments. Data were statistically analyzed with one-way analysis of variance and least significant difference test.  Results  Compared with the protein expression in normal control group, the protein expressions of P62 of cells in high glucose 24 h group, high glucose 48 h group, and high glucose 72 h group were significantly increased (P<0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose group was stronger than that in normal control group. At PTH 72, compared with the protein expression in negative control siRNA group, the protein expressions of P62 of cells in P62-siRNA-1 group, P62-siRNA-2 group, and P62-siRNA-3 group were significantly decreased (P<0.01). At PTH 72, compared with the protein expression in normal glucose+negative control siRNA group, the protein expression of P62 of cells in normal glucose+P62-siRNA group was significantly decreased (P<0.01), while the protein expression of P62 of cells in high glucose+negative control siRNA group was significantly increased (P<0.01); compared with the protein expression in high glucose+negative control siRNA group, the protein expression of P62 of cells in high glucose+P62-siRNA group was significantly decreased (P<0.01). At 24 h after scratching, compared with (55±7)% in normal glucose+negative control siRNA group, the cell migration rate in normal glucose+P62-siRNA group was significantly increased ((72±14)%, P<0.01), while the cell migration rate in high glucose+negative control siRNA group was significantly decreased ((37±7)%, P<0.01); compared with that in high glucose+negative control siRNA group, the cell migration rate in high glucose+P62-siRNA group was significantly increased ((54±10)%, P<0.01). Within 3 h of observation, the cell movement range in high glucose+negative control siRNA group was smaller than that in normal glucose+negative control siRNA group, while the cell movement range in normal glucose+P62-siRNA group was larger than that in normal glucose+negative control siRNA group, and the cell movement range in high glucose+P62-siRNA group was larger than that in high glucose+negative control siRNA group. Compared with that in normal glucose+negative control siRNA group, the cell trajectory speed in normal glucose+P62-siRNA group was significantly increased (P<0.01), while the cell trajectory speed in high glucose+negative control siRNA group was significantly decreased (P<0.01); compared with that in high glucose+negative control siRNA group, the cell trajectory speed in high glucose+P62-siRNA group was significantly increased (P<0.01). At 48 h of culture, compared with that in normal glucose+PBS group, the protein expression of P62 of cells in high glucose+PBS group was significantly increased (P<0.01); compared with that in high glucose+PBS group, the protein expression of P62 of cells in high glucose+NAC group was significantly decreased (P<0.01). At 48 h of culture, the green fluorescence of P62 of cells in high glucose+PBS group was stronger than that in normal glucose+PBS group, while the green fluorescence of P62 of cells in high glucose+NAC group was weaker than that in high glucose+PBS group.  Conclusions  In HaCaT cells, high glucose microenvironment can promote the protein expression of P62; knockdown of P62 protein can promote the migration and increase the mobility of HaCaT cells; and the increase of reactive oxygen species in high glucose microenvironment may be the underlying mechanism for the increase of P62 expression.

     

  • 严重烧伤后机体出现持续高代谢反应,且分解代谢变化幅度远超合成代谢,表现为葡萄糖利用障碍、糖酵解和糖异生增强,蛋白分解亢进、呈现蛋白净释放,长链脂肪酸转运受阻、长链脂肪酸β氧化受到部分抑制等,使得血中存在大量葡萄糖、氨基酸和脂肪酸,引起机体代谢紊乱,诱导休克发生1。严重烧伤后,大量血浆渗漏到组织间隙或从创面丢失,引起有效循环血量锐减;同时严重烧伤也会损害心肌2,导致心脏泵血功能减弱,诱导或加重休克的发生和发展,严重的细胞缺血缺氧损伤进一步加重代谢紊乱。因此,烧伤后高代谢引起的代谢紊乱和有效循环血容量减少导致的烧伤休克互为因果、相互促进,形成恶性循环,从而导致MODS、甚至死亡。现已证实,糖代谢异常是导致烧伤高代谢的首要因素,蛋白质和脂肪代谢模式的改变是为了适应糖代谢的变化。胰岛素作为促合成代谢激素,是体内目前已知的唯一降血糖激素,能够促进组织细胞对糖分的摄取,促进糖原合成、抑制糖原分解,促进脂肪酸的合成与酯化,促进蛋白质合成、抑制蛋白质分解,改善机体营养状况3。谷氨酰胺作为一种能源物质,不仅可以为机体蛋白质的合成提供氮源,改善肠黏膜屏障通透性,降低肠源性高代谢,减轻肠道损伤,下调炎症因子水平,抑制氧化应激和调控全身炎症反应;还可以保护心肌细胞,改善心脏泵血功能,最终改善患者的营养状况4, 5。因此,本研究团队行前瞻性随机对照试验联合使用胰岛素和谷氨酰胺,期望打断代谢紊乱和烧伤休克的恶性循环,改善患者的营养代谢、炎症反应和心脏泵血功能,提高严重烧伤的救治水平。

