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Article(id=1207433495677346025, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207433493215289544, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2022.08.0764, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1636992000000, receivedDateStr=2021-11-16, revisedDate=null, revisedDateStr=null, acceptedDate=1644422400000, acceptedDateStr=2022-02-10, onlineDate=1765804178399, onlineDateStr=2025-12-15, pubDate=1661616000000, pubDateStr=2022-08-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1765804178399, onlineIssueDateStr=2025-12-15, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1765804178399, creator=13701087609, updateTime=1765804178399, updator=13701087609, issue=Issue{id=1207433493215289544, tenantId=1146029695717560320, journalId=1189873630562394117, year='2022', volume='47', issue='8', pageStart='745', pageEnd='850', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1765804177811, creator=13701087609, updateTime=1765804292764, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1207433975413444883, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207433493215289544, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1207433975413444884, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1207433493215289544, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=764, endPage=770, ext={EN=ArticleExt(id=1207433496029667573, articleId=1207433495677346025, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=The mechanism of artificial ulcer fibrosis of stenosis after full circumcision of esophageal mucosal dissection based on TGF-β1/Smads/ACTA2 signaling pathway: A porcine model, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the mechanism of artificial ulcer fibrosis of stenosis after full circumcision of esophageal mucosal dissection in porcine model based on TGF-β1/Smads/ACTA2 signaling pathway. Methods A total of eight pigs were randomized into two groups (4 in each group): sham operation group and model group. Animals in the model group received full circumcision of ESD to establish the esophageal artificial ulcer fibrosis model. Three weeks after the surgery, we collected esophageal tissues from animals. We further analyzed the tissues with Hematoxylin-eosin (HE) staining to observe the pathological characteristics of esophageal tissues. The real-time quantitative polymerase chain reaction (qRT-PCR) was employed to detect the mRNA relative expression levels of TGF-β1, Smad2, Smad3, and ACTA2. We then examined the positive expression of CTGF and ACTA2 using immunohistochemistry. Lastly, we detected the protein relative expression levels of TGF-β1, Smad2/3,p-Smad2/3, Smad4, Smad7, CTGF, and ACTA2 using Western blotting. Results Compared with the sham operation group, the fibroblasts in the artificial ulcer site proliferated rapidly with a more transformed myofibroblast phenotype in the model group. In the model group, the qRT-PCR results showed up-regulated mRNA levels of TGF-β1 (P<0.001), Smad3 (P=0.004), and ACTA2(P=0.001). The results of immunohistochemistry showed that the positive expression of CTGF (P<0.001) and ACTA2 (P<0.001)in the model group were higher than those in the sham operation group. We also observed up-regulated levels of TGF-β1 (P=0.002),Smad2/3 (P=0.003), p-Smad2/3 (P=0.002), Smad4 (P<0.001), Smad7 (P=0.016), CTGF (P<0.001), and ACTA2 in the model group, compared with the sham operation group. Conclusion A porcine model of stenosis after full circumcision of esophageal mucosal dissection was successfully established, and the mechanism may be related to the artificial ulcer fibrosis by TGF-β1/Smads/ACTA2 signaling pathway.

, correspAuthors=Jie Chen, Zhi Li, authorNote=null, correspAuthorsNote=
* Li Zhi, E-mail: ;
Chen Jie, E-mail:
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目的 基于转化生长因子β1(TGF-β1)/Smads/α-肌动蛋白-2(ACTA2)信号通路探讨猪食管内镜黏膜下剥离术(ESD)环切术后人工溃疡纤维化的机制。方法 将8头实验白猪分为假手术组(n=4)与模型组(n=4)，模型组通过ESD环切术建立猪食管狭窄模型。术后第3周分别采集两组猪食管组织，采用HE染色观察食管组织的病理特征，采用实时荧光定量PCR检测TGF-β1、Smad2、Smad3、ACTA2 mRNA的相对表达水平，采用免疫组化法检测结缔组织生长因子(CTGF)、ACTA2的阳性表达情况，采用Western blotting检测TGF-β1、Smad2/3、p-Smad2/3、Smad4、Smad7、CTGF、ACTA2蛋白的相对表达水平。结果 与假手术组比较，模型组人工溃疡部位成纤维细胞(FB)大量增殖，并向肌成纤维细胞(MFB)表型转化。实时荧光定量PCR显示，与假手术组比较，模型组TGF-β1 (P<0.001)、Smad3 (P=0.004)、ACTA2 (P=0.001) mRNA表达均明显上调。免疫组化结果显示，与假手术组比较，模型组CTGF(P<0.001)、ACTA2(P<0.001)的表达明显升高。Western blotting结果显示，与假手术组比较，模型组TGF-β1(P=0.002)、Smad2/3(P=0.003)、p-Smad2/3(P=0.002)、Smad4(P<0.001)、Smad7(P=0.016)、CTGF(P<0.001)、ACTA2(P<0.001)蛋白表达均明显上调，差异有统计学意义。结论 成功建立ESD环切术后猪食管狭窄模型，该模型人工溃疡纤维化的形成可能与TGF-β1/Smads/ACTA2信号通路相关。

