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. 2022 Jan 28;47(1):1–7. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2022.200993

不同路径肝素对门静脉胰岛移植术后立即经血液介导炎症反应的影响

Effects of different routes of heparin on instant blood-mediated inflammatory reaction after portal vein islet transplantation

ZHANG Shengwang 1,1, YAN Haixiong 1, MA Xiaoqian 1, ZHENG Wei 1,✉, WANG Wei 1,✉
Editor: 傅 希文
PMCID: PMC10930478  PMID: 35545357

Abstract

Objective

Heparin is mainly used as an anticoagulant in clinic, and it also has a certain anti-inflammatory effect. At present, after portal vein islet transplantation in diabetic patients, heparin is mainly infused through the peripheral veins of the limbs to achieve the purpose of anticoagulation and protection of the graft, rather than through the portal vein. In this study, animal experiments were conducted to investigate the effect of heparin infusion via the portal vein and marginal ear vein on the instant blood-mediated inflammatory reaction (IBMIR) after portal vein islet transplantation, which is the choice of anticoagulation methods for clinical islet transplantation to provide a basis for decision-making.

Methods

A total of 50 neonatal pigs (Xeno-1 type, 3-5 days) were selected. Islets were isolated and purified from the pancreas of neonatal pigs. Ten non-diabetic Landrace pigs (1.5-2.0 months) served as recipients, and 12 000 IEQ/kg neonatal porcine islets were transplanted into the liver through the portal vein. All recipients received bolus injection of 50 U/kg of heparin 10 minutes before transplantation. After the bolus injection of heparin, the experimental group received heparin via the portal vein [10 U/(kg·h), 5 recipients], and the control group received heparin via the marginal ear vein [10 U/(kg·h), 5 recipients]. The superior vena cava blood was collected from the 2 groups pre-operation at 1, 3, 24 h post-operation of the transplantation. The portal vein blood was collected from the experimental group at 1 and 3 h after the transplantation as well. The levels of complement C3a, C5a, thrombin-antithrombin complex (TAT), β-thromboglobulin (β-TG), and D-dimer as well as activated partial thromboplastin time (APTT) in superior vena cava blood from 1 and 3 h post-transplantation were detected in the 2 groups, and the levels of anti-Xa and anti-IIa in the portal vein and superior vena cava blood from 1 and 3 h post-transplantation in the experimental group were detected. Twenty four hours after the transplantation, the liver tissues in the 2 groups were collected for pathological examination to observe the inflammatory cell infiltration and peripheral thrombosis around the islets graft in liver.

Results

Before transplantation, there was no statistically significant difference in C3a, C5a, TAT, β-TG, D-dimer levels and APTT between the 2 groups (all P>0.05). At 1 and 3 h after transplantation, the C3a, TAT, and D-dimer levels in the experimental group were significant decreased than those in the control groups (all P<0.05), and at 3 h after transplantation the C5a was significant decreased than that in the control group (P<0.05). At 1 and 3 h after transplantation, the anti-Xa and anti-IIa levels in the portal vein blood were significantly increased than those in the superior vena cava blood in the experimental group (all P<0.05). Pathological results showed the presence of islet cell clusters in the liver blood vessels. The thrombus formation and neutrophil infiltration around islet graft was not obvious in the experimental group, while massive thrombus formation and neutrophil infiltration in the control group.

Conclusion

Compared with marginal ear vein infusion of heparin, the direct infusion of heparin in the portal vein has a certain inhibitory effect on complement system, coagulation system activation and inflammatory cell infiltration in portal vein islet transplantation, which may attenuate the occurrence of IBMIR.