    本研究属于陆军军医大学(第三军医大学)第一附属医院临床试验项目的子项目,统一通过该医院伦理委员会审批,批件号:2014年科研第(46)号。参与试验的患者自愿签署知情同意书,因病情原因无法亲自签署者由其直系亲属代为签署。

    纳入标准:(1)年龄为18~60岁,性别不限。(2)烧伤总面积为30%~70%TBSA,Ⅲ度烧伤面积>20%TBSA。(3)伤后24 h内送至徐州医科大学附属淮海医院接受完整治疗,且入院时创面无感染。

    排除标准:(1)入院时已存在严重心血管、肝、肾等器官功能障碍或糖尿病、皮质醇增多症等内分泌系统疾病。(2)入院时合并严重外伤或存在呼吸道烧伤。(3)正在使用谷氨酰胺、胰岛素及胰岛素类似物制剂及其他降糖药,或对试验药物过敏以及存在其他不适合使用脉搏轮廓心输出量(PiCCO)监护仪的情况。(4)试验依从性差或在试验过程中失访以及其他判断为不适合入选者。剔除标准:不愿意继续配合试验或因各种原因住院时间<14 d者。

    2017年6月—2019年1月,徐州医科大学附属淮海医院烧伤整形科收治的32例严重烧伤患者符合入选标准,纳入本研究。按照随机数字表法将患者分为单纯胰岛素常规治疗组、单纯胰岛素强化治疗组、胰岛素常规治疗+谷氨酰胺组与胰岛素强化治疗+谷氨酰胺组,每组8例。4组患者一般资料比较,差异无统计学意义(P>0.05),见表1

    表1  4组严重烧伤患者一般资料比较
    组别例数性别(例)年龄(岁,x¯±s烧伤面积(%TBSA,x¯±s烧伤指数(%TBSA,x¯±s
    总面积Ⅲ度面积
    单纯胰岛素常规治疗组85335±748±1128±738±6
    胰岛素常规治疗+谷氨酰胺组84436±946±1332±640±6
    单纯胰岛素强化治疗组83533±1151±833±842±7
    胰岛素强化治疗+谷氨酰胺组84438±750±729±739±4
    F0.2850.2891.2590.763
    P>0.05>0.05>0.05>0.05>0.05
    注:“—”表示无此统计量值;TBSA为体表总面积
    下载: 导出CSV 
    | 显示表格

    常规治疗具体如下。患者入院后按照第三军医大学烧伤补液公式进行个体化液体复苏治疗,复苏成功的标准为患者心率、呼吸、血压等生命体征较为平稳,血液循环稳定,每小时尿量达0.5~1.0 mL/kg;常规给予抗生素预防感染,未达深Ⅱ度的烧伤创面清创后行包扎或半暴露治疗,深Ⅱ度及Ⅲ度烧伤创面在患者入院后3~4 d行切削痂手术治疗;连接PiCCO 2型监护仪(德国Pulsion公司)并校准,校准后监护仪于每日8:00、16:00、24:00自动测量患者各项血流动力学参数;在伤后2 d起给予等氮、等热量的营养支持,按照第三军医大学烧伤热量公式计算所需热量:所需热量(kJ/d)=4 184 kJ×体表面积(m2)+105 kJ×烧伤面积(%TBSA),体表面积(m2)=[身高(m)-0.6]×1.5。结合患者病情选择适合的营养支持方式,在患者能经口补充营养情况下,优先经口补充肠内营养,可通过微量泵经胃管持续恒速泵入,以患者能耐受的摄入量为准,不足热量经肠外途径补充,保证患者每日补充蛋白质2.0 g/kg;非蛋白热量通过给予葡萄糖和脂肪进行补充,非蛋白热氮比为628 kJ∶1 g。伤后3 d进入回吸收期后,按照徐州医科大学附属淮海医院烧伤整形科常规治疗模式进行液体复苏治疗和容量管理。

    单纯胰岛素常规治疗组患者在常规治疗基础上,行胰岛素常规治疗。单纯胰岛素强化治疗组患者在常规治疗基础上,行胰岛素强化治疗。胰岛素常规治疗+谷氨酰胺组患者在单纯胰岛素常规治疗组基础上,给予的蛋白质中,0.3 g/kg通过丙氨酰谷氨酰胺(华瑞制药有限公司)经肠外途径补充,持续14 d以上。胰岛素强化治疗+谷氨酰胺组患者在单纯胰岛素强化治疗组基础上另同前补充丙氨酰谷氨酰胺。

