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中华损伤与修复杂志(电子版) ›› 2021, Vol. 16 ›› Issue (03) : 224 -231. doi: 10.3877/cma.j.issn.1673-9450.2021.03.011

所属专题： 文献；

论著

小分子药物Tideglusib促进大鼠创面愈合的机制研究
孙佳辰1, 刘馨竹1, 申传安2,†(), 张文1, 马景龙1, 钮跃增2, 李大伟1, 刘兆兴1, 张博涵1   
  1. 1. 100089　北京，解放军总医院第四医学中心烧伤整形医学部；100089　北京，解放军总医院研究生院
    2. 100089　北京，解放军总医院第四医学中心烧伤整形医学部
  • 收稿日期:2021-03-05 出版日期:2021-06-01
  • 通信作者: 申传安
  • 基金资助:
    北京市自然科学基金重点项目(7171009); 首都临床特色应用研究与成果推广重点课题(Z17110001017146); 国家重点研发计划(2017YFC1103503); "十三五"军队后勤科研项目重大项目(ALB18J001); "十三五"军队重点学科专业建设项目(A350109)

Study on the mechanism of small molecule drug Tideglusib in promoting wound healing in rats

Jiachen Sun1, Xinzhu Liu1, Chuanan Shen2,†(), Wen Zhang1, Jinglong Ma1, Yuezeng Niu2, Dawei Li1, Zhaoxing Liu1, Bohan Zhang1   

  1. 1. Department of Burns and Plastic Surgery, Fourth Medical Center of Chinese People′s Liberation Army General Hospital, Beijing 100089, China; Graduate School of Chinese People′s Liberation Army General Hospital, Beijing 100089, China
    2. Department of Burns and Plastic Surgery, Fourth Medical Center of Chinese People′s Liberation Army General Hospital, Beijing 100089, China
  • Received:2021-03-05 Published:2021-06-01
  • Corresponding author: Chuanan Shen
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引用本文：

孙佳辰, 刘馨竹, 申传安, 张文, 马景龙, 钮跃增, 李大伟, 刘兆兴, 张博涵. 小分子药物Tideglusib促进大鼠创面愈合的机制研究[J]. 中华损伤与修复杂志(电子版), 2021, 16(03): 224-231.

Jiachen Sun, Xinzhu Liu, Chuanan Shen, Wen Zhang, Jinglong Ma, Yuezeng Niu, Dawei Li, Zhaoxing Liu, Bohan Zhang. Study on the mechanism of small molecule drug Tideglusib in promoting wound healing in rats[J]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2021, 16(03): 224-231.

目的

研究小分子药物Tideglusib对大鼠创面愈合的影响及其机制。

方法

选择40只健康雄性2月龄SD大鼠，采用随机数字表法随机分为对照组和Tideglusib组，每组20只，在其背部制作直径8 mm的圆形全层皮肤缺损创面，伤后即刻起，对照组创面滴加50 μL磷酸盐缓冲溶液(PBS)，Tideglusib组创面滴加50 μL 40 μmol/L的Tideglusib，1次/d。(1)每组按照随机数字表法选定8只大鼠，分别于伤后3、7、10 d观察创面愈合情况，并计算、比较创面愈合率。(2)每组从未进行创面观察的12只大鼠中选定6只，分别于伤后3、7、10 d取创缘组织，通过苏木精-伊红染色观察创面愈合过程中再上皮化情况、新生毛细血管情况、新生表皮厚度，Masson染色观察真皮胶原纤维排列情况，免疫组织化学染色检测驱动蛋白家族成员14(KIF14)表达水平和分布。(3)将每组剩余的6只大鼠在伤后3 d取创缘组织，经蛋白质印迹法检测蛋白激酶(PKB)、磷酸化蛋白激酶B(p-PKB)、KIF14表达水平变化。对数据行独立样本t检验。