Keywords: islet, portal vein, heparin, instant blood mediated inflammatory reaction, diabetes mellitus

胰岛异种移植是一种有前途的1型糖尿病治疗方法[1-2]。移植后早期移植物大量丢失是影响胰岛移植效果的主要障碍[3-4]，其中胰岛细胞接触受体血液引起立即经血液介导炎症反应(instant blood mediated inflammatory reaction，IBMIR)是造成细胞移植物丢失的最主要因素[5-7]。IBMIR是胰岛细胞接触受体血液立即引起的非特异性炎症反应，根据其特点以凝血激活过程、补体激活过程以及炎症过程为标志[8-9]。选择一种或联合应用多种抑制方法使这种炎症反应最小化，以提高临床胰岛移植成功率是胰岛移植领域的热点。本研究通过门静脉将胰岛移植于肝脏，分别通过门静脉与耳缘静脉输注肝素，探讨两种路径输注肝素对门静脉胰岛移植术后IBMIR的影响。

1. 材料与方法

1.1. 动物

选取月龄为1.5~2.0个月、体重10~12 kg的非糖尿病模型长白猪10只作为受体。胰岛供体为50只新生猪(Xeno-1型，由湖南赛诺生物科技有限责任公司提供)，年龄3~5 d，体重0.9~2.0 kg[10]。门静脉胰岛移植术后通过门静脉输注肝素5只(实验组)，通过耳缘静脉输注肝素5只(对照组)。术前受体适应环境至少3 d，术前24 h禁食、禁水，术前12 h口饲二甲硅油10 mL以清除肠道内气体。该动物实验得到了中南大学湘雅三医院医学伦理委员会的批准(审批号：2019sydw0121，http://xy3irb.xy3yy.com/)。

1.2. 试剂

补体检测试剂盒购自美国Abcan公司；抗Xa(anti-Xa)、抗-IIa(anti-IIa)活性测试试剂盒购自法国Boatman Biotech公司；Ham's F-10完全培养基购自美国Hyclone公司；V型胶原酶购自美国Sigma公司；丙泊酚购自广东嘉博制药有限公司；利多卡因购自长沙双鹤医药有限公司。

1.3. 方法

1.3.1. 胰岛消化、分离及纯化

本研究按照2006年中国科学技术部《关于善待实验动物的指导性意见》的要求妥善处理动物。新生猪胰岛细胞的消化、分离、纯化及计数基本按照文献[11-12]所述方法进行。

1.3.2. 胰岛移植及肝素输注

用24G静脉留置针穿刺猪双侧耳缘静脉，推注丙泊酚(2.0~2.5 mg/kg)麻醉诱导。将猪仰卧捆绑于实验台，经输液泵输注丙泊酚4~12 mg/(kg·h)以维持麻醉。对腹壁进行消毒，于腹中线位置注射利多卡因10 mL以行局部麻醉，于中上腹部正中切口暴露肠系膜上静脉及门静脉。用24G留置针向肝脏穿刺肠系膜上静脉，通过留置针输注胰岛(12 000 IEQ/kg)，将胰岛移植于肝内[13]。

实验组采用24G静脉留置针穿刺门静脉，胰岛移植前10 min团注肝素50 U/kg，然后注射泵输注肝素10 U/(kg·h)，至手术结束后3 h。对照组采用24G留置针穿刺耳缘静脉，胰岛移植前10 min团注肝素(50 U/kg)，然后用注射泵输注肝素10 U/(kg·h)，至手术结束后3 h[14]。胰岛移植后3 h拔除肠系膜上静脉穿刺针，回纳肠道，缝合腹壁切口，体表适当包扎后饲养至24 h。

1.3.3. 血液采集

实验组与对照组均采用5F血管穿刺套装穿刺上腔静脉，分别于术前30 min、术后1、3、24 h各采集血液15 mL。实验组再通过门静脉用24G静脉留置针分别于术后1、3 h各采集血液5 mL。

1.3.4. 血液学检测

取实验组与对照组猪，分别检测术前、术后1、3及24 h补体(C3a、C5a)、凝血酶-抗凝血酶复合物(thrombin-antithrombin complex，TAT)、β-血小板球蛋白(β-thromboglobulin，β-TG)及D-二聚体(D-dimer)水平，检测血液活化部分凝血活酶时间(activated partial thromboplastin time，APTT)。实验组分别检测术后1与3 h门静脉、上腔静脉血液的anti-Xa、anti-IIa浓度。