    4组患者具体血糖控制措施如下。于每日2:00、6:00、三餐后2 h共5个时间点对4组患者进行指尖血糖测定,除三餐后2 h外其余均为空腹血糖。每个时间点连续测定3次血糖,取3次的平均值作为该时间点患者指尖血糖值。单纯胰岛素常规治疗组及胰岛素常规治疗+谷氨酰胺组患者血糖水平>10.0 mmol/L时,给予皮下注射胰岛素注射液(北京赛升药业股份有限公司)控制患者血糖水平在7.0~10.0 mmol/L。单纯胰岛素强化治疗组及胰岛素强化治疗+谷氨酰胺组采取更为严格的血糖控制手段使血糖控制在更低范围:于三餐前通过皮下输液泵持续泵入短效胰岛素类似物(赖脯胰岛素注射液,礼来苏州制药有限公司),睡前通过皮下输液泵持续泵入长效胰岛素类似物[甘精胰岛素注射液,赛诺菲安万特(北京)制药有限公司];每日所用上述胰岛素类似物起始总量为0.4 U·kg-1·d-1,三餐前短效胰岛素占起始总量的70%~80%(每餐餐前胰岛素用量在前述基础上再分配成三等份),睡前长效胰岛素占起始总量的20%~30%。在此基础上,若患者初始血糖>10.0 mmol/L时,调整皮下输液泵输液速率,以2 U/h的起始量持续泵入胰岛素注射液;若患者初始血糖>12.0 mmol/L,则以3 U/h的起始量持续泵入胰岛素注射液;若患者初始血糖>20.0 mmol/L或血糖测量仪显示“HIGH”,则先快速泵入胰岛素注射液5 U,再以3~5 U/h的速率持续泵入胰岛素注射液。调整泵速以维持患者2:00和6:00空腹指尖血糖4.4~6.1 mmol/L、餐后2 h指尖血糖<8.0 mmol/L。4组患者血糖达到目标范围后,减少或停止使用胰岛素或胰岛素类似物;同时警惕低血糖的发生,当患者血糖<3.8 mmol/L时,补充适量葡萄糖注射液,复测指尖血糖达4.4~6.1 mmol/L后停止输注。

    (1)分别于治疗1、3、7、14 d 8:00抽取4组患者静脉血5 mL,送至徐州医科大学附属淮海医院检验科检测血糖、白蛋白、前白蛋白、白细胞计数、降钙素原和C反应蛋白(CRP)。(2)每日取3次PiCCO监测参数的平均值为最终结果。统计4组患者治疗1、3、7 d心脏指数、每搏量指数(SVI)、全心舒张末期容积指数(GEDVI)、外周血管阻力指数(SVRI)、血管外肺水指数(EVLWI)、肺血管通透性指数(PVPI)。

    采用SPSS 19.0统计软件对数据进行分析,计数资料数据以频数表示,组间比较行Fisher确切概率法检验(软件自动略去该统计量值);计量资料数据均符合正态分布,以x¯±s表示,一般资料数据组间总体比较仅行单因素方差分析,重复测量资料数据组间总体比较另同时行重复测量方差分析,各时间点组间两两比较采用Bonferroni法(软件自动略去该统计量值)。P<0.05为差异有统计学意义。

    4组患者均平稳度过休克期,未出现休克延迟复苏情况,病程中未出现明显的感染及脏器功能不全等并发症,均顺利完成研究,无退出病例。

    4组患者治疗1 d血糖均高于正常值,治疗3~14 d均有所降低。治疗3、7、14 d,单纯胰岛素强化治疗组和胰岛素强化治疗+谷氨酰胺组患者血糖均明显低于单纯胰岛素常规治疗组(P<0.05);其余组间两两比较,差异均无统计学意义(P>0.05)。见表2

    表2  4组严重烧伤患者治疗各时间点血糖比较(mmol/L,x¯±s
    组别例数1 d3 d7 d14 d
    单纯胰岛素常规治疗组89.6±1.29.1±0.58.4±0.97.4±1.1
    胰岛素常规治疗+谷氨酰胺组88.5±0.88.5±0.67.1±1.26.0±0.9
    单纯胰岛素强化治疗组89.3±0.55.9±1.3a5.8±0.6a5.5±0.5a
    胰岛素强化治疗+谷氨酰胺组89.2±0.95.9±1.1a5.6±1.1a5.2±0.8a
    F3.13734.66018.50715.933
    P<0.05<0.01<0.01<0.01
    注:成人空腹血糖正常值为3.9~6.1 mmol/L;处理因素主效应,F=49.598,P<0.01;时间因素主效应,F=62.512,P<0.01;两者交互作用,F=5.119,P<0.01;F值、P值为组间各时间点总体比较所得;与单纯胰岛素常规治疗组比较,aP<0.05
    下载: 导出CSV 
    | 显示表格

    4组患者治疗1 d白蛋白均低于正常值;治疗3~14 d,4组患者白蛋白有所升高。与单纯胰岛素常规治疗组比,胰岛素常规治疗+谷氨酰胺组、单纯胰岛素强化治疗组、胰岛素强化治疗+谷氨酰胺组患者治疗7、14 d白蛋白明显升高(P<0.05);与胰岛素强化治疗+谷氨酰胺组比,胰岛素常规治疗+谷氨酰胺组、单纯胰岛素强化治疗组患者治疗14 d白蛋白明显降低(P<0.05);其余组间两两比较,差异均无统计学意义(P>0.05)。治疗1~14 d,4组患者前白蛋白均先降低后升高。与胰岛素强化治疗+谷氨酰胺组比,单纯胰岛素常规治疗组、胰岛素常规治疗+谷氨酰胺组和单纯胰岛素强化治疗组患者治疗1、7、14 d前白蛋白明显降低(P<0.05);与单纯胰岛素常规治疗组比,胰岛素常规治疗+谷氨酰胺组和单纯胰岛素强化治疗组患者治疗7、14 d前白蛋白明显升高(P<0.05);其余组间两两比较,差异均无统计学意义(P>0.05)。见表34

