严重烫伤大鼠早期胰腺外分泌功能变化的机制研究

罗鹏; 张博涵; 孙佳辰; 李志生; 刘馨竹; 杨键秋; 申传安

doi:10.3760/cma.j.cn501225-20230216-00051

严重烫伤大鼠早期胰腺外分泌功能变化的机制研究

doi: 10.3760/cma.j.cn501225-20230216-00051

解放军总医院第四医学中心烧伤整形医学部，北京　　100048

基金项目:

国家自然科学基金面上项目 82072169, 82272279

军队后勤科研项目保健专项 22BJZ35

军队后勤科研重大项目 ALB18J001

详细信息

通讯作者:
申传安，Email：shenchuanan@301hospital.com.cn

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出版历程
- 收稿日期: 2023-02-16

Study on the mechanism of early pancreatic exocrine function changes in severely scalded rats

Department of Burns and Plastic Surgery, the Fourth Medical Center of PLA General Hospital, Beijing 100048, China

Funds:

General Program of National Natural Science Foundation of China 82072169, 82272279

Military Logistics Scientific Research Project Health Special Project 22BJZ35

Major Program of Military Logistics Research Plan ALB18J001

More Information

Corresponding author: Shen Chuan'an, Email: shenchuanan@301hospital.com.cn

摘要

摘要: 目的探讨严重烫伤大鼠早期胰腺外分泌功能变化的机制。方法采用实验研究方法。取80只7~8周龄雄性SD大鼠，按随机数字表法分为单纯假伤组（8只）、假伤+胆囊收缩素八肽（CCK8）组（8只）、严重烫伤+CCK8组（32只）和特重烫伤+CCK8组（32只），分别作相应处理。2组假伤大鼠伤后即刻及2组烫伤大鼠伤后1、2、3、7 d，采用改进的胰管穿刺置管法动态收集大鼠胆胰混合液（PBJ），记录1 h内分泌PBJ的体积，采用酶联免疫吸附测定（ELISA）法检测并计算PBJ中胰脂肪酶、α-淀粉酶和胰蛋白酶的含量（样本数为8）；收集股静脉血，采用标准比色法检测血清中胰脂肪酶和α-淀粉酶的浓度，反映其活力（样本数为8）；提取胰腺组织，采用ELISA法检测胰腺组织中白细胞介素1β（IL-1β）和IL-6水平（样本数为8），采用免疫荧光法检测胰腺组织中缺氧诱导因子1α（HIF-1α）的表达，采用苏木精-伊红染色观察胰腺组织病理学变化，采用改良Schmidt法评估（仅2组烫伤大鼠）胰腺组织损伤的严重程度（样本数为6），采用透射电子显微镜观察胰腺组织腺泡细胞超微结构。对数据行析因设计方差分析、Tukey检验、独立样本 t检验和LSD检验。结果与单纯假伤组大鼠伤后即刻胰腺组织1 h内的PBJ分泌体积（0.740±0.030）mL相比，假伤+CCK8组的（0.823±0.033）mL显著升高（ t=4.92， P<0.05）。与假伤+CCK8组伤后即刻相比，严重烫伤+CCK8组［（0.681±0.024）、（0.608±0.056）、（0.525±0.025）、（0.720±0.044）mL］、特重烫伤+CCK8组［（0.540±0.025）、（0.406±0.021）、（0.475±0.036）、（0.690±0.018）mL］大鼠伤后1、2、3、7 d胰腺组织1 h内的PBJ分泌体积均显著下降（ P<0.05）。与严重烫伤+CCK8组相比，特重烫伤+CCK8组大鼠伤后1、2 d胰腺组织1 h内的PBJ分泌体积均显著下降（ P<0.05）。相较于单纯假伤组伤后即刻，假伤+CCK8组大鼠伤后即刻PBJ中胰脂肪酶、α-淀粉酶和胰蛋白酶含量均显著升高（ t值分别为4.56、3.30、4.99， P<0.05）。与假伤+CCK8组大鼠伤后即刻相比，严重烫伤+CCK8组和特重烫伤+CCK8组大鼠伤后1、2、3、7 d的PBJ中胰脂肪酶和α-淀粉酶含量均显著降低（ P<0.05），特重烫伤+CCK8组大鼠伤后2 d的PBJ中胰蛋白酶含量显著降低（ P<0.05）。与严重烫伤+CCK8组相比，特重烫伤+CCK8组大鼠伤后1、2、3 d的PBJ中胰脂肪酶含量均显著降低（ P<0.05），伤后1、2 d的PBJ中α-淀粉酶和胰蛋白酶含量均显著降低（ P<0.05）。4组大鼠伤后各时间点血清中胰脂肪酶、α-淀粉酶活力比较，差异均无统计学意义（ P>0.05）。与假伤+CCK8组大鼠伤后即刻相比，严重烫伤+CCK8组大鼠伤后1、2、3 d和特重烫伤+CCK8组大鼠伤后1、2、3、7 d胰腺组织中的IL-1β水平均显著升高（ P<0.05），严重烫伤+CCK8组和特重烫伤+CCK8组大鼠伤后1、2、3、7 d胰腺组织中的IL-6水平均显著升高（ P<0.05）。与严重烫伤+CCK8组相比，特重烫伤+CCK8组大鼠伤后2、3 d胰腺组织中的IL-1β水平均显著升高（ P<0.05），伤后2 d胰腺组织中的IL-6水平均显著升高（ P<0.05）。单纯假伤组和假伤+CCK8组大鼠伤后即刻胰腺组织中HIF-1α表达水平均较低；相较于假伤+CCK8组伤后即刻，2组烫伤大鼠胰腺组织中HIF-1α表达水平于伤后不同时间点均呈一定程度的升高，其表达位置由胰腺组织边缘向全胰腺过渡，2组烫伤大鼠胰腺组织中HIF-1α表达水平于伤后7 d趋于正常。相较于单纯假伤组伤后即刻，假伤+CCK8组大鼠胰腺组织中腺泡细胞胞质占比增大；2组烫伤大鼠随伤后时间的延长，胰腺组织出现不同程度的水肿、出血、坏死及炎症浸润。与严重烫伤+CCK8组相比较，特重烫伤+CCK8组大鼠伤后各时间点胰腺组织水肿、炎症细胞浸润、出血和坏死得分表现出不同程度的升高，且2组烫伤大鼠胰腺组织各项目评分均于伤后7 d基本恢复正常。相较于单纯假伤组伤后即刻，假伤+CCK8组大鼠胰腺组织腺泡细胞内酶原颗粒数量增加；2组烫伤大鼠随伤后时间的延长，腺泡细胞内酶原颗粒基本呈逐渐减少趋势。结论严重烫伤大鼠早期胰酶合成和分泌等胰腺外分泌功能下降；且烫伤面积越大，外分泌功能下降程度越显著。这一变化可能与严重烫伤后胰腺组织发生缺氧损伤和炎症反应有关。
- 烧伤 /
- 胰腺外分泌功能不全 /
- 胰脂肪酶 /
- α淀粉酶 /
- 胆囊收缩素