, correspAuthors=陈洁, 李志, authorNote=null, correspAuthorsNote=
李志，E-mail：;
陈洁，E-mail：
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周鑫，硕士研究生，主要从事中西医结合防治消化系统疾病的临床及基础研究

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周鑫，硕士研究生，主要从事中西医结合防治消化系统疾病的临床及基础研究

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周鑫，硕士研究生，主要从事中西医结合防治消化系统疾病的临床及基础研究

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Cell Tissue Res, 2012, 347(1): 103-116., articleTitle=The role of EMT in renal fibrosis, refAbstract=null)], funds=[Fund(id=1207433506662228629, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, awardId=2020YFS0376, language=EN, fundingSource=Plan Project of Science and Technology Department of Sichuan Province(2020YFS0376), fundOrder=null, country=null), Fund(id=1207433506750309018, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, awardId=2020YFS0376, language=CN, fundingSource=四川省科技厅计划项目(2020YFS0376), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1207433498621747544, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, xref=1, ext=[AuthorCompanyExt(id=1207433498630136152, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, companyId=1207433498621747544, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1School of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China), AuthorCompanyExt(id=1207433498638524761, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, companyId=1207433498621747544, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1西南医科大学中西医结合学院，四川泸州 646000)]), AuthorCompany(id=1207433498722410845, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, xref=2, ext=[AuthorCompanyExt(id=1207433498726605151, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, companyId=1207433498722410845, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Department of Spleen and Stomach Diseases, Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, Sichuan 646000, China), AuthorCompanyExt(id=1207433498755965279, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, companyId=1207433498722410845, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2西南医科大学附属中医医院脾胃病科，四川泸州 646000)]), AuthorCompany(id=1207433498844045671, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, xref=3, ext=[AuthorCompanyExt(id=1207433498852434280, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, companyId=1207433498844045671, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3Department of Gastroenterology, the First Affiliated Hospital of Naval Medical University, Shanghai 200082, China), AuthorCompanyExt(id=1207433498860822889, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, companyId=1207433498844045671, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3海军军医大学第一附属医院消化内科，上海 200082)])], figs=[ArticleFig(id=1207433504007234141, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=EN, label=Fig. 1, caption=Endoscopic esophageal morphology of each group of tested pigs at 3rd week after endoscopic mucosal dissection, figureFileSmall=Fw2qrELNiPs3XovOzC4wrw==, figureFileBig=kZ1FvJsU6lqMZQWoBAEsmQ==, tableContent=null), ArticleFig(id=1207433504082731619, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=CN, label=图1, caption=两组实验白猪造模后第3周内镜下食管形态

A. 假手术组(食管未见明显狭窄)；B. 模型组(可见人工溃疡部位食管明显狭窄，内镜不能通过)

, figureFileSmall=Fw2qrELNiPs3XovOzC4wrw==, figureFileBig=kZ1FvJsU6lqMZQWoBAEsmQ==, tableContent=null), ArticleFig(id=1207433504296641132, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=EN, label=Fig. 2, caption=Morphology of esophageal tissues in each group of tested pigs, figureFileSmall=stBEDFrq9kOY36alMqYUpg==, figureFileBig=Lj0R8X21qZl9uGOJW7lFqw==, tableContent=null), ArticleFig(id=1207433504405693039, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=CN, label=图2, caption=两组实验白猪食管组织形态

FB. 成纤维细胞；MFB. 肌成纤维细胞；A. 食管黏膜下层形态(HE染色)；B.食管黏膜下层FB/MFB半定量分析；(1)P<0.001

, figureFileSmall=stBEDFrq9kOY36alMqYUpg==, figureFileBig=Lj0R8X21qZl9uGOJW7lFqw==, tableContent=null), ArticleFig(id=1207433504481190513, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=EN, label=Fig. 3, caption=Relative expression levels of TGF-β1, Smad2, Smad3,and ACTA2 mRNA in each group of esophageal tissues of tested pigs (qRT-PCR), figureFileSmall=DYxHN/qVUmCX7ZO4VClOzg==, figureFileBig=RMUfWWDlXumc7pQLqnp6sw==, tableContent=null), ArticleFig(id=1207433504577659507, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=CN, label=图3, caption=qRT-PCR检测两组食管组织中TGF-β1、Smad2、Smad3、ACTA2 mRNA的表达