    表3  4组严重烧伤患者治疗各时间点白蛋白比较(g/L,x¯±s
    组别例数1 d3 d7 d14 d
    单纯胰岛素常规治疗组823.6±22.4±24.2±25.3±
    5.45.67.33.0
    胰岛素常规治疗+谷氨酰胺组824.2±23.2±28.4±30.4±
    7.26.53.4a3.6ab
    单纯胰岛素强化治疗组823.8±23.2±29.1±31.0±
    6.38.61.6a2.7ab
    胰岛素强化治疗+谷氨酰胺组824.0±24.8±31.4±36.8±
    4.15.42.6a2.9a
    F0.0140.1693.83319.069
    P<0.01<0.01<0.05<0.01
    注:白蛋白正常值>35 g/L;处理因素主效应,F=5.794,P<0.01;时间因素主效应,F=39.626,P<0.01;两者交互作用,F=3.636,P<0.05;F值、P值为组间各时间点总体比较所得;与单纯胰岛素常规治疗组比较,aP<0.05;与胰岛素强化治疗+谷氨酰胺组比较,bP<0.05
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    表4  4组严重烧伤患者治疗各时间点前白蛋白比较(mg/L,x¯±s
    组别例数1 d3 d7 d14 d
    单纯胰岛素常规治疗组8154±10a113±1582±9a108±8a
    胰岛素常规治疗+谷氨酰胺组8151±15a118±14104±13ab159±24ab
    单纯胰岛素强化治疗组8155±24a116±16108±16ab173±43ab
    胰岛素强化治疗+谷氨酰胺组8157±20141±17129±20170±58
    F0.1335.29212.63218.977
    P<0.01<0.05<0.01<0.01
    注:前白蛋白正常值为280~360 mg/L;处理因素主效应,F=14.586,P<0.01;时间因素主效应,F=2.388,P>0.05;两者交互作用,F=17.254,P<0.01;F值、P值为组间各时间点总体比较所得;与胰岛素强化治疗+谷氨酰胺组比较,aP<0.05;与单纯胰岛素常规治疗组比较,bP<0.05
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    4组患者治疗1 d白细胞计数、降钙素原、CRP均高于正常值;治疗3~14 d,4组患者白细胞计数、降钙素原、CRP有降低,但仍高于正常值;4组患者治疗1、3、7、14 d白细胞计数、降钙素原、CRP组间两两比较差异均无统计学意义(P>0.05)。见表5, 6, 7

    表5  4组严重烧伤患者治疗各时间点白细胞计数比较(×109/L,x¯±s
    组别例数1 d3 d7 d14 d
    单纯胰岛素常规治疗组820.9±13.4±13.3±13.1±
    2.81.10.92.6
    胰岛素常规治疗+谷氨酰胺组820.2±13.9±13.2±12.2±
    3.22.20.70.6
    单纯胰岛素强化治疗组818.8±12.6±14.0±12.9±
    7.42.01.61.5
    胰岛素强化治疗+谷氨酰胺组820.2±12.3±12.7±13.0±
    5.61.01.91.4
    F0.5341.1480.7930.825
    P<0.01<0.01<0.01<0.01
    注:成人白细胞计数正常值为(4.0~10.0)×109/L;处理因素主效应,F=1.593,P>0.05;时间因素主效应,F=47.331,P<0.01;两者交互作用,F=0.173,P>0.05;F值、P值为组间各时间点总体比较所得
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    表6  4组严重烧伤患者治疗各时间点降钙素原比较(ng/mL,x¯±s
    组别例数1 d3 d7 d14 d
    单纯胰岛素常规治疗组86.00±3.67±1.07±0.66±
    0.560.310.160.32
    胰岛素常规治疗+谷氨酰胺组86.12±3.81±0.96±0.94±
    1.380.410.170.15
    单纯胰岛素强化治疗组85.91±3.62±0.94±0.84±
    0.900.260.150.24
    胰岛素强化治疗+谷氨酰胺组85.72±3.34±0.99±0.92±
    0.670.410.130.32
    F0.2622.5571.0572.012
    P<0.01<0.01<0.01<0.01
    注:降钙素原正常值为<0.5 ng/mL;处理因素主效应,F=0.318,P>0.05;时间因素主效应,F=998.094,P<0.01;两者交互作用,F=1.018,P>0.05;F值、P值为组间各时间点总体比较所得
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    表7  4组严重烧伤患者治疗各时间点C反应蛋白比较(mg/L,x¯±s
    组别例数1 d3 d7 d14 d
    单纯胰岛素常规治疗组891±3478±871±1843±10
    胰岛素常规治疗+谷氨酰胺组881±2377±1265±1538±14
    单纯胰岛素强化治疗组872±2384±1175±1649±20
    胰岛素强化治疗+谷氨酰胺组868±1577±1070±1350±25
    F1.4330.7800.5080.700
    P<0.01<0.01<0.01<0.01
    注:C反应蛋白正常值为0~5 mg/L;处理因素主效应,F=0.806,P>0.05;时间因素主效应,F=40.417,P<0.01;两者交互作用,F=1.748,P>0.05;F值、P值为组间各时间点总体比较所得
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    4组患者治疗1 d心脏指数均处于较低水平,治疗3~7 d均逐渐上升。治疗3、7 d,胰岛素强化治疗+谷氨酰胺组患者心脏指数均明显高于单纯胰岛素常规治疗组(P<0.05);其余组间两两比较,差异均无统计学意义(P>0.05)。见表8