Abstract: Objective To explore the mechanism of early pancreatic exocrine function changes in severely scalded rats. Methods The experimental research methods was used. Eighty male Sprague-Dawley rats aged 7-8 weeks were divided into simple sham injury group ( n=8), sham injury+cholecystokinin octapeptide (CCK8) group ( n=8), severe scald+CCK8 group ( n=32), and extremely severe scald+CCK8 group ( n=32) by the random number table, which were treated accordingly. Immediately after injury of rats in the 2 sham injury groups and 1, 2, 3, and 7 days after injury of rats in the 2 scald groups, the improved methods including pancreatic duct puncture and catheterization were used to dynamically collect the pancreatic-bile juice (PBJ) of rats. The PBJ secretory volume within 1 h was recorded, and the content of pancreatic lipase, α-amylase, and trypsin in PBJ was detected by enzyme-linked immunosorbent assay (ELISA), and the number of samples was 8. The femoral venous blood was collected, and the concentrations of pancreatic lipase and α-amylase in serum were detected by standard colorimetry to reflect their activity ( n=8). The pancreatic tissue was extracted, and the levels of interleukin-1β (IL-1β) and IL-6 in pancreatic tissue were detected by ELISA ( n=8), the expression of hypoxia-inducible factor 1α (HIF-1α) in pancreatic tissue was detected by immunofluorescence method, and the histopathological changes in pancreatic tissue were observed by hematoxylin-eosin staining, the severity of pancreatic tissue injury in the 2 scald groups was evaluated by modified Schmidt method ( n=6), and the ultrastructure of acinar cells in pancreatic tissue was observed by transmission electron microscopy. Data were statistically analyzed with analysis of variance for factorial design, Tukey test, independent sample t test, and least significant difference test. Results Compared with the PBJ secretory volume (0.740±0.030) mL in the pancreatic tissue of rats in simple sham injury group within 1 h immediately after injury, the (0.823±0.033) mL in sham injury+CCK8 group was significantly increased ( t=4.92, P<0.05). Compared with that of rats in sham injury+CCK8 group immediately after injury, the PBJ secretory volume of rats within 1 h in severe scald+CCK8 group ((0.681±0.024), (0.608±0.056), (0.525±0.025), and (0.720±0.044) mL) and extremely severe scald+CCK8 group ((0.540±0.025), (0.406±0.021), (0.475±0.036), and (0.690±0.018) mL) was significantly decreased on 1, 2, 3, and 7 days after injury ( P<0.05). Compared with that in severe scald+CCK8 group, the PBJ secretory volume of rats within 1 h in extremely severe scald+CCK8 group was significantly decreased on 1 and 2 days after injury ( P<0.05). Compared with that of rats in simple sham injury group immediately after injury, the content of pancreatic lipase, α-amylase, and trypsin in PBJ of rats in sham injury+CCK8 group immediately after injury was significantly increased (with t values of 4.56, 3.30, and 4.99, respectively, P<0.05). Compared with that of rats in sham injury+CCK8 group immediately after injury, the content of pancreatic lipase and α-amylase in PBJ of rats in severe scald+CCK8 group and extremely severe scald+CCK8 group was significantly decreased on 1, 2, 3, and 7 days after injury ( P<0.05), the trypsin content in PBJ of rats in extremely severe scald+CCK8 group was significantly decreased on 2 days after injury ( P<0.05). Compared with that in severe scald+CCK8 group, the content of pancreatic lipase in PBJ of rats in extremely severe scald+CCK8 group was significantly decreased on 1, 2, and 3 days after injury ( P<0.05), and the content of