银杏达莫注射液对大鼠肝缺血再灌注损伤的保护作用机制研究

doi:10.3877/cma.j.issn.2095-655X.2022.04.009

目的

探讨银杏达莫注射液(Gin)对大鼠肝缺血再灌注损伤的保护作用机制。

方法

选取36只Wistar实验大鼠，按随机数字表法分为正常组(N组)、肝缺血再灌注模型组(M组)和银杏达莫注射液干预组(T组)，每组12只，M组、T组采用夹闭肝固有动脉1 h再灌注1 h的方法模拟大鼠肝缺血再灌注模型。T组造模前1周开始每日按3.6 ml/kg腹腔注射Gin，N、M组造模前1周开始每日注射同量生理盐水。采用苏木精-伊红(HE)染色检测肝组织细胞形态，Masson染色和天狼星红染色检测肝组织胶原纤维；免疫印迹(Western blot)检测肝组织B细胞淋巴瘤/白血病-2(Bcl-2)，Bcl-相关X蛋白(Bax)、Smad和蛋白激酶B(Akt)的蛋白表达水平；聚合酶链式反应(PCR)检测肝组织中Bax、Bcl-2、Smad和Akt mRNA表达水平；免疫组织化学检测肝组织中Bax、Bcl-2、白介素6(IL-6)和IL-10的表达情况，以及检测血清中超氧化物歧化酶(SOD)和丙二醛(MDA)水平。

结果

HE染色显示，M组肝组织细胞损伤严重且炎症细胞多、细胞水肿明显；Masson和天狼星红染色表明，M组胶原纤维沉积较N组明显；3种染色结果均显示，T组肝组织炎性浸润、胶原纤维沉积程度均较M组轻。Western blot结果发现，以β-actin为内参，M组Bax、Bcl-2蛋白相对表达量(0.91±0.28，0.68±0.24)高于N组(0.22±0.19，0.23±0.12)(均P<0.01)，T组Bax蛋白相对表达量(0.48±0.11)低于M组(P<0.01)，Bcl-2蛋白相对表达量(0.89±0.25)高于M组(P<0.01)；以GAPDH为内参，M组Akt、Smad蛋白相对表达量(0.72±0.34，1.03±0.13)高于N组(0.17±0.09，0.57±0.26)(均P<0.01)，T组Akt蛋白相对表达量(1.47±0.89)高于M组(P<0.01)，Smad蛋白相对表达量(0.62±0.42)低于M组(P<0.01)。PCR结果显示，M组Bax、Bcl-2、Akt和Smad mRNA表达水平(0.76±0.03，0.55±0.06，0.96±0.09，1.58±0.16)均高于N组(0.29±0.04，0.36±0.05，0.64±0.06，0.53±0.14)(均P<0.01)，T组Bax和Smad mRNA表达水平(0.36±0.04，1.05±0.26)低于M组(均P<0.01)，Bcl-2和Akt mRNA表达水平(0.85±0.04，1.46±0.19)高于M组(均P<0.01)。免疫组织化学结果显示，M组Bax、Bcl-2、IL-6、IL-10阳性表达面积[(39.52±0.78)%，(4.62±0.94)%，(38.04±3.11)%，(6.48±1.14)%]均高于N组[(0.99±0.13)%，(0.96±0.12)%，(0.46±0.06)%，(0.47±0.17)%](均P<0.01)；T组Bax、IL-6阳性表达面积[(8.18±1.22)%，(6.05±0.92)%]低于M组(均P<0.01)，Bcl-2、IL-10阳性表达面积[(48.13±2.65)%，(31.91±4.86)%]高于M组(均P<0.01)。与N组SOD、MDA水平[(274.81±10.42)U/ml，(2.25±0.51)nmol/ml]相比，M组SOD水平[(113.24±8.52)U/ml]下降，MDA水平[(5.19±0.99)nmol/ml]升高(均P<0.01)。T组SOD水平[(221.51±6.25)U/ml]高于M组(P<0.01)，MDA水平[(3.91±0.86)nmol/ml]低于M组(P<0.01)。

结论

银杏达莫注射液预处理可能通过PI3K/Akt和TGF-β/Smad信号通路介导的抑制细胞凋亡和纤维化发挥对大鼠肝缺血再灌注损伤的保护作用。

关键词: 银杏达莫注射液, 肝缺血再灌注损伤, 肝纤维化, PI3K/Akt, TGF-β/Smad

Objective

To investigate the mechanism of protective effect of ginkgo leaf extract and dipyridamole injection (Gin) on hepatic ischemia reperfusion injury (HIRI) in rats.