    表8  4组严重烧伤患者治疗各时间点心脏指数比较(L·min-1·m-2x¯±s
    组别例数1 d3 d7 d
    单纯胰岛素常规治疗组83.24±0.434.67±0.496.21±0.68
    胰岛素常规治疗+谷氨酰胺组83.13±0.165.39±1.146.39±1.12
    单纯胰岛素强化治疗组83.28±0.335.21±0.416.32±0.58
    胰岛素强化治疗+谷氨酰胺组83.49±0.245.82±0.44a6.52±0.43a
    F1.9643.7990.275
    P<0.01<0.01<0.01
    注:心脏指数正常值为3.0~5.0 L·min-1·m-2;处理因素主效应,F=3.560,P<0.05;时间因素主效应,F=207.235,P<0.01;两者交互作用,F=1.067,P>0.05;F值、P值为组间各时间点总体比较所得;与单纯胰岛素常规治疗组比较,aP<0.05
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    4组患者治疗1 d SVI均低于正常值,治疗3~7 d均逐渐上升。治疗3、7 d,胰岛素强化治疗+谷氨酰胺组患者SVI均明显高于单纯胰岛素常规治疗组(P<0.05);其余组间两两比较,差异均无统计学意义(P>0.05)。见表9

    表9  4组严重烧伤患者治疗各时间点每搏量指数比较(mL/m2x¯±s
    组别例数1 d3 d7 d
    单纯胰岛素常规治疗组832.1±2.343.3±7.954.8±3.9
    胰岛素常规治疗+谷氨酰胺组834.8±7.651.2±13.255.3±2.6
    单纯胰岛素强化治疗组837.1±6.245.3±6.754.9±3.2
    胰岛素强化治疗+谷氨酰胺组832.1±5.255.6±5.3a61.1±1.5a
    F1.4623.2858.752
    P<0.01<0.05<0.01
    注:每搏量指数正常值为40~60 mL/m2;处理因素主效应,F=4.134,P<0.01;时间因素主效应,F=106.187,P<0.01;两者交互作用,F=2.717,P<0.05;F值、P值为组间各时间点总体比较所得;与单纯胰岛素常规治疗组比较,aP<0.05
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    4组患者治疗1 d GEDVI均低于正常低值,治疗3~7 d均逐渐上升并最终超过正常值。治疗3、7 d,胰岛素强化治疗+谷氨酰胺组患者GEDVI均明显高于单纯胰岛素常规治疗组(P<0.05);其余组间两两比较,差异均无统计学意义(P>0.05)。见表10

    表10  4组严重烧伤患者治疗各时间点全心舒张末期容积指数比较(mL/m2x¯±s
    组别例数1 d3 d7 d
    单纯胰岛素常规治疗组8618±175733±124812±103
    胰岛素常规治疗+谷氨酰胺组8671±181803±69850±121
    单纯胰岛素强化治疗组8640±192768±101841±135
    胰岛素强化治疗+谷氨酰胺组8651±125872±77a845±112a
    F0.0763.1220.168
    P<0.01<0.05<0.01
    注:全心舒张末期容积指数正常值为600~800 mL/m2;处理因素主效应,F=1.084,P<0.05;时间因素主效应,F=21.610,P<0.01;两者交互作用,F=0.401,P<0.01;F值、P值为组间各时间点总体比较所得;与单纯胰岛素常规治疗组比较,aP<0.05
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    4组患者治疗1 d SVRI均处于正常高值,治疗3~7 d均逐渐下降并最终低于正常值。治疗3、7 d,胰岛素强化治疗+谷氨酰胺组患者SVRI均明显高于单纯胰岛素常规治疗组(P<0.05);其余组间两两比较,差异均无统计学意义(P>0.05)。见表11