α-amylase and trypsin in PBJ was significantly decreased on 1 and 2 days after injury ( P<0.05). There were no statistically significant differences in the activities of pancreatic lipase and α-amylase in serum of rats among the 4 groups at various time points after injury ( P>0.05). Compared with that of rats in sham injury+CCK8 group immediately after injury, the levels of IL-1β in pancreatic tissue of rats in severe scald+CCK8 group on 1, 2, and 3 days after injury and in extremely severe scald+CCK8 group on 1, 2, 3, and 7 days after injury were significantly increased ( P<0.05), and the levels of IL-6 in pancreatic tissue of rats in severe scald+CCK8 group and extremely severe scald+CCK8 group were significantly increased on 1, 2, 3, and 7 days after injury ( P<0.05). Compared with that in severe scald+CCK8 group, the IL-1β level in pancreatic tissue of rats in extremely severe scald+CCK8 group was significantly increased on 2 and 3 days after injury ( P<0.05), and IL-6 level in pancreatic tissue was significantly increased on 2 days after injury ( P<0.05). The expression levels of HIF-1α in pancreatic tissue of rats in simple sham injury group and sham injury+CCK8 group immediately after injury were lower; and compared with that in sham injury+CCK8 group immediately after injury, the expression levels of HIF-1α in pancreatic tissue of rats in the 2 scald groups increased to a certain extent at different time points after injury, and the expression position was transited from the edge of the pancreatic tissue to the whole pancreas, the expression levels of HIF-1α in pancreatic tissue of rats in the 2 scald groups tended to be normal on 7 days after injury. Compared with that in simple sham injury group immediately after injury, the proportion of acinar cell cytoplasm in pancreatic tissue of rats in sham injury+CCK8 group was increased; and with the increase of time after injury, edema, hemorrhage, necrosis, and inflammatory infiltration appeared in pancreatic tissue of rats in the 2 scald groups. Compared with that in severe scald+CCK8 group, the scores of edema, inflammatory cell infiltration, bleeding, and necrosis in pancreatic tissue of rats in extremely severe scald+CCK8 group were increased to varying degrees at various time points after injury, and the scores of pancreatic tissue of rats in the 2 scald groups basically recovered to normal on 7 days after injury. Compared with that in simple sham injury group immediately after injury, the number of enzyme granules in acinar cells of pancreatic tissue of rats in sham injury+CCK8 group was increased, and with the increase of time after injury, the enzyme granules in acinar cells of rats in the 2 scald groups were gradually reduced basically. Conclusions The exocrine functions of pancreas, such as synthesis and secretion of pancreatic enzymes, are decreased in the early stage in severely scalded rats. And the greater the scalded area, the more significant the decline of pancreatic exocrine function. This change may be related to hypoxic injury and inflammation in pancreatic tissue after severe scald.
- Burns /
- Exocrine pancreatic insufficiency /
- Lipase /
- Alpha-amylases /
- Cholecystokinin
罗鹏：酝酿和设计实验，实施研究，采集、分析、解释数据，撰写论文；张博涵、孙佳辰：实施研究，统计、分析数据；李志生、杨键秋：实施研究，采集数据；刘馨竹：指导、支持性贡献；申传安：论文评阅，经费支持

