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Article(id=1241025202889478646, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241025201983508979, articleNumber=null, orderNo=null, doi=10.20043/j.cnki.MPM.202412036, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1733155200000, receivedDateStr=2024-12-03, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1773813065501, onlineDateStr=2026-03-18, pubDate=1744214400000, pubDateStr=2025-04-10, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1773813065501, onlineIssueDateStr=2026-03-18, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1773813065501, creator=13701087609, updateTime=1773813065501, updator=13701087609, issue=Issue{id=1241025201983508979, tenantId=1146029695717560320, journalId=1227665162245664772, year='2025', volume='52', issue='7', pageStart='1153', pageEnd='1344', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1773813065285, creator=13701087609, updateTime=1773815493878, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1241035388320543403, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241025201983508979, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1241035388320543404, tenantId=1146029695717560320, journalId=1227665162245664772, issueId=1241025201983508979, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1201, endPage=1208, ext={EN=ArticleExt(id=1241025203170497018, articleId=1241025202889478646, tenantId=1146029695717560320, journalId=1227665162245664772, language=EN, title=Mechanism of astragal side IV combined with quercetin in inhibiting silica-induced macrophage proptosis activation, columnId=1228016570660745413, journalTitle=Modern Preventive Medicine, columnName=Environmental and Occupational Health, runingTitle=null, highlight=null, articleAbstract=
Objective

To investigate the molecular mechanism by which Astragal side IV (ASV) combined with Quercetin (QUE) inhibits silica (SiO2)-induced macrophage proptosis activation.

Methods

An in vitro co-culture system was established using rat alveolar macrophages (NR8383) and rat fibroblasts (RFL-6). The experiment was divided into six groups: control group, drug group, SiO2 group, SiO2 + drug group, SiO2 + Balmacaan (Bel) group, and SiO2 + drug + Bel group. After 24 hours of intervention, cell and supernatant samples were collected. The levels of transforming growth factor β1 (TGF-β1), tumor necrosis factor alpha (TNF-α), and high mobility group box-1 (HMGB1) in the supernatant were measured using ELISA. The protein levels of α-SMA,Vimentin, and E-Cadherin (E-cad) in RFL-6 cells were detected using Western blot. The mRNA and protein expression levels of Caspase-1, interleukin-1β (IL-1β), and IL-18 in NR8383 cells were assessed using PCR and Western blot, respectively.

Results

Compared to the control group, the levels of TGF-β1, TNF-α, and HMGB1 in the supernatant of the SiO2 group were significantly increased (P<0.05), the protein levels of α-SMA and Vimentin in RFL-6 cells were elevated, while E-cad protein levels were reduced. The expression levels of (Cleaved-) Caspase-1, IL-1β, and IL-18 mRNA and protein in NR8383 cells were also significantly increased (P<0.05). Compared to the SiO2 group, the levels of TGF-β1, TNF-α, and HMGB1 in the supernatants of the SiO2 + drug group, SiO2 + Bel group, and SiO2 + drug + Bel group were significantly decreased (P<0.05). The protein levels of α-SMA and Vimentin in RFL-6 cells were reduced, and E-cad protein levels were elevated. The expression levels of (Cleaved-) Caspase-1, IL-1β, and IL-18 mRNA and protein in NR8383 cells were also significantly decreased (P<0.05).

Conclusion

ASV combined with QUE may reduce the secretion of inflammatory factors by inhibiting the proptosis levels of macrophages exposed to SiO2 in the co-culture system, thereby suppressing the fibrosis levels in fibroblasts.

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目的

探究黄芪甲苷（astragaloside IV， ASV）联合槲皮素（quercetin， QUE）抑制二氧化硅（silicon dioxide， SiO2）诱导的巨噬细胞焦亡活化的分子机制。

方法

建立大鼠肺泡巨噬细胞（NR8383）和大鼠成纤维细胞（RFL-6）体外共培养体系，实验分为6组，对照组、药物组、SiO2组、SiO2+药物组、SiO2+Belnacasan(Bel)组、SiO2+药物+Bel组，干预24h后，收集细胞和上清液，采用ELISA法检测上清液中转化生长因子β1（transforming growth factor β1， TGF-β1）、肿瘤坏死因子α（tumor necrosis factor alpha， TNF-α）、高迁移率族蛋白B1（high mobility group box-1， HMGB1）的水平，Western blot法检测RFL-6细胞中α-SMA、Vimentin、E-Cadherin(E-cad)蛋白含量，PT-PCR及Western blot法分别检测NR8383细胞中的半胱氨酸天冬氨酸蛋白酶1（Caspase-1）、白介素-1β（interleukin-1β， IL-1β）和IL-18的mRNA及蛋白表达水平。