    表11  4组严重烧伤患者治疗各时间点外周血管阻力指数比较(dyn·s·cm-5·m2x¯±s
    组别例数1 d3 d7 d
    单纯胰岛素常规治疗组82 187±1441 528±191988±145
    胰岛素常规治疗+谷氨酰胺组82 342±3441 592±1441 102±113
    单纯胰岛素强化治疗组82 204±2231 449±1331 125±103
    胰岛素强化治疗+谷氨酰胺组82 201±1791 783±253a1 201±141a
    F0.7624.6603.850
    P<0.01<0.05<0.05
    注:外周血管阻力指数正常值为1 700~2 400 dyn·s·cm-5·m2;处理因素主效应,F=3.776,P<0.05;时间因素主效应,F=290.214,P<0.01;两者交互作用,F=1.872,P>0.05;F值、P值为组间各时间点总体比较所得;与单纯胰岛素常规治疗组比较,aP<0.05
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    4组患者治疗1 d EVLWI处于正常高值。治疗3、7 d,胰岛素强化治疗+谷氨酰胺组患者EVLWI均明显低于单纯胰岛素常规治疗组(P<0.05);其余组间两两比较,差异均无统计学意义(P>0.05)。见表12

    表12  4组严重烧伤患者治疗各时间点血管外肺水指数比较(mL/kg,x¯±s
    组别例数1 d3 d7 d
    单纯胰岛素常规治疗组86.6±0.57.2±0.67.8±0.5
    胰岛素常规治疗+谷氨酰胺组86.3±0.76.4±1.37.2±0.9
    单纯胰岛素强化治疗组86.3±0.46.7±0.87.4±0.6
    胰岛素强化治疗+谷氨酰胺组86.4±0.65.7±0.8a6.6±0.5a
    F0.3703.9984.583
    P<0.05<0.05<0.05
    注:血管外肺水指数正常值为3~7 mL/kg;处理因素主效应,F=7.278,P<0.01;时间因素主效应,F=13.412,P<0.01;两者交互作用,F=1.418,P>0.05;F值、P值为组间各时间点总体比较所得;与单纯胰岛素常规治疗组比较,aP<0.05
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    4组患者治疗1~7 d PVPI均处于正常范围并逐渐下降。治疗3、7 d,胰岛素强化治疗+谷氨酰胺组患者PVPI均明显低于单纯胰岛素常规治疗组(P<0.05);其余组间两两比较,差异均无统计学意义(P>0.05)。见表13

    表13  4组严重烧伤患者治疗各时间点肺血管通透性指数比较(x¯±s
    组别例数1 d3 d7 d
    单纯胰岛素常规治疗组81.68±0.191.62±0.211.31±0.22
    胰岛素常规治疗+谷氨酰胺组81.63±0.101.51±0.171.19±0.17
    单纯胰岛素强化治疗组81.57±0.211.49±0.111.17±0.15
    胰岛素强化治疗+谷氨酰胺组81.58±0.141.31±0.09a0.91±0.18a
    F0.8755.3286.685
    P<0.05<0.05<0.05
    注:肺血管通透性指数正常值为1.0~3.0;处理因素主效应,F=10.508,P<0.01;时间因素主效应,F=67.452,P<0.01;两者交互作用,F=1.382,P>0.05;F值、P值为组间各时间点总体比较所得;与单纯胰岛素常规治疗组比较,aP<0.05
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    严重烧伤诱发的炎症反应、代谢亢进、肌肉消瘦和胰岛素抵抗等都是标志性的病理生理反应,这些代谢变化在烧伤后即可出现,数年内仍持续存在6。彭曦7认为蛋白质能量营养不良能使机体免疫功能下降、组织和器官水肿、血液运送氧能力下降、发生MODS、增加患者病死率。应激性高血糖是重症烧伤患者普遍存在的一种现象,并成为独立危险因素,直接影响患者的预后8。烧伤应激性高血糖的诊断标准和理想的血糖控制目标目前仍未达成共识,部分学者提出在排除糖尿病的基础上,由烧伤作为应激原引起随机血糖升高超过11.1 mmol/L可考虑诊断为应激性高血糖9。有研究显示,使用相关胰岛素强化治疗控制危重症患者血糖在正常生理范围内可有效减少患者病死率及并发症发生率10

    本课题组通过胰岛素强化治疗更为严格地控制单纯胰岛素强化治疗组和胰岛素强化治疗+谷氨酰胺组患者血糖,使患者指尖血糖控制在空腹4.4~6.1 mmol/L、餐后2 h<8.0 mmol/L;谷氨酰胺则通过丙氨酰谷氨酰胺补充。结果提示4组患者治疗1 d血糖均高于正常值,单纯胰岛素常规治疗组患者治疗1~14 d血糖基本可以控制在10.0 mol/L以下;治疗3、7、14 d,单纯胰岛素强化治疗组和胰岛素强化治疗+谷氨酰胺组患者血糖均明显低于单纯胰岛素常规治疗组。说明在使用相关胰岛素强化治疗后,患者血糖得到了更好的控制,血糖降低幅度更大。与单纯胰岛素强化治疗组比,胰岛素强化治疗+谷氨酰胺组患者血糖更低,但差异无统计学意义(P>0.05),因此尚不能证明谷氨酰胺与胰岛素强化治疗联用对降低严重烧伤后高血糖有协同效应。