结果

(1)相较于对照组，Tideglusib组在各时相点创面明显缩小，创面渗出物更少，炎症反应更轻，肉芽组织质量更好，新生表皮延伸更多；伤后3 d，Tideglusib组创面愈合率为(12.42±3.48)%，对照组创面愈合率为(8.35±1.73)%，2组比较差异无统计学意义(t＝1.48, P＝0.56)；伤后7、10 d，Tideglusib组创面愈合率分别为(33.69±2.18)%、(73.69±3.23)%，与对照组[(21.44±2.11)%、(56.12±3.65)%]，比较，差异均有统计学意义(t＝5.71、5.08, P＝0.01、0.02)。(2)相较于对照组，Tideglusib组在各时相点创面新生表皮层次更多，同真皮连接更加完善，钉突数量更多，且厚度均厚于对照组；伤后3、7、10 d，Tideglusib组新生表皮厚度分别为(15.86±1.78)、(40.42±4.07)、(60.39±7.68) μm，厚于对照组[(6.07±1.12)、(22.25±3.24)、(36.36±6.46) μm]，2组比较差异均有统计学意义(t＝6.58、4.94、5.36，P＝0.003、0.008、<0.05)。相较于对照组，Tideglusib组在各时相点真皮形态更接近于正常大鼠皮肤，胶原更加粗大，排列更加有序，胶原纤维含量更高；伤后3、7、10 d，Tideglusib组真皮胶原纤维含量分别为(16.33±2.35)%、(37.61±3.88)%、(49.72±1.98)%，高于对照组[(7.53±2.99)%、(16.97±3.55)%、(27.06±3.81)%]，2组比较差异均有统计学意义(t＝3.27、5.55、7.47, P＝0.03、0.01、<0.05)。伤后3 d，对照组和Tideglusib组KIF14均主要表达在创缘的表皮和毛囊处；伤后7、10 d，Tideglusib组可在表皮层观察到大量棕黄色KIF14阳性表达，真皮层内也可见棕黄色颗粒分布，而对照组棕黄色颗粒分布稀疏且仅局限于表皮层；伤后3 d，Tideglusib组KIF14免疫组织化学染色平均吸光度值同对照组比较，差异无统计学意义(t＝0.994, P＝0.344)；伤后7、10 d，Tideglusib组KIF14平均吸光度值高于对照组，差异均有统计学意义(t＝3.440、2.826, P＝0.006、0.018)。(3)伤后3 d，Tideglusib组PKB蛋白相对表达量相较于对照组，差异无统计学意义(P>0.05)，p-PKB、KIF14蛋白相对表达量相较于对照组，差异均有统计学意义(P<0.05)。

结论

小分子药物Tideglusib可加速SD大鼠创面愈合，其机制可能与上调PI3K/PKB/KIF14信号通路有关。

关键词: 大鼠, 创伤和损伤, 伤口愈合, Tideglusib, KIF14, PI3K/PKB信号通路
Objective

To study the effect of the small molecule drug Tideglusib on wound healing in rats and its mechanism.

Methods

Fourty healthy male SD rats of 2 months old were divided into the control group and the Tideglusib group by the random number table method, with 20 rats in each group. Wounds with a diameter of 8 mm were made on their backs. Immediately after the injury, 50 μL phosphate buffer saline (PBS) was dripped onto the wound surface of the control group, and 50 μL 40 μmol/L Tideglusib was dripped onto the wound surface of the Tideglusib group, once a day. (1) Eight rats in each group were randomly selected according to the random number table method, and wound healing process were observed and the wound healing rates were compared at 3, 7, and 10 days after injury. (2) Six rats were selected from the 12 rats in each group without wound observation, the wound edge tissues were taken respectively at 3, 7, and 10 days after injury. Hematoxylin-eosin staining was used to observe the re-epithelialization, new capillaries, and new epidermal thickness during wound healing, and Masson staining was used to observe the arrangement of collagen fibers, immunohistochemical staining was used to detect the expression level and distribution of kinesin family member 14 (KIF14). (3) The wound margin tissues were taken from the remained 6 rats in each group 3 days after injury to detect the changes in the expression levels of protein kinase B (PKB), phospho-PKB (p-PKB), and KIF14 by western blotting. Data was processed with t test.