Methods

A total of 36 Wistar rats were selected and divided into normal group (N group), hepatic ischemia reperfusion model group (M group) and Gin intervention group (T group) according to the random number table, with 12 rats in each group. Group N was the control group, and group M and T were simulated by clamping the proper hepatic artery for 1 h follawing 1 h reperfusion. The T group was intraperitoneally injected with Gin at 3.6 ml/kg daily 1 week before modeling, and the N and M groups were intraperitoneally injected with the same amount of normal saline 1 week before modeling. Hematoxylin-eosin (HE) staining was used to detect the cell morphology of liver tissue. Masson and Sirius red staining were used to detect the collagen fibers. Western blot was used to detect the protein expression levels of B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-associated X protein (Bax), Smad and protein kinase B (Akt) in liver tissue. The mRNA expression levels of Bax, Bcl-2, Smad and Akt in liver tissues were detected by polymerase chain reaction (PCR). The expressions of Bax and Bcl-2, interleukin-6 (IL-6) and IL-10 in liver tissues were detected by immunohistochemistry, and the levels of superoxide dismutase (SOD) and malondialdehyde (MDA) in serum were detected.

Results

HE staining showed that the liver tissue cells in group M were seriously damaged, with more inflammatory cells and obvious edema. Masson and Sirius red staining showed that the accumulation of collagen fibers in group M was more obvious than that in group N. Moreover, the three staining results showed that the degree of hepatic inflammatory infiltration and collagen fiber in group T was lighter than that in group M. Using β-actin as internal reference, the relative expression levels of Bax and Bcl-2 in group M (0.91±0.28, 0.68±0.24) were higher than those in group N (0.22±0.19, 0.23±0.12) (all P<0.01). The relative expression level of Bax protein in T group (0.48±0.11) was lower than that in group M (P<0.01), and the relative expression level of Bcl-2 protein in group T (0.89±0.25) was higher than that in group M (P<0.01). Using GAPDH as internal reference, the relative expression levels of Akt and Smad protein in group M (0.72±0.34, 1.03±0.13) were higher than those in group N (0.17±0.09, 0.57±0.26) (all P<0.01). The relative expression level of Akt in group T (1.47±0.89) was higher than that in group M (P<0.01), and the relative expression level of Smad in group T (0.62±0.42) was lower than that in group M (P<0.01). PCR results showed that the mRNA expression levels of Bax, Bcl-2, Akt and Smad in group M (0.76±0.03, 0.55±0.06, 0.96±0.09, 1.58±0.16) were higher than those in group N (0.29±0.04, 0.36±0.05, 0.64±0.06, 0.53±0.14) (all P<0.01). The mRNA expression levels of Bax and Smad in group T (0.36±0.04, 1.05±0.26) were lower than those in group M (all P<0.01). The mRNA expression levels of Bcl-2 and Akt in group T (0.85±0.04, 1.46±0.19) were lower than those in group M (all P<0.01). Immunohistochemical results showed that the positive expression area of Bax, Bcl-2, IL-6 and IL-10 in group M [(39.52±0.78)%, (4.62±0.94)%, (38.04±3.11)%, (6.48±1.14)%] was higher than that in group N [(0.99±0.13)%, (0.96±0.12)%, (0.46±0.06)%, (0.47±0.17)%] (all P<0.01). The positive expression area of Bax and IL-6 in T group [(8.18±1.22)%, (6.05±0.92)%] was lower than that in group M (all P<0.01), and the positive expression area of Bcl-2 and IL-10 [(48.13±2.65)%, (31.91±4.86)%] was higher than that in group M (all P<0.01). SOD and MDA levels were (274.81±10.42)U/ml and (2.25±0.51)nmol/ml in the N group, respectively. In comparison, the SOD level in group M [(113.24±8.52)U/ml] was decreased, the MDA level in group M [(5.19±0.99)nmol/ml] was increased (all P<0.01). The SOD level in group T [(221.51±6.25)U/ml] was higher than that in group M (P<0.01), and the MDA level in group T [(3.91±0.86)nmol/ml] was lower than that in group M (P<0.01).

Conclusion

Gin may play a protective role against HIRI in rats through inhibition of apoptosis and fibrosis mediated by PI3K/Akt and TGF-β/Smad signaling pathways.