结果

与对照相比，SiO2组上清液中TGF-β1、TNF-α、HMGB1水平明显升高（P<0.05），RFL-6细胞中α-SMA、Vimentin蛋白含量升高，E-cad蛋白含量降低，NR8338细胞中(Cleaved-) Caspase-1、IL-1β、 IL-18 mRNA及蛋白表达水平均升高（P<0.05）；与SiO2组相比，SiO2+药物组、SiO2+Bel组和SiO2+药物+Bel组上清液中TGF-β1、TNF-α、HMGB1水平明显降低（P<0.05），RFL-6细胞中α-SMA、Vimentin蛋白含量降低，E-cad蛋白含量升高，NR8338细胞中(Cleaved-) Caspase-1、IL-1β、 IL-18 mRNA及蛋白表达水平均降低（P<0.05）。

结论

ASV联合QUE可能通过抑制共培养体系中暴露于SiO2的巨噬细胞的焦亡水平来降低炎性因子的分泌，进而抑制成纤维细胞的纤维化水平。

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邵华，E-mail:
, copyrightStatement=本刊刊出的所有文章不代表中华预防医学会和本刊编委会的观点，除非特别声明。, copyrightOwner=中华预防医学会和四川大学华西公共卫生学院, extLink=null, articleAbsUrl=null, sourceXml=Sz7iHyrZ/6iHbYwacmdjTg==, magXml=dGbfeE/H9YMzZVN0Ev+1Kw==, pdfUrl=null, pdf=wcdcOdgizhuQHcsdiYqPgg==, pdfFileSize=3816066, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=uB+nzZ+F1NaYAqlTMN18Kw==, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=VTaoxzftCARSKI4icWeGSg==, mapNumber=null, authorCompany=null, fund=null, authors=

朱文文（1987—），女，博士在读，主管技师，研究方向：肺部纤维化及中西医结合治疗研究

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2.山东第一医科大学（山东省医学科学院），山东省职业卫生与职业病防治研究院毒理学研究中心，山东 济南 250062, bio={"content":"

朱文文（1987—），女，博士在读，主管技师，研究方向：肺部纤维化及中西医结合治疗研究

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朱文文（1987—），女，博士在读，主管技师，研究方向：肺部纤维化及中西医结合治疗研究

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Protective effect of quercetin on pulmonary dysfunction in streptozotocin-induced diabetic rats via inhibition of NLRP3 signaling pathway[J].Environmental Science and Pollution Research International, 2023,30(14): 42390-42398., articleTitle=Protective effect of quercetin on pulmonary dysfunction in streptozotocin-induced diabetic rats via inhibition of NLRP3 signaling pathway, refAbstract=null)], funds=[Fund(id=1241025211919815419, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, awardId=2022YFC2503202, language=CN, fundingSource=国家重点研发计划(2022YFC2503202), fundOrder=null, country=null), Fund(id=1241025212112753409, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, awardId=M-2023238, language=CN, fundingSource=山东省中医药科技项目(M-2023238), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1241025205959709215, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, xref=1., ext=[AuthorCompanyExt(id=1241025205968097824, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, companyId=1241025205959709215, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China), AuthorCompanyExt(id=1241025205972292129, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, companyId=1241025205959709215, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1.山东中医药大学中医学院，山东 济南 250355)]), AuthorCompany(id=1241025206072955431, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, xref=2., ext=[AuthorCompanyExt(id=1241025206081344040, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, companyId=1241025206072955431, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.山东第一医科大学（山东省医学科学院），山东省职业卫生与职业病防治研究院毒理学研究中心，山东 济南 250062)]), AuthorCompany(id=1241025206135869997, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, xref=3., ext=[AuthorCompanyExt(id=1241025206144258605, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, companyId=1241025206135869997, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3.康复大学青岛中心医院（青岛市中心医疗集团）重症医学科)])], figs=[ArticleFig(id=1241025210565055159, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=EN, label=Figure 1, caption=Determination of drug dose of ASV+QUE combination, figureFileSmall=NBszR9bIFGeGgTrhGDqQDg==, figureFileBig=uB+nzZ+F1NaYAqlTMN18Kw==, tableContent=null), ArticleFig(id=1241025210661524157, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=CN, label=图1, caption=ASV+QUE联合药物剂量的确定