Results

(1) Compared with the control group, the wound area of the Tideglusib group was significantly reduced at each time point, with fewer wound exudates, less inflammation, better granulation tissue quality, and more neoplastic epidermis extension. At 3 days after injury, the wound healing rate was (12.42±3.48)% in the Tideglusib group and (8.35±1.73)% in the control group , which was not statistically significant (t=1.48, P=0.56). At 7, 10 days after injury, the wound healing rates were (33.69±2.18)% and (73.69±3.23)% in the Tideglusib group, which were (21.44±2.11)% and (56.12±3.65)% in the control group, respectively, the differences were statistically significant (t=5.71, 5.08; P=0.01, 0.02). Compared with the control group, the newborn epidermis of Tideglusib group had more layers, more connection with the dermis, more spikes, and better thickness than the control group at each time point. At 3, 7, 10 days after injury, the thickness of the newborn epidermis were (15.86±1.78), (40.42±4.07), (60.39±7.68) μm in the Tideglusib group, thicker than the control group [(6.07±1.12), (22.25±3.24), (36.36±6.46) μm]respectively, the differences were statistically significant at each time point (t=6.58, 4.94, 5.36; P=0.003, 0.008, <0.05). Meanwhile, compared with the control group, the dermal morphology of the Tideglusib group was closer to normal rat skin whose collagen arrangement was not only thicker and more orderly but also higher in content at each time point. At 3, 7, 10 days after injury, the dermal collagen fiber content were (16.33±2.35)%, (37.61±3.88)%, (49.72±1.98)% in the Tideglusib group, higher than the control group [(7.53±2.99)%, (16.97±3.55)%, (27.06±3.81)%], the differences were statistically significant at each time point (t=3.27, 5.55, 7.47; P=0.03, 0.01, <0.05). At 3 days after injury, KIF14 in the control group and Tideglusib group were mainly expressed in the epidermis and hair follicles at the wound edge. At 7, 10 days after injury, a large number of brown-yellow KIF14 positive expressions were observed in the epidermis as well as the dermis of the Tideglusib group, while the brown-yellow particles in the control group were sparsely distributed and only confined to the epidermal layer. At 3 days after injury, the average absorbance of KIF14 immunohistochemical staining in Tideglusib group was not statistically different from that of control group (t=0.994, P=0.344). At 7, 10 days after injury, the average absorbance of KIF14 in Tideglusib group were (0.452±0.072) and (0.473±0.076), higher than the control group [(0.337±0.039) and (0.367±0.051)], the differences were statistically significant in each time point (t=3.440, 2.826; P=0.006, 0.018). (3)At 3 days after injury, the PKB expression level of Tideglusib group was not statistically different from that of the control group, the difference was not statistically significant (P>0.05), while the expression levels of p-PKB and KIF14 were higher than that of the control group, the differences were statistically significant (P<0.05).

Conclusions

The small molecule drug Tideglusib can accelerate wound healing in rats. The mechanism may be related to the up-regulation of the PI3K/PKB/KIF14 signaling pathway.