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1 改进的胆胰混合液动态收集模型。1A.示意图；1B.实际操作图

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2 2组假伤大鼠伤后即刻和2组烫伤大鼠伤后不同时间点胰腺组织中HIF-1α表达水平 Alexa Fluor 488-4',6-二脒基-2-苯基吲哚×100。2A.单纯假伤组胰腺中HIF-1α表达弱，且基本分布在胰腺小叶边缘；2B、2C、2D、2E.分别为严重烫伤+CCK8组伤后1、2、3、7 d胰腺组织，可见HIF-1α表达增加并随时间逐渐过渡至充满整个胰腺大部分组织，且其在伤后3 d表达最强，7 d逐渐减弱；2F.假伤+CCK8组胰腺中HIF-1α表达亦弱；2G、2H、2I、2J.分别为特重烫伤+CCK8组伤后1、2、3、7 d胰腺组织，可见HIF-1α表达分别与图2B、2D、2C、2E近似，且其在伤后2 d表达最强

注：假伤指于37 ℃温水中模拟烫伤，严重烫伤指30%体表总面积（TBSA）烫伤，特重烫伤指50%TBSA烫伤；CCK8为胆囊收缩素八肽；缺氧诱导因子1α（HIF-1α）阳性染色为绿色(反映组织缺氧损伤程度)，细胞核阳性染色为蓝色

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3 2组假伤大鼠伤后即刻和2组烫伤大鼠伤后不同时间点胰腺组织病理结构苏木精-伊红×40。3A.单纯假伤组胰腺组织结构正常；3B、3C、3D、3E.分别为严重烫伤+CCK8组伤后1、2、3、7 d胰腺组织，可见组织结构逐渐出现异常后又恢复正常，其中图3D可见大面积坏死且部分组织间隙可见中性粒细胞浸润；3F.假伤+CCK8组胰腺组织结构基本同图3A；3G、3H、3I、3J.分别为特重烫伤+CCK8组伤后1、2、3、7 d，可见组织损伤变化规律基本分别同图3B、3D、3C、3E

注：假伤指于37 ℃温水中模拟烫伤，严重烫伤指30%体表总面积（TBSA）烫伤，特重烫伤指50%TBSA烫伤；CCK8为胆囊收缩素八肽；黄色箭头指示小叶间导管细胞，蓝色箭头指示炎症细胞

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4 2组烫伤大鼠伤后不同时间点胰腺组织的改良Schmidt评分情况（样本数为6， x ¯ ± s ）。4A、4B、4C、4D.分别为水肿、出血、变性坏死、炎症浸润评分比较

注：严重烫伤指30%体表总面积（TBSA）烫伤，特重烫伤指50%TBSA烫伤；蓝绿色指严重烫伤+CCK8为胆囊收缩素八肽（CCK8），橘色指特重烫伤+CCK8组

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5 2组假伤大鼠伤后即刻和2组烫伤大鼠伤后不同时间点胰腺组织腺泡细胞超微结构透射电子显微镜×5 000。5A. 单纯假伤组胰腺组织结构正常；5B、5C、5D、5E.分别为严重烫伤+CCK8组大鼠伤后1、2、3、7 d胰腺组织，可见腺泡细胞间隙逐渐变窄，结构不清，细胞内酶原颗粒染色淡，其中图5D的腺泡细胞变化最大，图5E中的组织结构基本恢复正常，酶原颗粒数量及密度亦基本恢复正常；5F.假伤+CCK8组胰腺组织结构基本同图6A，但腺泡细胞内酶原颗粒数量显著增加；5G、5H、5I、5J.分别为特重烫伤+CCK8组伤后1、2、3、7 d胰腺组织，可见其变化规律基本同图5B、5D、5C、5E