注：*与对照组相比，P<0.05；#与SiO2组相比，P<0.05；@与药物(10)组相比，P<0.05；&与药物(20)组相比，P<0.05。

, figureFileSmall=NBszR9bIFGeGgTrhGDqQDg==, figureFileBig=uB+nzZ+F1NaYAqlTMN18Kw==, tableContent=null), ArticleFig(id=1241025210854462149, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=EN, label=Figure 2, caption=Changes of inflammatory factors in the supernatant of co-culture system (n=3), figureFileSmall=sKyf54+QJK93LltOLmbsBg==, figureFileBig=07omNf0uWkJQnflJiWlk8g==, tableContent=null), ArticleFig(id=1241025210938348233, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=CN, label=图2, caption=共培养体系上清中炎症因子的变化（n=3）

注：a与对照组相比，P<0.05；b与SiO2组相比，P<0.05；c与SiO2+药物组相比，P<0.05；d与SiO2+Bel组相比，P<0.05。

, figureFileSmall=sKyf54+QJK93LltOLmbsBg==, figureFileBig=07omNf0uWkJQnflJiWlk8g==, tableContent=null), ArticleFig(id=1241025211047400140, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=EN, label=Figure 3, caption=Changes of Vimentin, α-SMA and E-cad protein levels in RFL-6 cells in co-culture system (n=3), figureFileSmall=ysoSf6cpLtNfZd2MuSUIDQ==, figureFileBig=wdyhSWbGrgo3DFJHQB+vEA==, tableContent=null), ArticleFig(id=1241025211122897617, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=CN, label=图3, caption=共培养体系中RFL-6细胞Vimentin、α-SMA、E-cad蛋白表达水平的变化（n=3）

注：a与对照组相比，P<0.05；b与SiO2组相比，P<0.05；c与SiO2+药物组相比，P<0.05；d与SiO2+Bel组相比，P<0.05。

, figureFileSmall=ysoSf6cpLtNfZd2MuSUIDQ==, figureFileBig=wdyhSWbGrgo3DFJHQB+vEA==, tableContent=null), ArticleFig(id=1241025211227755223, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=EN, label=Figure 4, caption=Changes of Caspase-1, IL-18 and IL-1β mRNA levels in NR8383 cells in co-culture system (n=3), figureFileSmall=hBE5xnYEBvLQyud0I6RfcQ==, figureFileBig=KVLuOdKxrDCaXRPjhiPoXw==, tableContent=null), ArticleFig(id=1241025211315835611, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=CN, label=图4, caption=共培养体系中NR8383细胞中Caspase-1、IL-18和IL-1β mRNA水平的变化（n=3）

注：a与对照组相比，P<0.05；b与SiO2组相比，P<0.05；c与SiO2+药物组相比，P<0.05；d与SiO2+Bel组相比，P<0.05。

, figureFileSmall=hBE5xnYEBvLQyud0I6RfcQ==, figureFileBig=KVLuOdKxrDCaXRPjhiPoXw==, tableContent=null), ArticleFig(id=1241025211420693214, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=EN, label=Figure 5, caption=Changes of Cleaved-Caspase-1, IL-18 and IL-1β protein levels in NR8383 cells in co-culture system (n=3), figureFileSmall=R9Lt3dZ6u4NQqmKhVAqkTg==, figureFileBig=7ZErG98a0ndDgC2lh9t7SQ==, tableContent=null), ArticleFig(id=1241025211550716645, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=CN, label=图5, caption=共培养体系中NR8383细胞中Cleaved-Caspase-1、IL-18和IL-1β蛋白表达水平的变化（n=3）

注：a与对照组相比，P<0.05；b与SiO2组相比，P<0.05；c与SiO2+药物组相比，P<0.05；d与SiO2+Bel组相比，P<0.05。

, figureFileSmall=R9Lt3dZ6u4NQqmKhVAqkTg==, figureFileBig=7ZErG98a0ndDgC2lh9t7SQ==, tableContent=null), ArticleFig(id=1241025211689128683, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=EN, label=Table 1, caption=