1.3.5. 病理学检查

胰岛移植术后24 h处死猪，采集肝脏标本行病理HE染色和免疫组织化学检测。

1.4. 统计学处理

采用SPSS 25.0统计学软件进行数据分析，计量资料以均数±标准差( x¯ ±s)表示，采用Mann-Whitney U检验对实验组和对照组的差异进行统计分析，以α=0.05作为双侧检验水准，以P<0.05为差异有统计学意义。

2. 结 果

2.1. 血液学检测结果

实验组与对照组术前C3a、C5a、TAT、β-TG、APTT、D-dimer组间差异均无统计学意义(均P>0.05，图1)。术后1、3 h，两组C3a、TAT及D-dimer组间差异有统计学意义(均P<0.05)；术后3、24 h，两组C5a的组间差异有统计学意义(均P<0.05，图1)。

图1.

图1

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实验组与对照组血液学检测结果

Figure 1 Blood test results in the experimental group and the control group A: C3a; B: C5a; C: TAT; D: β-TG; E: APTT; F: D-Dimer

2.2. Anti-Xa和anti-IIa水平

实验组术后1、3 h门静脉与上腔静脉血液anti-Xa、anti-IIa差异均有统计学意义(均P<0.05，表1)。

表1.

实验组门静脉、上腔静脉肝素抗凝浓度检测(n=5)

Table 1 Detection of anticoagulant concentration of heparin in portal vein and superior vena cava of the experimental group (n=5)

时间/h Anti-Xa/(U·mL-1) P Anti-IIa/(U·mL-1) P
门静脉 上腔静脉 门静脉 上腔静脉
1 0.156±0.041 0.075±0.012 0.007 0.128±0.055 0.057±0.023 0.010
3 0.201±0.041 0.053±0.013 0.001 0.174±0.094 0.068±0.022 0.003
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2.3. 病理学改变

两组动物肝病理切片HE、免疫组织化学图片见图2。实验组(门静脉输注肝素)肝血管内胰岛周围仅见少量血栓与中性粒细胞，对照组(耳缘静脉输注肝素)肝血管内胰岛周围可见大量血栓与中性粒细胞。

图2.

图2

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门静脉胰岛移植术后实验组与对照组肝组织病理检查结果

Figure 2 Pathological results of liver tissues in the experimental group and the control group after portal vein islet transplantation

A: Hematoxylin and eosin for porcine liver in the experimental groups. The thrombus formation and neutrophil infiltration around islet graft are not obvious (×200). B: Immunohistochemical analysis for insulin secreting cells in the experimental group (×200). C: Immunohistochemical analysis for hepatocytes in the experimental group (×200). D: Hematoxylin and eosin for porcine liver in the control groups. Islet graft is surrounded by massive thrombus formation and neutrophil infiltration (×200). E: Immunohistochemical analysis for insulin secreting cells in the control group (×200). F: Immunohistochemical analysis for hepatocytes in the control groups (×200).

3. 讨 论

本研究显示门静脉胰岛移植术前实验组与对照组之间C3a、C5a差异不存在统计学意义，而术后1、3 h两组之间C3a差异存在统计学意义，术后3 h两组之间C5a差异存在统计学意义，因此可以推断门静脉胰岛移植术后通过门静脉输注肝素，与耳缘静脉输注肝素比较，肝素首先到达靶器官肝脏，局部高浓度肝素可以部分抑制胰岛移植术后血液内补体系统的激活。Zaferani等[15]报道肝素具有一定的抑制补体激活的作用，本研究结果支持该结论。胰岛与受体血液的直接接触，可以激活补体系统，促进IBMIR的发生[16-17]；因此可以推断，门静脉胰岛移植术后通过门静脉直接输注肝素，可维持肝内肝素的相对高浓度，可以抑制补体系统的激活，可能会缓解IBMIR的发生、促进胰岛的存活。Cabric等[18]报道肝素-胰岛复合物对IBMIR的发生具有一定的保护作用，Koh等[19]报道采用肝素和胰岛混合团注可以改善胰岛成活率。本研究显示术后24 h实验组与对照组间C3a和C5a水平差异不具有统计学意义，笔者推测此结果与胰岛移植术后3 h缝合腹部切口、停止输注肝素有关，肝素在动物体内半衰期短(30~150 min)[20]，至术后24 h两组动物体内肝素基本完成代谢。