    白蛋白与前白蛋白是反映机体营养代谢的常用指标11。本研究中4组患者治疗1 d白蛋白和前白蛋白均低于正常值;治疗3~14 d,4组患者白蛋白有所升高、前白蛋白先降低再升高。该变化早期是由于烧伤后血管通透性增高、血浆蛋白大量丢失导致,后期则和烧伤后持续高代谢,蛋白合成减少、分解增加有关12。治疗3 d,多数患者白蛋白降至最低;治疗7 d,4组患者前白蛋白均降至最低。随着治疗的进行与病情的好转,患者的血管通透性恢复,营养代谢有所改善,治疗7、14 d,患者白蛋白与前白蛋白分别开始升高。本研究显示,与单纯胰岛素常规治疗组比,胰岛素强化治疗+谷氨酰胺组患者治疗7、14 d白蛋白、前白蛋白升高;与胰岛素强化治疗+谷氨酰胺组比,胰岛素常规治疗+谷氨酰胺组、单纯胰岛素强化治疗组患者治疗14 d白蛋白降低,单纯胰岛素常规治疗组、胰岛素常规治疗+谷氨酰胺组和单纯胰岛素强化治疗组患者治疗1、7、14 d前白蛋白明显降低。分析这些营养指标的变化,本课题组认为是在联合使用胰岛素与谷氨酰胺治疗时,胰岛素作为合成代谢激素,也促进了体内白蛋白与前白蛋白的合成,抑制体内白蛋白和前白蛋白的分解与消耗13;谷氨酰胺作为条件必需氨基酸,在烧伤时体内含量锐减,通过给予外源性谷氨酰胺补充了机体所需,从而减少了内源性营养底物的消耗14, 15。二者联合使用,对改善机体营养代谢水平发挥了协同作用。

    感染也是烧伤后的常见并发症之一。临床上严重烧伤患者病程长、病情复杂,可进一步发展为脓毒症、脓毒症休克、SIRS甚至MODS等16,因此烧伤后对患者的感染情况进行尽早干预具有重要意义。本研究中4组患者在治疗1 d白细胞计数、降钙素原、CRP均高于正常值,提示烧伤后机体并发全身感染。治疗3~14 d,4组患者白细胞计数、降钙素原、CRP虽有下降,但仍高于正常值,且组间两两比较差异均无统计学意义(P>0.05),尚无法证明谷氨酰胺以及胰岛素强化治疗对严重烧伤患者伤后机体炎症反应有控制作用。这有可能是由于纳入本次研究的炎症反应观测指标不够全面或样本量过小造成功效不足,有待进一步研究。

    烧伤引起的休克同样应当引起重视。研究显示,烧伤总面积超过15%TBSA的成年烧伤患者就有休克风险17。烧伤后由于热力的直接作用,创面内蛋白凝固变性,创面周围血管扩张,致使血管通透性增加,大量水分流失到血管外造成机体有效循环血量不足,组织器官灌注不足,组织细胞无氧酵解造成乳酸堆积,如不能及时有效地改善缺血缺氧会导致一系列并发症18。除了有效循环血容量的明显变化,研究显示在严重烧伤后半小时内即可造成心肌损害19,心肌细胞血流灌注减少,心肌缺血缺氧损伤,造成心肌自噬或凋亡,心脏泵血功能减弱。心脏作为循环动力器官,心肌损伤造成的心输出量减少进一步加重了休克20。因此,在纠正休克的同时需要缓解心肌损伤,改善心功能。作为三大营养素的促合成激素,已有研究表明胰岛素具有减少血中游离氨基酸和脂肪酸的作用,从而改善微循环,继而改善液体复苏的效果21。此外,有研究表明谷氨酰胺可改善心肌缺血再灌注损伤,保护心肌,对心脏血流动力学也有一定改善作用22

    及时有效的液体复苏是烧伤休克救治的关键23。然而,进行液体复苏需要注意补液量的问题。补液不足,液体过少,难以恢复有效循环血量,无法改善组织器官灌注,休克无法得到纠正;补液过多,液体负荷过重,可导致心力衰竭与肺水肿等并发症的发生。单纯依赖烧伤补液公式无法及时准确评估患者血流动力学恢复情况,临床上常通过观察患者心率、血压、尿量及精神状况、肢端温度来评估。然而,这些指标通常都滞后于有效循环血量的变化,因此不能及时准确反映机体循环恢复的真实情况24。随着对烧伤休克的深入研究与微创技术的发展与应用,目前PiCCO监测仪已应用于临床危重症患者的监护管理25。PiCCO监护仪可在床旁监测患者心脏泵血功能、前后负荷、EVLWI等,通过这些参数准确反映患者血流动力学变化情况,在危重患者的液体管理与监测中发挥越来越重要的作用26。PiCCO同样已被用于严重烧伤患者的容量管理。因此,本研究使用PiCCO监护仪检测胰岛素强化治疗联合谷氨酰胺对严重烧伤患者血流动力学的影响。