Key words: Ginkgo leaf extract and dipyridamole injection, Hepatic ischemia reperfusion injury, Hepatic fibrosis, PI3K/Akt, TGF-β/Smad

表1 各基因引物序列

基因	引物序列
Bcl-2	5′-GGTGAACTGGGGGAGGATTG-3′
	5′-AGAGCGATGTTGTCCACCAG-3′
Bax	5′-AGACACCTGAGCTGACCTTG-3′
	5′-AAGTTGCCATCAGCAAACAT-3′
β-actin	5′-CCTCACTGTCCACCTTCCA-3′
	5′-GGGTGTAAAACGCAGCTCA-3′
Akt	5′-AGTCCCCACTCAACAACTTCT-3′
	5′-AAGTAGGGAGGCATCTCG-3′
Smad	5′-CCATCTCCTACTACGAGCTGAA-3′
	5′-CACTGCTGCATTCCTGTTGAC-3′
GAPDH	5′-CAACGGGAAACCCATCACCA-3′
	5′-ACGCCAGTAGACTCCACGACAT-3′

表1 各基因引物序列

基因	引物序列
Bcl-2	5′-GGTGAACTGGGGGAGGATTG-3′
	5′-AGAGCGATGTTGTCCACCAG-3′
Bax	5′-AGACACCTGAGCTGACCTTG-3′
	5′-AAGTTGCCATCAGCAAACAT-3′
β-actin	5′-CCTCACTGTCCACCTTCCA-3′
	5′-GGGTGTAAAACGCAGCTCA-3′
Akt	5′-AGTCCCCACTCAACAACTTCT-3′
	5′-AAGTAGGGAGGCATCTCG-3′
Smad	5′-CCATCTCCTACTACGAGCTGAA-3′
	5′-CACTGCTGCATTCCTGTTGAC-3′
GAPDH	5′-CAACGGGAAACCCATCACCA-3′
	5′-ACGCCAGTAGACTCCACGACAT-3′

图1 3组大鼠肝组织病理形态学及胶原纤维检测图像注：a图为正常组，细胞形态正常；b图为肝缺血再灌注模型组，出现大量炎性细胞，以及细胞水肿；c图为银杏达莫注射液干预组，炎性细胞减少(HE ×100)；d、g图为正常组，无胶原纤维沉积；e、h图为肝缺血再灌注模型组，大量胶原纤维沉积；f、i图为银杏达莫注射液干预组，胶原纤维沉积减少(Masson ×100，天狼星红×100)(箭头所示)

表2 3组大鼠肝组织中胶原容积比较(±s)

组别	例数	Masson染色	天狼星红染色
N组	12	2.85±0.74	3.26±1.24
M组	12	27.11±1.62^a	32.79±5.13^a
T组	12	9.06±0.69^b	16.58±4.06^b
F值		1 424.05	162.75
P值		<0.01	<0.01

表2 3组大鼠肝组织中胶原容积比较(±s)

组别	例数	Masson染色	天狼星红染色
N组	12	2.85±0.74	3.26±1.24
M组	12	27.11±1.62^a	32.79±5.13^a
T组	12	9.06±0.69^b	16.58±4.06^b
F值		1 424.05	162.75
P值		<0.01	<0.01

表3 3组肝脏中Bax、Bcl-2、Akt、Smad蛋白表达水平比较(±s)

组别	例数	Bax	Bcl-2	Akt	Smad
N组	12	0.22±0.19	0.23±0.12	0.17±0.09	0.57±0.26
M组	12	0.91±0.28^a	0.68±0.24^a	0.72±0.34^a	1.03±0.13^a
T组	12	0.48±0.11^b	0.89±0.25^b	1.47±0.89^b	0.62±0.42^b
F值		636.84	562.75	329.04	293.31
P值		<0.01	<0.01	<0.01	<0.01

表3 3组肝脏中Bax、Bcl-2、Akt、Smad蛋白表达水平比较(±s)

组别	例数	Bax	Bcl-2	Akt	Smad
N组	12	0.22±0.19	0.23±0.12	0.17±0.09	0.57±0.26
M组	12	0.91±0.28^a	0.68±0.24^a	0.72±0.34^a	1.03±0.13^a
T组	12	0.48±0.11^b	0.89±0.25^b	1.47±0.89^b	0.62±0.42^b
F值		636.84	562.75	329.04	293.31
P值		<0.01	<0.01	<0.01	<0.01