D-dimer与TAT是临床常用的反映凝血变化的指标[21-22]。肝素具有抗凝作用[23]，本研究显示实验组与对照组术前TAT和D-dimer水平的差异不具有统计学意义，而术后1、3 h实验组的TAT和D-dimer水平明显降低，且组间差异具有统计学意义，因此可以推断在门静脉胰岛移植术后，与耳缘静脉输注肝素比较，门静脉直接输注肝素可导致肝内肝素浓度相对增高，在一定程度上可以抑制凝血系统的激活。本研究病理学结果显示实验组胰岛周围血栓与耳缘静脉静脉组比较明显减轻，进一步证实通过门静脉直接输注肝素可以部分抑制凝血系统的激活。Mulloy等[23]报道肝素通过诱导抗凝血酶活化来增强对Xa因子的抑制，Xa因子可以将凝血酶原转化为凝血酶(IIa因子)的蛋白酶。本研究进一步分析实验组的门静脉与上腔静脉anti-Xa、anti-IIa浓度，显示二者在门静脉中的浓度明显高于上腔静脉，因此进一步证实胰岛移植术后肝脏内相对高浓度肝素对于凝血系统激活具有一定的抑制作用。von Zur-Mühlen等[24]报道门静脉胰岛移植后15~60 min TAT即可达到峰值，因此有理由认为肝素可通过抑制凝血系统而缓解IBMIR的发生。本研究显示术后24 h实验组与对照组TAT、D-dimer组间差异不存在统计学意义，笔者推测与术后3 h停止输注肝素有关。肝素的抗凝血作用可导致APTT延长[25]，本研究显示术后1、3 h两组之间APTT差异不具有统计学意义，推测与两组动物的血液均采自上腔静脉有关。β-TG是血小板分泌的特异性蛋白质，是血小板激活的特异性指标[26]，本研究显示实验组与对照组术后β-TG均较术前升高，但两组之间差异不具有统计学意义，可能与样本量偏少有关系，仍需进一步的实验研究。

研究[27-29]报道肝素具有一定的抗炎作用。本研究组织病理学发现实验组胰岛周围及胰岛内中性粒细胞浸润较对照组明显减轻，可能与肝素的抗炎作用有关，因此可以推测胰岛移植术后门脉系统相对高浓度肝素部分抑制了炎症细胞的聚集与浸润，在一定程度上缓解了IBMIR的发生。本研究证实门静脉胰岛移植术后，与外周静脉输注肝素比较，通过门静脉直接输注肝素可以维持门脉系统肝素相对高浓度，提示两种路径输注肝素可达到门脉系统相同的肝素浓度，通过门静脉直接输注肝素可以减少肝素用量，而肝素有可能导致出血、血小板减少、骨质疏松等并发症[30-32]，因此，通过门静脉直接输注肝素具有更高的安全性，但此结论尚需进一步的研究。

本研究也存在一定的局限性，如胰岛来源为Xeno-1型新生猪，与受体长白猪属同种，而临床部分糖尿病患者接受的为异种胰岛移植；本研究术后血液学检测为术后1、3及24 h，时间点相对较少。

综上所述，与外周静脉输注肝素比较，通过门静脉直接输注肝素可以维持门脉系统内肝素相对高浓度，对补体系统、凝血系统激活及炎性细胞浸润具有一定的抑制作用，可在一定程度上缓解IBMIR的发生。

基金资助

国家重点研发计划(2019YFA0110703)；湖南省科技重大专项(2018SK2010)；湖南省科技人才托举工程(2020TJ-Y07)。

This work was supported by the National Key Research and Development Program (2019YFA0110703), the Major Scientific and Technological Projects of Hunan Province (2018SK2010), and the Hunan Science and Technology Talent Support Project (2020TJ-Y07), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

张声旺 实验操作，论文撰写与修订；颜海雄 实验材料准备；马小倩 数据采集；郑薇 统计分析、指导论文修改；王维 实验设计者、负责人，提供实验指导、指导论文修改。全体作者都阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2022011.pdf

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