    通过PiCCO监测仪观察到,严重烧伤患者入院24 h内,正处于休克期,反映患者心功能的相关参数,如心脏指数和SVI以及反映前负荷的参数GEDVI均处于较低水平,这是患者烧伤后有效循环血容量减少所致。在治疗3 d患者逐渐进入回吸收期,通过有效的补液,有效循环血量逐渐恢复,患者的心脏指数也随之恢复正常并趋于稳定。在本研究中,治疗3、7 d,胰岛素强化治疗+谷氨酰胺组患者心脏指数、SVI均高于单纯胰岛素常规治疗组,可能机制是谷氨酰胺发挥了保护心肌、改善心功能、增加心输出量的作用。Zhang等27研究显示,谷氨酰胺可以转化为谷胱甘肽,有助于体内谷胱甘肽合成,为心肌细胞提供养分,减少氧自由基对心肌的损伤,抑制细胞凋亡,从而保护心肌细胞,改善心功能。胰岛素强化治疗则通过降低烧伤后应激性高血糖,保护心肌细胞以及血管内皮细胞免受高血糖损伤,抑制过度炎症反应,进而改善患者心血管功能28

    由于血容量恢复,大量组织间液从组织间隙重新进入血循环中,导致回心血量增加,使得心脏前负荷也随之上升。GEDVI可作为反映心脏前负荷的指标。本研究显示,治疗3、7 d,胰岛素强化治疗+谷氨酰胺组患者GEDVI均明显高于单纯胰岛素常规治疗组,这和胰岛素强化治疗与谷氨酰胺联合使用可改善严重烧伤患者心血管功能,致使患者回心血量增加有关。需要注意的是,如果此时没有及时减少补液量,容易造成容量负荷过重导致肺水肿等并发症的发生29。SVRI可作为反映心脏后负荷的指标,本研究同时观察到4组患者SVRI在治疗1 d处于正常高值,并随着时间的推移逐步降低,这是由于烧伤后早期血容量相对减少,机体通过加压反射、应激反应释放大量血管活性物质等代偿机制维持血压保证灌注所致30。胰岛素强化治疗+谷氨酰胺组患者治疗3、7 d SVRI明显高于单纯胰岛素常规治疗组,这是由于谷氨酰胺可阻止细胞储备中L-精氨酸的释放,从而增强机体对血管内皮素的反应,血管收缩得以加强31。已有研究证明血液中高胰岛素浓度可通过交感神经介导的血管收缩增加、激活MAPK/内皮素1信号通路等机制刺激血管收缩32, 33,本研究中应用谷氨酰胺联合胰岛素强化治疗以补充外源性胰岛素,最终使得患者外周血管收缩得到进一步加强。

    EVLWI可用来评估患者肺水肿程度,也可作为严重烧伤患者早期发生ARDS的独立预后因素34,近年有研究表明烧伤总面积是烧伤患者EVLWI异常的独立危险因素35。烧伤后EVLWI持续升高,可能与休克期体液渗出及后期液体复苏有关36。PVPI可用来反映肺血管通透性,从而评估严重烧伤患者肺水肿的病因。治疗1~7 d,4组患者PVPI均逐步降低,说明患者肺血管通透性逐步降低。通常在伴脓毒症时肺血管通透性升高,此时PVPI会高于正常值,并伴EVLWI升高;而容量负荷过重、血管静水压增高时,PVPI处于正常范围伴EVLWI升高。在本研究中,单纯胰岛素常规治疗组患者治疗1~7 d EVLWI持续升高;PVPI在治疗1 d即达峰值,随后缓慢下降;而治疗1 d心功能指标基本正常,这可能与肺部局部炎症、回吸收期后有效循环血量恢复有关。治疗3、7 d,胰岛素强化治疗+谷氨酰胺组患者EVLWI、PVPI明显低于单纯胰岛素常规治疗组,也是由于胰岛素与谷氨酰胺联合治疗可改善肺局部炎症。

    从患者整体情况来看,相比单纯胰岛素常规治疗、单纯胰岛素强化治疗和胰岛素常规治疗联合谷氨酰胺,胰岛素强化治疗联合谷氨酰胺能更好地降低严重烧伤患者的血糖,升高白蛋白和前白蛋白,改善心脏指数、SVI、GEDVI、SVRI、EVLWI和PVPI等血流动力学指标。提示胰岛素和谷氨酰胺可能通过某种协同作用共同改善患者的营养代谢和心脏泵血功能,中断代谢紊乱和烧伤休克的恶性循环,使休克期度过更加平稳,进一步提高严重烧伤的救治水平。

    本研究受限于现有样本量及评价指标,且对其他影响因素的控制不够全面,所得结果存在一定偏倚,本研究结论有待试验设计更为完善、更具科学性的研究进一步验证。

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