TGF-β1. 转化生长因子β1；Smad2. 共介导Smad蛋白2；Smad3. 共介导Smad蛋白3；ACTA2. α-肌动蛋白-2；(1)P<0.05

, figureFileSmall=DYxHN/qVUmCX7ZO4VClOzg==, figureFileBig=RMUfWWDlXumc7pQLqnp6sw==, tableContent=null), ArticleFig(id=1207433504669934197, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=EN, label=Fig. 4, caption=The positive expression of CTGF and ACTA2 protein in esophageal tissue of tested pigs (Immunohistochemistry), figureFileSmall=D06s2iM71ATVYRg7k+fg3A==, figureFileBig=ur0GJMnB3RZGXm4WOAwkzQ==, tableContent=null), ArticleFig(id=1207433504778986104, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=CN, label=图4, caption=CTGF、ACTA2蛋白在实验白猪食管组织中的表达(免疫组化)

CTGF. 结缔组织生长因子；ACTA2. α-肌动蛋白-2

, figureFileSmall=D06s2iM71ATVYRg7k+fg3A==, figureFileBig=ur0GJMnB3RZGXm4WOAwkzQ==, tableContent=null), ArticleFig(id=1207433504867066490, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=EN, label=Fig. 5, caption=Expression of TGF-β1/Smads/ACTA2 related proteins in esophageal tissues of each group of tested pigs (Western blotting), figureFileSmall=4No4EhQ6X+QOdS+nq7mmaA==, figureFileBig=+3LDeQu75DxSedEUZmAhew==, tableContent=null), ArticleFig(id=1207433504971924097, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=CN, label=图5, caption=实验白猪食管组织TGF-β1/Smads/ACTA2信号通路相关蛋白的表达(Western blotting)

TGF-β1. 转化生长因子β1；Smad2/3. 受体调节型Smad蛋白2/3；p-Smad2/3. 磷酸化受体调节型Smad蛋白2/3；Smad4. 共介导型Smad蛋白4；Smad7. 抑制型Smad蛋白7；CTGF. 结缔组织生长因子；ACTA2. α-肌动蛋白-2；(1)P<0.05

, figureFileSmall=4No4EhQ6X+QOdS+nq7mmaA==, figureFileBig=+3LDeQu75DxSedEUZmAhew==, tableContent=null), ArticleFig(id=1207433506184077951, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=EN, label=Tab. 1, caption=

Primer sequences of qRT-PCR

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
TGF-β1正义：CCCACCAAGAACCTGCTTTCGG
反义：TCTGACCCACACTGCCTTCCTG
Smad2正义：ATGTCGTCCATCTTGCCATTCACTC
反义：TGCTTTCTCACACCACTTCTCTTCC
Smad3正义：TGTCGTCCATCCTGCCCTTCAC
反义：ACTTCTCCTCCTGCCCGTTCTG
ACTA2正义：TAGAACACGGCATCATCACCAACTG
反义：TGGGGCAACACGAAGCTCATTG
), ArticleFig(id=1207433506309907076, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=CN, label=表1, caption=

qRT-PCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
TGF-β1正义：CCCACCAAGAACCTGCTTTCGG
反义：TCTGACCCACACTGCCTTCCTG
Smad2正义：ATGTCGTCCATCTTGCCATTCACTC
反义：TGCTTTCTCACACCACTTCTCTTCC
Smad3正义：TGTCGTCCATCCTGCCCTTCAC
反义：ACTTCTCCTCCTGCCCGTTCTG
ACTA2正义：TAGAACACGGCATCATCACCAACTG
反义：TGGGGCAACACGAAGCTCATTG
), ArticleFig(id=1207433506410570377, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=EN, label=Tab. 2, caption=

Semi-quantitative analysis of positive expression of CTGF and ACTA2 protein in esophageal tissues of each group of tested pigs (average optical density value, $\bar{x}±s$, n=4)

, figureFileSmall=null, figureFileBig=null, tableContent=
组别CTGFACTA2
假手术组0.017±0.0030.021±0.002
模型组0.082±0.0040.047±0.003
t12.8237.642
P<0.001<0.001
), ArticleFig(id=1207433506511233678, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1207433495677346025, language=CN, label=表2, caption=

实验白猪食管组织CTGF、ACTA2蛋白阳性表达半定量分析(平均光密度值，$\bar{x}±s$，n=4)

, figureFileSmall=null, figureFileBig=null, tableContent=
组别CTGFACTA2
假手术组0.017±0.0030.021±0.002
模型组0.082±0.0040.047±0.003
t12.8237.642
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基于TGF-β1/Smads/ACTA2信号通路探讨猪食管ESD环切术后狭窄模型人工溃疡纤维化的机制
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周鑫 1, 2 , 马丹 3 , 付娟 2 , 王云锋 3 , 苏胜昌 3 , 唐祖鑫 1, 2 , 李晓渝 1, 2 , 陈洁 2, 3, * , 李志 2, *
解放军医学杂志 | 基础研究 2022,47(8): 764-770
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解放军医学杂志 | 基础研究 2022, 47(8): 764-770
基于TGF-β1/Smads/ACTA2信号通路探讨猪食管ESD环切术后狭窄模型人工溃疡纤维化的机制
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周鑫1, 2, 马丹3, 付娟2, 王云锋3, 苏胜昌3, 唐祖鑫1, 2, 李晓渝1, 2, 陈洁2, 3, * , 李志2, *
作者信息
  • 1西南医科大学中西医结合学院，四川泸州 646000
  • 2西南医科大学附属中医医院脾胃病科，四川泸州 646000
  • 3海军军医大学第一附属医院消化内科，上海 200082

