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Chinese Journal of Reparative and Reconstructive Surgery logoLink to Chinese Journal of Reparative and Reconstructive Surgery
. 2018 Apr;32(4):484–490. [Article in Chinese] doi: 10.7507/1002-1892.201711135

天然水蛭素联合高压氧治疗对大鼠随意皮瓣成活的影响研究

Effects of combined natural hirudin and hyperbaric oxygen therapy on survival of transplanted random-pattern skin flap in rats

Jieyun CAI 1, Bojie LIN 1, Xinyuan PAN 2, Jia CUI 1, Rohan Pradhan 1, Guoqian YIN 1,*
PMCID: PMC8414342  PMID: 29806308

Abstract

Objective

To investigate the effect of natural hirudin combined with hyperbaric oxygen therapy on the survival of transplanted random-pattern skin flap in rats.

Methods

A random-pattern skin flap in size of 10.0 cm×2.5 cm was elevated on the dorsum of 72 Sprague Dawley rats. Then the 72 rats were randomly divided into 4 groups (n=18) according to the therapy method. At immediate and within 4 days after operation, the rats were treated with normal saline injection in control group, normal saline injection combined with hyperbaric oxygen treatment in hyperbaric oxygen group, the natural hirudin injection in natural hirudin group, and the natural hirudin injection combined with hyperbaric oxygen treatment in combined group. The flap survival was observed after operation, and survival rate was evaluated at 6 days after operation. The skin samples were collected for histological analysis, microvessel density (MVD) measurement, and evaluation of tumor necrosis factor α (TNF-α) expression level by the immunohistochemical staining at 2 and 4 days after operation.

Results

Partial necrosis occurred in each group after operation, and the flap in combined group had the best survival. The survival rate of flap was significantly higher in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group, and in combined group than in hyperbaric oxygen group and natural hirudin group (P<0.05). There was no significant difference between hyperbaric oxygen group and natural hirudin group (P>0.05). At 2 days, more microvascular structure was observed in hyperbaric oxygen group, natural hirudin group, and combined group in comparison with control group; while plenty of inflammatory cells infiltration in all groups. At 4 days, the hyperbaric oxygen group, natural hirudin group, and the combined group still showed more angiogenesis. Meanwhile, there was still infiltration of inflammatory cells in control group, inflammatory cells in the other groups were significantly reduced when compared with at 2 days. At 2 days, the MVD was significantly higher in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group (P<0.05); the expression of TNF-α was significantly lower in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group (P<0.05). There was no significant difference in above indexes between hyperbaric oxygen group, natural hirudin group, and combined group (P>0.05). At 4 days, the MVD was significantly higher in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group, in natural hirudin group and combined group than in hyperbaric oxygen group (P<0.05). The expression of TNF-α was significantly lower in hyperbaric oxygen group, natural hirudin group, and combined group than that in control group, in combined group than in natural hirudin group and hyperbaric oxygen group (P<0.05).

Conclusion

Hyperbaric oxygen and natural hirudin therapy after random-pattern skin flap transplantation can improve the survival of flaps. Moreover, combined therapy is seen to exhibit significant synergistic effect. This effect maybe related to promotion of angiogenesis and the reduction of inflammation response.

Keywords: Natural hirudin, hyperbaric oxygen, random-pattern skin flap, angiogenesis, inflammation response, flap survival, rat

皮瓣移植是整形外科修复各种组织缺损的一种重要手段。随意皮瓣因其转移灵活、术式简单而被广泛应用。但随意皮瓣由于不含知名血管，皮瓣血液供应主要依靠蒂部皮肤及筋膜内的血管网，因而受皮瓣长宽比例的影响，若皮瓣发生血液循环障碍未得到及时纠正，会造成皮瓣部分或全部坏死[1]。因此，改善移植术后皮瓣的血液供应，减少炎性反应，对提高皮瓣的成活率至关重要。