注：假伤指于37 ℃温水中模拟烫伤，严重烫伤指30%体表总面积（TBSA）烫伤，特重烫伤指50%TBSA烫伤；CCK8为胆囊收缩素八肽；绿色箭头指示酶原颗粒，蓝色箭头指示细胞核

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表1 2组假伤大鼠伤后即刻和2组烫伤大鼠伤后不同时间点胰腺组织外分泌功能及炎症因子水平的比较（ x ¯ ± s ）

组别与时间点	样本数	1 h内PBJ分泌体积（mL）	胰酶含量			血清中胰酶活力（U/L）		胰腺组织中炎症因子水平（pg/g）
组别与时间点	样本数	1 h内PBJ分泌体积（mL）	胰脂肪酶（ng）	α-淀粉酶（ng）	胰蛋白酶（pg）	胰脂肪酶	α-淀粉酶	IL-1β	IL-6
单纯假伤组	8
伤后即刻		0.740±0.030	65.1±3.9	20.7±1.8	932±96	0.81±0.04	637±44	269±15	658±17
假伤+CCK8组	8
伤后即刻		0.823±0.033 ^a	73.3±2.7 ^a	23.2±1.8 ^a	1 184±93 ^a	0.86±0.08	657±25	265±9	649±31
严重烫伤+CCK8组	32
伤后1 d		0.681±0.024 ^b	61.0±2.2 ^b	20.3±1.1 ^b	1 262±52	0.88±0.22	641±16	291±7 ^b	1 060±95 ^b
伤后2 d		0.608±0.056 ^b	60.0±1.7 ^b	20.2±1.0 ^b	1 226±113	0.96±0.13	647±17	349±10 ^b	1 236±12 ^b
伤后3 d		0.525±0.025 ^b	52.0±2.5 ^b	17.0±0.8 ^b	1 059±83	1.00±0.22	651±17	381±15 ^b	1 316±63 ^b
伤后7 d		0.720±0.044 ^b	64.1±2.0 ^b	20.2±0.8 ^b	1 131±139	0.88±0.14	662±22	285±14	994±95 ^b
特重烫伤+CCK8组	32
伤后1 d		0.540±0.025 ^bc	51.6±2.7 ^bc	17.7±0.7 ^bc	1 094±93 ^c	1.13±0.31	654±31	303±12 ^b	1 178±136 ^b
伤后2 d		0.406±0.021 ^bc	41.7±1.3 ^bc	14.4±0.6 ^bc	947±67 ^bc	1.16±0.25	666±32	408±14 ^bc	1 487±183 ^bc
伤后3 d		0.475±0.036 ^b	43.8±2.0 ^bc	15.2±0.9 ^b	1 056±116	1.13±0.31	670±17	403±12 ^bc	1 390±28 ^b
伤后7 d		0.690±0.018 ^b	66.2±2.6 ^b	20.9±1.2 ^b	1 190±73	0.98±0.22	679±8	294±13 ^b	1 010±103 ^b
注：假伤指于37 ℃温水中模拟烫伤，严重烫伤指30%体表总面积（TBSA）烫伤，特重烫伤指50%TBSA烫伤；CCK8为胆囊收缩素八肽，PBJ为胆胰混合液，IL为白细胞介素；2个烫伤组各时间点样本数均为8；胰酶含量为1 h内PBJ分泌体积中含量；1 h内PBJ分泌体积，胰脂肪酶、α-淀粉酶、胰蛋白酶含量，血清中胰脂肪酶、α-淀粉酶活力，胰腺组织中IL-1β、IL-6水平的处理因素主效应， F值分别为566.18与700.91、209.42、11.60及10.99、2.88和442.72、329.04， P值分别为<0.001与<0.001、<0.001、<0.001及<0.001、0.127和<0.001、<0.001；时间因素主效应， F值分别为79.89与104.35、21.80、3.46及0.87、1.95和208.62、34.90， P值分别为<0.001与<0.001、<0.001、0.020及0.461、0.127和<0.001、<0.001；两者交互作用， F值分别为30.15与49.75、12.99、5.49及0.45、0.55和59.51、10.90， P值分别为<0.001与<0.001、<0.001、<0.001及0.846、0.766和<0.001、<0.001；与单纯假伤组相比， ^a P<0.05；与假伤+CCK8组相比， ^b P<0.05；与严重烫伤+CCK8组相比， ^c P<0.05

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