    • 周鑫，硕士研究生，主要从事中西医结合防治消化系统疾病的临床及基础研究

通讯作者:

李志，E-mail：;
陈洁，E-mail：
The mechanism of artificial ulcer fibrosis of stenosis after full circumcision of esophageal mucosal dissection based on TGF-β1/Smads/ACTA2 signaling pathway: A porcine model
Xin Zhou1, 2, Dan Ma3, Juan Fu2, Yun-Feng Wang3, Sheng-Chang Su3, Zu-Xin Tang1, 2, Xiao-Yu Li1, 2, Jie Chen2, 3, * , Zhi Li2, *
Affiliations
  • 1School of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China
  • 2Department of Spleen and Stomach Diseases, Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, Sichuan 646000, China
  • 3Department of Gastroenterology, the First Affiliated Hospital of Naval Medical University, Shanghai 200082, China
出版时间: 2022-08-28 doi: 10.11855/j.issn.0577-7402.2022.08.0764
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摘要
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目的 基于转化生长因子β1(TGF-β1)/Smads/α-肌动蛋白-2(ACTA2)信号通路探讨猪食管内镜黏膜下剥离术(ESD)环切术后人工溃疡纤维化的机制。方法 将8头实验白猪分为假手术组(n=4)与模型组(n=4)，模型组通过ESD环切术建立猪食管狭窄模型。术后第3周分别采集两组猪食管组织，采用HE染色观察食管组织的病理特征，采用实时荧光定量PCR检测TGF-β1、Smad2、Smad3、ACTA2 mRNA的相对表达水平，采用免疫组化法检测结缔组织生长因子(CTGF)、ACTA2的阳性表达情况，采用Western blotting检测TGF-β1、Smad2/3、p-Smad2/3、Smad4、Smad7、CTGF、ACTA2蛋白的相对表达水平。结果 与假手术组比较，模型组人工溃疡部位成纤维细胞(FB)大量增殖，并向肌成纤维细胞(MFB)表型转化。实时荧光定量PCR显示，与假手术组比较，模型组TGF-β1 (P<0.001)、Smad3 (P=0.004)、ACTA2 (P=0.001) mRNA表达均明显上调。免疫组化结果显示，与假手术组比较，模型组CTGF(P<0.001)、ACTA2(P<0.001)的表达明显升高。Western blotting结果显示，与假手术组比较，模型组TGF-β1(P=0.002)、Smad2/3(P=0.003)、p-Smad2/3(P=0.002)、Smad4(P<0.001)、Smad7(P=0.016)、CTGF(P<0.001)、ACTA2(P<0.001)蛋白表达均明显上调，差异有统计学意义。结论 成功建立ESD环切术后猪食管狭窄模型，该模型人工溃疡纤维化的形成可能与TGF-β1/Smads/ACTA2信号通路相关。

内镜黏膜下剥离术  /  食管狭窄  /  纤维化  /  转化生长因子β1  /  肌成纤维细胞

Objective To investigate the mechanism of artificial ulcer fibrosis of stenosis after full circumcision of esophageal mucosal dissection in porcine model based on TGF-β1/Smads/ACTA2 signaling pathway. Methods A total of eight pigs were randomized into two groups (4 in each group): sham operation group and model group. Animals in the model group received full circumcision of ESD to establish the esophageal artificial ulcer fibrosis model. Three weeks after the surgery, we collected esophageal tissues from animals. We further analyzed the tissues with Hematoxylin-eosin (HE) staining to observe the pathological characteristics of esophageal tissues. The real-time quantitative polymerase chain reaction (qRT-PCR) was employed to detect the mRNA relative expression levels of TGF-β1, Smad2, Smad3, and ACTA2. We then examined the positive expression of CTGF and ACTA2 using immunohistochemistry. Lastly, we detected the protein relative expression levels of TGF-β1, Smad2/3,p-Smad2/3, Smad4, Smad7, CTGF, and ACTA2 using Western blotting. Results Compared with the sham operation group, the fibroblasts in the artificial ulcer site proliferated rapidly with a more transformed myofibroblast phenotype in the model group. In the model group, the qRT-PCR results showed up-regulated mRNA levels of TGF-β1 (P<0.001), Smad3 (P=0.004), and ACTA2(P=0.001). The results of immunohistochemistry showed that the positive expression of CTGF (P<0.001) and ACTA2 (P<0.001)in the model group were higher than those in the sham operation group. We also observed up-regulated levels of TGF-β1 (P=0.002),Smad2/3 (P=0.003), p-Smad2/3 (P=0.002), Smad4 (P<0.001), Smad7 (P=0.016), CTGF (P<0.001), and ACTA2 in the model group, compared with the sham operation group. Conclusion A porcine model of stenosis after full circumcision of esophageal mucosal dissection was successfully established, and the mechanism may be related to the artificial ulcer fibrosis by TGF-β1/Smads/ACTA2 signaling pathway.