近年来，高压氧作为一种新的治疗方法逐渐受到临床重视。目前，学者们主要在提高脑和脊髓的缺血缺氧耐受[2]、抗凋亡[3-4]及抑制炎症[5]等方面，对高压氧的作用进行一系列研究。在整形外科领域，有报道将高压氧用于组织缺损修复和移植术后的辅助治疗[6-7]。有研究表明，高压氧处理对移植皮瓣的成活具有一定促进作用[8-9] 。水蛭素是天然的凝血酶拮抗剂，其能与凝血酶受体特异性结合而具备抗凝效应，可起到预防血栓形成、改善皮瓣微循环、提高组织血流灌注量的作用。本课题组前期实验也发现，天然水蛭素能通过促血管生成、抑制炎性反应等方面改善淤血皮瓣的微循环，从而促进移植后随意皮瓣的成活[10-11]。目前，有关高压氧和水蛭素两者在皮瓣移植中的联合应用鲜有报道。本研究通过探讨高压氧联合水蛭素治疗对移植术后皮瓣组织中微血管密度（microvessel density，MVD）、TNF-α 的影响及其与皮瓣成活的关系，旨在为两者用于临床促进移植术后皮瓣成活提供理论依据。

1. 材料与方法

1.1. 实验动物及主要试剂、仪器

健康 SD 大鼠 72 只，雌雄不限，体质量（275±15）g，购自广西医科大学实验动物中心。天然水蛭素冻干粉（南宁净雪皇生物工程有限公司）。兔抗大鼠 CD34 单克隆抗体、兔抗大鼠 TNF-α 多克隆抗体（Abcam 公司，英国）；免疫组织化学染色试剂盒（北京中杉金桥生物技术有限公司）。Olympus-BX50 显微镜（Olympus 公司，日本）；Image Pro-Plus 6.0 软件（Media Cybernetics 公司，美国）。

1.2. 实验分组及方法

1.2.1. 大鼠随意皮瓣移植模型制备

取 72 只 SD 大鼠，腹腔注射 10% 水合氯醛（3 mL/kg）麻醉后，在其背部设计一个面积为 10.0 cm×2.5 cm 的超长随意皮瓣。无菌条件下，按设计线切开皮肤至深筋膜层，分离并掀起皮瓣，如有轴型血管将其切断，保证皮瓣不携带轴型血管，彻底止血后皮瓣原位缝合。

1.2.2. 实验分组及方法

将大鼠随意皮瓣移植模型随机分为对照组、高压氧组、水蛭素组和联合组（水蛭素+高压氧治疗），每组 18 只。对照组：术后即刻及之后 4 d 内每天皮下注射生理盐水，皮瓣注射点选择为距蒂部 7.5、5.0、2.5 cm 处，每处各 2 个点，每个点注射 0.1 mL。高压氧组：同对照组方法注射生理盐水，同时术后 4 d 内每天行高压氧治疗 2 次，每次间隔 6 h。水蛭素组：参照对照组方法皮下注射天然水蛭素，每个点注射 0.1 mL，含 10 ATU。联合组：参照水蛭素组注射天然水蛭素，同时参照高压氧组行高压氧治疗。

高压氧治疗方法参考 Liu 等[8]实验方法和本课题组前期实验经验[12]。具体步骤：将大鼠置于大型空气加压舱内的自制实验动物容器中，对舱内进行空气加压 20 min，使舱内压力达到 2.0 ATA，稳压 60 min，加压开始时即对实验动物容器通氧，连续监测容器中氧浓度，稳压期间将氧浓度维持在 98% 以上，开始减压时即停止通氧，减压 20 min。

1.3. 观测指标

1.3.1. 大体观察

术后第 2、4、6 天观察大鼠皮瓣色泽、质地、有无水肿、有无渗出、有无破溃以及成活情况。术后第 6 天各组取 6 只大鼠同上法麻醉后，数码相机摄背部皮瓣照片，采用 Image Pro-Plus 6.0 软件计算皮瓣成活率。皮瓣成活率=皮瓣成活面积/皮瓣面积×100%。