Key words: Rats, Wounds and injuries, Wound healing, Tideglusib, KIF14, PI3K/PKB signal pathway
图1 2组大鼠背部圆形全层皮肤缺损创面不同时相点的愈合情况(n＝8)。相较于对照组，伤后3 d时，Tideglusib组创面渗出物更少，炎症反应轻微；伤后7 d，Tideglusib组创面明显缩小，肉芽组织颜色鲜红，创缘可见明显的新生表皮；伤后10 d，Tideglusib组仅有少量创面残留，肉芽组织呈粉红色，创缘可见明显的上皮爬伸
表1 2组大鼠背部圆形全层皮肤缺损创面不同时相点创面愈合率比较(%, ±s)
组别 鼠数 伤后3 d 伤后7 d 伤后10 d
对照组 8 8.35±1.73 21.44±2.11 56.12±3.65
Tideglusib组 8 12.42±3.48 33.69±2.18 73.69±3.23
t值   1.48 5.71 5.08
P值   0.56 0.01 0.02
图2 苏木精-伊红染色观察2组大鼠背部圆形全层皮肤缺损创面愈合质量和再上皮化状况(n＝6)。伤后3 d，对照组肉芽组织形成较差，而Tideglusib组已可见明显的肉芽组织增生。伤后7 d，对照组新生表皮菲薄，真皮组织内胶原纤维排列紊乱，炎症细胞较多；而Tideglusib组新生表皮较厚，肉芽组织形成良好，炎症细胞较少。伤后10 d，对照组新生表皮同真皮的连接较平整，胶原纤维较少，Tideglusib组新生表皮钉突数量多，真皮结构更加趋向正常，可见大量胶原纤维形成
表2 2组大鼠背部圆形全层皮肤缺损创面不同时相点新生表皮厚度比较(μm, ±s)
组别 鼠数 伤后3 d 伤后7 d 伤后10 d
对照组 6 6.07±1.12 22.25±3.24 36.36±6.46
Tideglusib组 6 15.86±1.78 40.42±4.07 60.39±7.68
t值   6.58 4.94 5.36
P值   0.03 0.08 <0.05
图3 Masson染色观察2组大鼠背部圆形全层皮肤缺损创面愈合过程中胶原纤维含量与排列方式(n＝6)。伤后3 d，对照组创面中蓝染胶原束极少，Tideglusib组已可见明显的胶原分布；伤后7 d，对照组创面胶原纤维较少，而Tideglusib组真皮层蓝染胶原束更多，排列更加有序；伤后10 d，对照组胶原沉积程度仍较低，蓝染胶原束较细，Tideglusib组真皮形态更接近于正常大鼠皮肤，可见大量呈波浪状排列的粗大胶原纤维束
表3 2组大鼠背部圆形全层皮肤缺损创面愈合过程中真皮胶原纤维含量的比较(%, ±s)
组别 鼠数 伤后3 d 伤后7 d 伤后10 d
对照组 6 7.53±2.99 16.97±3.55 27.06±3.81
Tideglusib组 6 16.33±2.35 37.61±3.88 49.72±1.98
t值   3.27 5.55 7.47
P值   0.03 0.01 <0.05
图4 免疫组织化学染色观察2组大鼠背部圆形皮肤缺损创面愈合过程中KIF14蛋白空间分布与表达水平(n＝6)。伤后3 d，对照组和Tideglusib组KIF14均主要表达在创缘的表皮和毛囊处，表达水平无明显差异；伤后7 d，对照组KIF14表达较少，KIF14阳性的棕黄色颗粒仅在表皮层内稀疏分布，而Tideglusib组除可在表皮层观察到大量棕黄色阳性表达外，真皮层内也可见棕黄色阳性表达；伤后10 d，对照组KIF14表达局限于表皮层，且表达较弱，Tideglusib组表皮层可观察到明显的棕黄色阳性表达，且真皮层内也可见棕黄色颗粒
表4 2组大鼠背部圆形全层皮肤缺损创面愈合过程中KIF14平均吸光度值的比较(±s)
组别 鼠数 伤后3 d 伤后7 d 伤后10 d
对照组 6 0.318±0.057 0.337±0.039 0.367±0.051
Tideglusib组 6 0.354±0.068 0.452±0.072 0.473±0.076
t值   0.994 3.440 2.826
P值   0.344 0.006 0.018
图5 蛋白质印迹法分析伤后3 d时2组大鼠背部圆形皮肤缺损创面创缘组织中PKB、p-PKB、KIF14蛋白表达水平，Tideglusib可在不影响PKB总蛋白表达水平的同时促进大鼠创缘皮肤中p-PKB、KIF14的表达；PKB为蛋白激酶B；p-PKB为磷酸化蛋白激酶B；KIF14为驱动蛋白家族成员14；GAPDH为磷酸甘油醛脱氢酶
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