endoscopic submucosal dissection  /  esophageal stenosis  /  fibrosis  /  transcription growth factor β1  /  myofibroblasts
周鑫, 马丹, 付娟, 王云锋, 苏胜昌, 唐祖鑫, 李晓渝, 陈洁, 李志. 基于TGF-β1/Smads/ACTA2信号通路探讨猪食管ESD环切术后狭窄模型人工溃疡纤维化的机制. 解放军医学杂志, 2022 , 47 (8) : 764 -770 . DOI: 10.11855/j.issn.0577-7402.2022.08.0764
Xin Zhou, Dan Ma, Juan Fu, Yun-Feng Wang, Sheng-Chang Su, Zu-Xin Tang, Xiao-Yu Li, Jie Chen, Zhi Li. The mechanism of artificial ulcer fibrosis of stenosis after full circumcision of esophageal mucosal dissection based on TGF-β1/Smads/ACTA2 signaling pathway: A porcine model[J]. Medical Journal of Chinese People’s Liberation Army, 2022 , 47 (8) : 764 -770 . DOI: 10.11855/j.issn.0577-7402.2022.08.0764
正文
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内镜黏膜下剥离术(endoscopic submucosal dissection，ESD)是治疗累及黏膜、黏膜下层的早期食管癌及癌前病变的主要措施之一，能有效地整块切除直径>2 cm的病灶[1]。人工溃疡部位狭窄是ESD术后最严重的并发症之一，当病变范围累及食管全周时，食管狭窄的发生率接近100%[2]，严重影响术后生活质量。有研究发现，食管ESD环切术后狭窄部位肌成纤维细胞(myofibroblasts，MFB)标志蛋白——α肌动蛋白2(actin alpha 2，ACTA2)的表达明显上调，提示食管ESD环切术后狭窄可能与人工溃疡过度纤维化有关[3]。人体食管组织可取材部位有限，诱导食管过度纤维化的上游机制尚不明确，本研究建立猪食管ESD环切术后狭窄模型，以探讨人工溃疡过度纤维化的可能机制。
1 材料与方法
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1.1 实验动物
8头普通级健康雄性实验白猪，体重(15.5±0.9) kg，购自上海市甲干生物科技有限公司[动物许可证号：SCXK(沪)2015-0005]。
1.2 试剂
注射用盐酸替来他明盐酸唑拉西泮(舒泰®50，批号：6477)购自维克中国公司，硫酸阿托品注射液(批号：040191511)购自山西省芮城科龙兽药有限公司，PrimeScriptTM RT反应混合物(批号：RR036Q)、TB Green®Premix EX TapTMⅡ(批号：RR820A)购自日本TAKARA公司，BCA蛋白定量试剂盒(批号：ZJ102)购自上海雅酶生物医药科技有限公司，转化生长因子β1(transforming growth factor β1，TGF-β1)抗体(批号：NBP1-80289)购自美国NOVUS公司，共介导Smad蛋白2/共介导Smad蛋白3(Smad2/3)抗体(批号：#8685)购自美国CST公司，p-Smad2/3抗体(批号：D160746)购自美国Affinity公司，Smad4抗体(批号：D220124)、Smad7抗体(批号：D160746)购自上海生工生物工程股份有限公司，结缔组织生长因子(connective tissue growth factor，CTGF)抗体(批号：23936-1-AP)、ACTA2抗体(批号：80008-1-RR)购自美国Proteintech公司，山羊抗兔IgG(批号：L3012)购自美国SAB公司。
1.3 仪器
TP1020石蜡组织包埋机、RM2235石蜡切片机购自德国LEICA公司；SpectraMax SM0260全自动酶标仪购自美国Molecular Devices公司；AXIO Scope A1光学显微镜购自德国ZEISS公司；Wonbio-48R高通量组织研磨仪购自上海Onebio Biotech公司，LightCycler 480实时荧光定量PCR仪购自瑞士Roche公司。
1.4 方法
1.4.1 实验分组与动物模型制备