1.3.2. 组织学观察

术后第 2、4 天各组分别取 6 只大鼠，同上法麻醉后，切取皮瓣距尾端 3～4 cm 处组织，置于 10% 甲醛固定 24 h 后，脱水、包埋、切片，片厚 3μm，取部分切片行 HE 染色，显微镜下观察皮瓣组织中微血管结构、炎性细胞数量及坏死情况。

1.3.3. 免疫组织化学染色

术后第 2、4 天取 1.3.2 中制备的剩余切片，采用 SP 法分别行 CD34 及 TNF-α 免疫组织化学染色观察，阳性染色呈棕黄色。CD34 染色切片置于低倍镜下确定血管密度最高区域，再在高倍镜下选取 3 个密度较多视野进行微血管计数，取均值作为 MVD。TNF-α 染色切片每张随机取 3 个视野，使用 Image Pro-Plus 6.0 软件测定吸光度（A）值，取均值，代表皮瓣组织中 TNF-α 蛋白表达量。

1.4. 统计学方法

采用 SPSS20.0 统计软件进行分析。数据以均数±标准差表示，组间比较采用单因素方差分析，两两比较采用 SNK 检验；检验水准 α=0.05。

2. 结果

2.1. 大体观察

术后第 2 天，各组大鼠皮瓣远端存在不同程度水肿，色泽变暗。其中，对照组水肿程度最严重、范围最大，水蛭素组与高压氧组水肿情况相似且较对照组轻，联合组皮瓣水肿程度最轻、色泽最浅。第 4 天，各组大鼠皮瓣远端色泽加深，出现淤血征象，组织质地稍变硬。其中，对照组淤血范围明显大于其余各组。第 6 天，各组皮瓣远端色泽进一步加深，呈灰黑色，组织质地变硬，部分皱缩，皮瓣出现明显坏死分界。其中，联合组皮瓣成活情况最佳；水蛭素组与高压氧组皮瓣均存在部分坏死，成活情况相近；对照组存在较大面积皮瓣坏死。见图 1。

图 1.

General observation of skin flap in each group after operation

术后各组皮瓣大体观察

从左至右分别为对照组、高压氧组、水蛭素组、联合组　a. 术后第 2 天；b. 术后第 4 天；c. 术后第 6 天

From left to right for control group, hyperbaric oxygen group, natural hirudin group, combined group, respectively　a. At 2 days after operation; b. At 4 days after operation; c. At 6 days after operation

图 1

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术后第 6 天对照组、高压氧组、水蛭素组、联合组皮瓣成活率分别为 69.53%±3.07%、85.03%±3.55%、87.29%±2.71%、91.51%±3.28%。高压氧组、水蛭素组及联合组皮瓣成活率明显高于对照组，联合组高于水蛭素组、高压氧组，比较差异有统计学意义（P<0.05）；水蛭素组与高压氧组比较，差异无统计学意义（P>0.05）。

2.2. 组织学观察

术后第 2 天，与对照组相比，水蛭素组、高压氧组及联合组中均可见微小血管形成，其中联合组微血管结构最多；各组均可见大量炎性细胞浸润，其中联合组炎性浸润情况最轻。第 4 天，与对照组相比，高压氧组、水蛭素组及联合组中仍可见较多微血管形成；对照组中则见大量炎性细胞浸润，部分细胞甚至出现核固缩、核碎裂，而其余各组炎性细胞浸润均较第 2 天时明显减少，炎性反应均较对照组轻。见图 2。

图 2.

Histological observation of each group after operation (HE×200)

术后各组组织学观察（HE×200）

从左至右分别为对照组、高压氧组、水蛭素组、联合组　a. 术后第 2 天；b. 术后第 4 天

From left to right for control group, hyperbaric oxygen group, natural hirudin group, and combined group, respectively　a. At 2 days after operation; b. At 4 days after operation

图 2

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2.3. 免疫组织化学染色

2.3.1. CD34 染色

术后第 2 天，联合组阳性染色细胞多于高压氧组及水蛭素组，视野内细胞形成微血管结构较多；对照组仅见稀疏阳性染色细胞，视野内微血管结构不明显。第 4 天，对照组未见明显阳性染色，联合组及水蛭素组阳性染色细胞较高压氧组多，视野内形成的微血管结构较多。见图 3。

图 3.