图2 3组肝组织中Bax、Bcl-2、Smad、Akt的蛋白表达免疫印迹图像注：a图为Bax、Bcl-2蛋白条带；b图为Akt、Smad蛋白条带；Bcl-2为B细胞淋巴瘤/白血病-2；Bax为Bcl-2相关X蛋白；β-actin为肌动蛋白；Akt为蛋白激酶B；GAPDH为甘油醛-3-磷酸脱氢酶

表4 3组肝组织中Bax、Bcl-2、Akt、Smad mRNA表达水平比较(±s)

组别	例数	Bax	Bcl-2	Akt	Smad
N组	12	0.29±0.04	0.36±0.05	0.64±0.06	0.53±0.14
M组	12	0.76±0.03^a	0.55±0.06^a	0.96±0.09^a	1.58±0.16^a
T组	12	0.36±0.04^b	0.85±0.04^b	1.46±0.19^b	1.05±0.26^b
F值		415.71	234.57	113.16	74.57
P值		<0.01	<0.01	<0.01	<0.01

表4 3组肝组织中Bax、Bcl-2、Akt、Smad mRNA表达水平比较(±s)

组别	例数	Bax	Bcl-2	Akt	Smad
N组	12	0.29±0.04	0.36±0.05	0.64±0.06	0.53±0.14
M组	12	0.76±0.03^a	0.55±0.06^a	0.96±0.09^a	1.58±0.16^a
T组	12	0.36±0.04^b	0.85±0.04^b	1.46±0.19^b	1.05±0.26^b
F值		415.71	234.57	113.16	74.57
P值		<0.01	<0.01	<0.01	<0.01

表5 3组大鼠肝脏中Bax、Bcl-2、IL-6、IL-10阳性表达面积比较(±s，%)

组别	例数	Bax	Bcl-2	IL-6	IL-10
N组	12	0.99±0.13	0.96±0.12	0.46±0.06	0.47±0.17
M组	12	39.52±0.78^a	4.62±0.94^a	38.04±3.11^a	6.48±1.14^a
T组	12	8.18±1.22^b	48.13±2.65^b	6.05±0.92^b	31.91±4.86^b
F值		14 083.75	9 119.03	44 940.03	4 986.52
P值		<0.01	<0.01	<0.01	<0.01

表5 3组大鼠肝脏中Bax、Bcl-2、IL-6、IL-10阳性表达面积比较(±s，%)

组别	例数	Bax	Bcl-2	IL-6	IL-10
N组	12	0.99±0.13	0.96±0.12	0.46±0.06	0.47±0.17
M组	12	39.52±0.78^a	4.62±0.94^a	38.04±3.11^a	6.48±1.14^a
T组	12	8.18±1.22^b	48.13±2.65^b	6.05±0.92^b	31.91±4.86^b
F值		14 083.75	9 119.03	44 940.03	4 986.52
P值		<0.01	<0.01	<0.01	<0.01

图3 3组大鼠肝脏组织中Bax、Bcl-2、IL-6、IL-10蛋白表达的免疫组化染色图像注：a~c图，d~f图，g~i图，j~l图分别为正常组、模型组、干预组大鼠肝脏中Bax、Bcl-2、IL-6、IL-10的表达图像；Bcl-2为B细胞淋巴瘤/白血病-2；Bax为Bcl-2相关X蛋白；IL-6为白介素6；IL-10为白介素10

表6 3组大鼠血清中SOD、MDA水平比较(±s)

组别	例数	SOD(U/ml)	MDA(nmol/ml)
N组	12	274.81±10.42	2.25±0.51
M组	12	113.24±8.52^a	5.19±0.99^a
T组	12	221.51±6.25^b	3.91±0.86^b
F值		461.32	74.57
P值		<0.01	<0.01

表6 3组大鼠血清中SOD、MDA水平比较(±s)

组别	例数	SOD(U/ml)	MDA(nmol/ml)
N组	12	274.81±10.42	2.25±0.51
M组	12	113.24±8.52^a	5.19±0.99^a
T组	12	221.51±6.25^b	3.91±0.86^b
F值		461.32	74.57
P值		<0.01	<0.01

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Protective mechanism of ginkgo leaf extract and dipyridamole injection on hepatic ischemia reperfusion injury in rats

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Protective mechanism of ginkgo leaf extract and dipyridamole injection on hepatic ischemia reperfusion injury in rats