将实验白猪适应性饲养1周后，随机均分为假手术组与模型组(n=4)。所有动物术前禁食24 h，禁水6 h。麻醉诱导前15 min肌内注射硫酸阿托品(0.05 mg/kg)抑制腺体分泌，随后肌内注射舒泰®50(10 mg/kg)诱导麻醉。麻醉后模型组给予气管插管，术中吸入1%~2%异氟烷维持麻醉深度，假手术组给予面罩吸氧。所有内镜操作过程中均使用心电图监测器观察白猪的生命体征。
实验白猪取左侧卧位，由经验丰富的消化内镜副主任医师用带有透明帽(ND-201-1802，Olympus公司)的上消化道内镜(GIF-Q260J，Olympus公司)进行操作，均已排除可能干扰本研究结果的食管病变。模型组采用“隧道法”，通过黏膜下注射分离黏膜层与固有肌层，在距离贲门10~14 cm处使用Dual刀(KD-650L，Olympus公司)进行人工溃疡颅侧及尾侧的圆周标记，先沿尾侧标记切开黏膜，再沿颅侧标记建立黏膜下隧道，然后逐渐与尾侧切口连接，联合使用Dual刀及IT-2刀(KD-611L，Olympus公司)完成黏膜下剥离。假手术组仅用带有透明帽的上消化道内镜轻触贲门上10~14 cm处的食管黏膜数次。实验过程符合国家和单位有关实验动物的管理和使用规定。
内镜操作结束后，将动物转移至安静温暖处，采用血氧饱和度监测仪观察生命体征直至麻醉苏醒。两组术后均禁食24 h，先给予流质饮食，再逐渐过渡至固体饮食，当模型组出现进食困难时，两组均切换为流质饮食。模型组造模后连续3 d肌内注射氨苄西林20 mg/(kg·d)抗炎，连续7 d喂服奥美拉唑10 mg/d抑酸。
1.4.2 标本采集
造模后间隔7 d行1次食管内镜检查，第3周模型组动物食管人工溃疡部位已明显狭窄且内镜不能通过，提示造模成功(图1)。处死动物后分别沿颅侧、尾侧横轴采集模型组食管人工溃疡部位组织，假手术组采集与模型组对应长度的食管组织。取部分组织全层于4%多聚甲醛中固定24 h，乙醇梯度脱水，石蜡包埋。剩余组织剔除固有肌层及外膜后，于–80 ℃保存。
1.4.3 HE染色
组织蜡块经切片、脱水、复水后，苏木精染色5 min，水洗，再于1%盐酸乙醇中分色5 s，自来水冲洗15 min，甩干，75%乙醇处理10 s后，直接置于1%醇溶性伊红染色1 min，水洗，无水乙醇脱水2 min，晾干，再以二甲苯透明10 min后，于通风处晾干，中性快干片封片。采用Image J图像处理软件对两组食管黏膜下层的成纤维细胞(fibroblasts，FB)与肌成纤维细胞(muscle fibroblasts，MFB)进行半定量分析(每张切片随机挑选5个视野)，以细胞总个数/细胞总面积为最终测定结果。
1.4.4 实时荧光定量PCR(qRT-PCR)检测相关基因mRNA的表达
称取100 mg食管组织，用高通量组织研磨仪研磨。采用Trizol法，依次加入Trizol、氯仿、异丙醇、75%乙醇提取总RNA，根据反转录试剂盒说明书分别反转录为cDNA，反转录条件为37 ℃ 15 min，85 ℃ 5 s，保持4 ℃。参照Green®Premix EX TapTMⅡ试剂盒说明书进行qRT-PCR检测，扩增引物见表1。扩增条件为：95 ℃预变性30 s；95 ℃变性5 s，60 ℃退火，延伸30 s，40个循环。采用2–ΔΔCt法分析mRNA的相对表达量。
1.4.5 免疫组化检测CTGF、ACTA2的表达
组织蜡块经切片、脱水、复水、枸橼酸100 ℃水浴修复抗原、过氧化物酶阻断、封闭、CTGF及ACTA2一抗及相应种属的二抗孵育、显色、苏木精复染、盐酸乙醇分色、脱水、封片，在光镜下观察CTGF、ACTA2的表达情况。使用Image-Pro Plus图像处理软件对阳性结果行半定量分析(每张切片随机挑选5个视野)，结果采用平均光密度值表示(目的蛋白光密度值/图像面积)。
1.4.6 Western blotting检测TGF-β1/Smads/ACTA2信号通路相关蛋白的表达
取–80 ℃保存的100 mg食管组织，加入1 ml含蛋白酶及磷酸酶抑制剂的RIPA裂解液，采用组织研磨仪研磨后于冰上裂解30 min，涡旋振荡数次，15 000 r/min离心15 min；吸取上清液，使用BCA蛋白定量试剂盒测定蛋白浓度，加入SDS上样缓冲液，于100 ℃干热块上加热7 min使蛋白变性，微量离心2 min后于–80 ℃保存。蛋白经聚丙烯酰胺凝胶电泳后，转至PVDF膜上，室温封闭2 h，TGF-β1(1:1000)、Smad2/3(1:1000)、p-Smad2/3(1:1000)、Smad4(1:500)、Smad7(1:1000)、CTGF(1:1000)、ACTA2(1:5000)一抗按比例稀释后，置于摇床上4 ℃孵育过夜，洗膜，二抗室温孵育60 min，洗膜，显色，每组重复4次。采用凝胶图像分析成像系统进行条带检测，采用Image J图像处理软件对条带灰度值进行半定量分析，结果以目的蛋白与内参蛋白的相对表达量表示。