CD34 immunohistochemical staining observation of each group after operation (×400)

术后各组 CD34 免疫组织化学染色观察（×400）

从左至右分别为对照组、高压氧组、水蛭素组、联合组　a. 术后第 2 天；b. 术后第 4 天

From left to right for control group, hyperbaric oxygen group, natural hirudin group, and combined group, respectively　a. At 2 days after operation; b. At 4 days after operation

图 3

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术后第 2 天，对照组、高压氧组、水蛭素组、联合组皮瓣 MVD 分别为（10.78±2.94）、（15.06±1.61）、（18.61±2.50）、（17.94±3.43）个/视野；其中高压氧组、水蛭素组及联合组 MVD 均显著高于对照组，比较差异有统计学意义（P<0.05）；高压氧组、水蛭素组及联合组间比较差异无统计学意义（P>0.05）。第 4 天，对照组、高压氧组、水蛭素组、联合组皮瓣 MVD 分别为（9.28±1.44）、（19.94±2.86）、（24.44±5.37）、（25.28±3.06）个/视野；其中高压氧组、水蛭素组及联合组 MVD 均显著高于对照组，联合组及水蛭素组高于高压氧组，比较差异有统计学意义（P<0.05）；联合组及水蛭素组间比较差异无统计学意义（P>0.05）。

2.3.2. TNF-α 染色

术后第 2 天，与对照组相比，高压氧组与水蛭素组 TNF-α 表达水平较低，且两者较相近，而联合组最低；第 4 天，各组 TNF-α 阳性表达均较前增多，但联合组 TNF-α 表达水平仍最低，高压氧组和水蛭素组较高，而对照组 TNF-α 表达水平仍最高。见图 4。

图 4.

TNF-α immunohistochemical staining observation of each group after operation (×400)

术后各组 TNF-α 免疫组织化学染色观察（×400）

从左至右分别为对照组、高压氧组、水蛭素组、联合组　a. 术后第 2 天；b. 术后第 4 天

From left to right for control group, hyperbaric oxygen group, natural hirudin group, and combined group, respectively　a. At 2 days after operation; b. At 4 days after operation

图 4

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术后第 2 天，对照组、高压氧组、水蛭素组、联合组 TNF-α 蛋白表达量分别为 0.008 6±0.002 7、0.002 5±0.001 3、0.003 6±0.002 1、0.001 4±0.001 0；其中高压氧组、水蛭素组及联合组均显著低于对照组，比较差异有统计学意义（P<0.05）；高压氧组、水蛭素组及联合组间比较差异无统计学意义（P>0.05）。第 4 天，对照组、高压氧组、水蛭素组、联合组 TNF-α 蛋白表达量分别为 0.010 7±0.002 0、0.003 9±0.001 8、0.005 5±0.001 7、0.001 8±0.001 0；其中高压氧组、水蛭素组及联合组表达水平仍显著低于对照组，联合组低于水蛭素组、高压氧组，比较差异有统计学意义（P<0.05）；水蛭素组及高压氧组间比较，差异无统计学意义（P>0.05）。