1.5 统计学处理
采用SPSS 22.0软件进行统计分析。符合正态分布的计量资料以$\bar{x}±s$表示，两组间比较采用独立样本t检验。P<0.05为差异有统计学意义。
2 结果
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2.1 食管组织HE染色
模型组食管人工溃疡部位复层鳞状上皮层变薄，再生上皮在人工溃疡部位不能连续分布；黏膜肌层缺失；黏膜下层新生的结缔组织增厚、致密，可见大量炎性细胞浸润。与假手术组比较，模型组FB/MFB大量增殖(14.992±0.291 vs. 28.510±0.612，P<0.001)。FB形态呈多角形或扁平星形，细胞质染色较浅，细胞核大且呈规则卵圆形，核内可见细小黑色斑点，呈方向一致地束状排列。MFB呈长梭形，细胞核扁圆，与细胞外间质连接紧密，呈波浪形平行排列。假手术组食管组织黏膜层及黏膜下层完整，结缔组织疏松，内含少量排列杂乱的纤维细胞，除血管壁外几乎无MFB分布(图2)。
2.2 qRT-PCR检测食管组织TGF-β1、Smad2、Smad3、ACTA2 mRNA的表达
与假手术组比较，模型组食管组织TGF-β1、Smad2、Smad3、ACTA2的mRNA表达均明显上调(P<0.05，图3)。
2.3 食管组织TGF-β1/Smads/ACTA2信号通路相关蛋白的表达
2.3.1 免疫组化检测CTGF、ACTA2表达
CTGF蛋白在模型组食管人工溃疡部位组织中的阳性表达升高，致密纤维组织中FB的细胞质可见黄色或棕褐色颗粒沉积；假手术组仅疏松结缔组织中纤维细胞的细胞质有少量CTGF蛋白表达。ACTA2蛋白在模型组增生纤维层MFB的细胞质中表达增强，部分细胞核可见表达，呈黄色或棕褐色平行的波浪形分布；而在假手术组的疏松结缔组织中仅血管壁肌细胞可见ACTA2阳性表达，在疏松结缔组织中的纤维细胞几乎不表达(图4)。对免疫组化染色结果进行半定量分析显示，模型组中CTGF、ACTA2的阳性表达水平均高于假手术组(P<0.001，表2)。
2.3.2 Western blotting检测TGF-β1及其下游蛋白的表达
与假手术组比较，模型组TGF-β1、Smad2/3、p-Smad2/3、Smad4、Smad7、CTGF、ACTA2蛋白表达均明显上调(P<0.05，图5)。
3 讨论
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我国是世界上食管癌发病人数最多的国家之一，2015年食管癌新发病例数为24.6万例，占全球发病人数的50%以上，并呈逐年上升趋势[4-6]。2012年、2017年日本食管协会发布的食管癌诊疗指南指出，食管切除范围不再是限制其内镜下治疗的禁忌证[7-8]，意味着ESD在食管癌诊疗中的应用将越来越广泛，但与此同时ESD相关并发症的发生率也将随之升高，食管狭窄就是其中之一。研究表明，食管ESD术后人工溃疡面积是狭窄发生的独立危险因素，且治疗范围越大，病变纵径越长，术后食管狭窄发生的风险就越高，当病变范围>3/4食管周径、病变纵径>5 cm时，极易出现顽固性食管狭窄，使患者术后生活质量严重降低[2, 9]。因此，对食管ESD环切术后人工溃疡纤维化修复的机制研究变得尤为迫切。
本研究通过食管ESD环切术建立纵向约4 cm的人工溃疡，在术后第3周左右，模型组实验白猪半流质饮食进食困难，甚至有呕吐症状，电子胃镜检查提示人工溃疡部位出现明显狭窄，且直径为9.8 mm的内镜不能通过时，定义为造模成功，与Nonaka等[10]的研究结果基本吻合。从食管黏膜缺损愈合的时间进程来看，模型组白猪在食管ESD环切术后3周左右可形成明显狭窄。
TGF-β超家族在调节细胞生长、增殖、分化等方面有重要意义[11]，其中TGF-β1是一种来源广泛的关键致纤维化细胞因子，多种细胞(如FB、肝星状细胞、内皮细胞等)均可分泌TGF-β1[12]。当机体受到损伤时，多种细胞会分泌大量TGF-β1，通过调节Smad2/3蛋白磷酸化水平激活Smads信号通路，在共同介导蛋白Smad4的作用下，进一步与活化的转化生长因子-β1受体(transforming growth factor β receptor-Ⅰ，TβR-Ⅰ)结合，向细胞核传递相应的转录信号，激活转录因子，调节FB的增殖及分化，故TGF-β1又称为组织器官纤维化的“启动子”。Smad7是Smads信号转导通路的抑制性蛋白，通过竞争性地与活化的TβR-Ⅰ结合，使Smad2/3去磷酸化而失活，可以从侧面反映Smads通路的信号转导水平[13]。纤维化相关研究结果显示，TGF-β1拮抗剂可以抑制Smad2/3磷酸化，从而下调TGF-β1/Smads信号通路相关蛋白的表达，进而抑制FB的增殖[14]。Tang等[3]的研究表明，食管狭窄模型动物的血清TGF-β1水平明显升高，且与狭窄程度呈正相关。