3. 讨论

随意皮瓣的血液供应主要依赖于真皮下血管网，而皮瓣基底和周边长入的新生血管，也对皮瓣的血运发挥了一定作用[13]。MVD 即单位面积内微血管数，能反映组织的血管生成活性[14]。已有研究证实，高压氧治疗能促进移植皮瓣的新生血管形成[8, 15-16]，并能提高组织中 VEGF 的表达水平[17-18]。值得注意的是，由于皮瓣移植后的构建本质上是一个创伤修复的过程，因而当组织发生损伤时，损伤处及周边组织会合成并释放大量凝血酶，进而通过激活凝血酶受体诱导一系列病理生理反应，抑制血管生成[19]。我们前期研究[20]也发现，皮瓣移植术后第 6 天，组织中凝血酶水平明显升高并呈持续高表达状态，使抑制血管生成的因子表达增多，抑制了组织新生血管形成。而天然水蛭素作为凝血酶的特异性拮抗剂，通过拮抗凝血酶的相关信号通路，调节了血管生成因子（如 VEGF）与抗血管生成因子（如 TSP-1、内皮抑素）之间的平衡，从而对移植后的皮瓣起到促血管生成作用。

本实验中，我们通过免疫组织化学染色检测并计数各组皮瓣 MVD，以评估其新生血管情况。结果显示皮瓣移植术后第 2 天，高压氧组、水蛭素组及联合组皮瓣 MVD 均明显高于对照组。表明皮瓣移植术后，给予天然水蛭素和高压氧治疗对皮瓣新生血管形成均有明显促进作用。通过早期干预形成较多的新生血管，改善了皮瓣的微循环灌注，使皮瓣的缺血、淤血情况得以明显改善。至术后第 4 天时，联合组大鼠皮瓣的 MVD 最高，明显高于高压氧组和水蛭素组；同时，术后第 6 天联合组皮瓣成活率也最高，提示术后高压氧联合天然水蛭素治疗具有协同作用，能促进术后早期皮瓣微循环的建立，明显提高移植皮瓣成活率。

然而，移植后的皮瓣组织构建不仅依赖于血管生成，还取决于组织的炎性反应及损伤修复。TNF-α 是一种由活化的巨噬细胞及单核细胞分泌的细胞因子，作为启动炎性反应的关键因子，可诱导 NF-κB 磷酸化，从而激活一系列联级反应，进而促进多种细胞因子及炎性介质的释放[21-22]，并能通过显著增加细胞黏附分子的表达来增强内皮细胞与白细胞的相互作用，介导炎性反应的进一步发展[23]。此外，TNF-α 还可以诱导组织细胞发生凋亡[24]。因而，组织中 TNF-α 的含量可代表其炎性反应程度。

理论上，减轻组织损伤的炎性反应有利于创伤愈合[25]，促进移植皮瓣的成活。有研究表明，高压氧治疗能通过抑制 NF-κB 的活化来抑制大鼠外周血和组织中炎性因子的产生[26-27]，并能下调血清和组织中 IL-1β 和 TNF-α 的水平[28-29]，抑制炎性反应。我们前期研究显示，局部应用天然水蛭素，能明显降低皮瓣移植术后 TNF-α、IL-6 等炎性因子的表达水平[11]。本研究中，我们对皮瓣组织进行 TNF-α 免疫组织化学染色观察，结果显示术后第 2、4 天，高压氧组、水蛭素组和联合组的 TNF-α 蛋白表达量均显著低于对照组，表明术后给予高压氧处理及天然水蛭素治疗均能明显减轻皮瓣移植术后炎性反应。其中第 4 天时，联合组中的 TNF-α 蛋白表达量最低，显著低于高压氧组及水蛭素组，表明天然水蛭素联合高压氧治疗具有协同效应，能明显抑制术后皮瓣组织的炎性应激反应。

综上述，局部应用天然水蛭素和高压氧治疗均能促进移植皮瓣的新生血管形成、减轻皮瓣炎性反应，两者联合治疗时能发挥协同效应，进一步提高移植皮瓣的成活率。但两者联合治疗条件及其具体的交互作用机制尚需进一步研究和探讨。

Funding Statement

广西壮族自治区教育厅高校重点科研项目（ZD2014034）；国家自然科学基金资助项目（81460297）

Key Scientific Research Projects of Colleges and Universities of the Education Department of Guangxi Zhuang Autonomous Region (ZD2014034); National Natural Science Foundation of China (81460297)

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Articles from Chinese Journal of Reparative and Reconstructive Surgery are provided here courtesy of Sichuan University

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