本研究结果显示，无论在基因水平还是蛋白水平，模型组TGF-β1、Smad2/3、p-Smad2/3的表达均上调；Western blotting结果进一步提示，作为Smads信号转导的共介导蛋白之一，模型组Smad4的表达亦高于假手术组；抑制性蛋白Smad7的表达升高，可竞争性地与活化受体结合，促进Smad2/3的去磷酸化，从侧面反映出该通路的活化水平提高，这与现有的研究结果基本吻合[15]。因此，食管ESD环切术后人工溃疡部位管腔狭窄可能与组织损伤后多种细胞分泌TGF-β1增多及Smads信号通路过度活化有关。
CTGF是一类富含半胱氨酸的生长因子家族，具有明显的丝裂原性及趋化性，可调节多种类型细胞的黏附、迁移、增殖、存活及分化，在组织纤维化过程中发挥了重要作用[16]。Arias等[17]在纤维化体外实验中证实，CTGF启动子序列上存在TGF-β诱导CTGF所必需的功能性Smads结合位点，CTGF可能是TGF-β1/Smads信号转导通路的直接下游效应介质之一。Mori等[18]在小鼠皮肤纤维化模型中发现CTGF的持续表达是纤维化缓慢持续进展的重要环节之一。ACTA2是MFB的标志性蛋白之一，可以反映MFB的分化活性。有研究证实，CTGF与TGF-β1发挥协同作用，诱导肾小管上皮细胞发生表型转化，上调间质细胞中ACTA2的表达，促进肾脏间质中的FB转化为MFB[19]。Nonaka等[10]发现食管狭窄的特征性病理改变之一是大量MFB平行排列，水平延伸，从而促进凸起的管腔嵴形成。因此在纤维化病程中，CTGF是TGF-β1/Smads信号转导的关键下游效应靶点，可能与TGF-β1发挥协同作用，上调ACTA2的表达，促进纤维化持续进展，诱导FB向MFB表型转化。本研究结果显示，模型组ACTA2 mRNA表达上调，CTGF、ACTA2蛋白表达明显高于假手术组，表明CTGF可能在TGF-β1/Smads转导通路的诱导下，上调功能性Smads位点结合水平，从而参与食管ESD环切术后人工溃疡部位过度纤维化的进程，促进FB增殖，并诱导其向MFB表型转化。但本研究对模型的观察周期仅为3周，尚不清楚相关蛋白在长期食管纤维化进展中的表达情况。
综上所述，本研究再次验证了猪食管ESD环切术后3周左右可形成食管狭窄；造模后人工溃疡部位多种细胞大量分泌TGF-β1，随后上调Smad2/3的磷酸化及核转位水平，促进Smads信号转导通路的进一步活化，以及下游转录介质CTGF的表达，从而上调细胞内ACTA2的表达，造成FB大量增殖并逐渐分化为MFB，并最终形成食管ESD环切术后狭窄。TGF-β1/Smads/ACTA2信号通路的过度活化可能是食管ESD环切术后人工溃疡过度纤维化修复的机制之一。
基金
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  • 四川省科技厅计划项目(2020YFS0376)
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2022年第47卷第8期
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doi: 10.11855/j.issn.0577-7402.2022.08.0764
  • 接收时间：2021-11-16
  • 首发时间：2025-12-15
  • 出版时间：2022-08-28
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  • 收稿日期：2021-11-16
  • 录用日期：2022-02-10
基金
Plan Project of Science and Technology Department of Sichuan Province(2020YFS0376)
四川省科技厅计划项目(2020YFS0376)
作者信息
    1西南医科大学中西医结合学院，四川泸州 646000
    2西南医科大学附属中医医院脾胃病科，四川泸州 646000
    3海军军医大学第一附属医院消化内科，上海 200082

通讯作者:

李志，E-mail：;
陈洁，E-mail：
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https://castjournals.cast.org.cn/joweb/jfjyxzz/CN/10.11855/j.issn.0577-7402.2022.08.0764
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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