List of primers for pyroptosis indicators in NR8383 cells

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物 (5'-3')产物长度 (bp)
Caspase-1F: TGCCTGGTCTTGTGACTTGGAG132
R: TGTCCTGGGAAGAGGTAGAAACG
IL-1βF:TGTGACTCGTGGGATGATGAC160
R:CCACTTGTTGGCTTATGTTCTGTC
IL-18F:GGCTGCCATACCAGAAGAAGG101
R:ATTCCAAGTCTCCATTATCTTCAGG
GAPDHF:CTGGAGAAACCTGCCAAGTATG138
R:GGTGGAAGAATGGGAGTTGCT
), ArticleFig(id=1241025211798180592, tenantId=1146029695717560320, journalId=1227665162245664772, articleId=1241025202889478646, language=CN, label=表1, caption=

NR8383细胞焦亡指标引物列表

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物 (5'-3')产物长度 (bp)
Caspase-1F: TGCCTGGTCTTGTGACTTGGAG132
R: TGTCCTGGGAAGAGGTAGAAACG
IL-1βF:TGTGACTCGTGGGATGATGAC160
R:CCACTTGTTGGCTTATGTTCTGTC
IL-18F:GGCTGCCATACCAGAAGAAGG101
R:ATTCCAAGTCTCCATTATCTTCAGG
GAPDHF:CTGGAGAAACCTGCCAAGTATG138
R:GGTGGAAGAATGGGAGTTGCT
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黄芪甲苷联合槲皮素抑制二氧化硅诱导的巨噬细胞焦亡活化的机制
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朱文文 1, 2 , 杜忠君 2 , 马英华 2 , 赵宁霞 3 , 孙世超 2 , 邵华 2
现代预防医学 | 环境与职业卫生 2025,52(7): 1201-1208
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现代预防医学 | 环境与职业卫生 2025, 52(7): 1201-1208
黄芪甲苷联合槲皮素抑制二氧化硅诱导的巨噬细胞焦亡活化的机制
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朱文文1, 2, 杜忠君2, 马英华2, 赵宁霞3, 孙世超2, 邵华2
作者信息
  • 1.山东中医药大学中医学院，山东 济南 250355
  • 2.山东第一医科大学（山东省医学科学院），山东省职业卫生与职业病防治研究院毒理学研究中心，山东 济南 250062
  • 3.康复大学青岛中心医院（青岛市中心医疗集团）重症医学科

    • 朱文文（1987—），女，博士在读，主管技师，研究方向：肺部纤维化及中西医结合治疗研究

通讯作者:

邵华，E-mail:
Mechanism of astragal side IV combined with quercetin in inhibiting silica-induced macrophage proptosis activation
Wen-wen ZHU1, 2, Zhong-jun DU2, Ying-hua MA2, Ning-xia ZHAO3, Shi-chao SUN2, Hua SHAO2
Affiliations
  • School of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China
出版时间: 2025-04-10 doi: 10.20043/j.cnki.MPM.202412036
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摘要
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目的

探究黄芪甲苷（astragaloside IV， ASV）联合槲皮素（quercetin， QUE）抑制二氧化硅（silicon dioxide， SiO2）诱导的巨噬细胞焦亡活化的分子机制。

方法

建立大鼠肺泡巨噬细胞（NR8383）和大鼠成纤维细胞（RFL-6）体外共培养体系，实验分为6组，对照组、药物组、SiO2组、SiO2+药物组、SiO2+Belnacasan(Bel)组、SiO2+药物+Bel组，干预24h后，收集细胞和上清液，采用ELISA法检测上清液中转化生长因子β1（transforming growth factor β1， TGF-β1）、肿瘤坏死因子α（tumor necrosis factor alpha， TNF-α）、高迁移率族蛋白B1（high mobility group box-1， HMGB1）的水平，Western blot法检测RFL-6细胞中α-SMA、Vimentin、E-Cadherin(E-cad)蛋白含量，PT-PCR及Western blot法分别检测NR8383细胞中的半胱氨酸天冬氨酸蛋白酶1（Caspase-1）、白介素-1β（interleukin-1β， IL-1β）和IL-18的mRNA及蛋白表达水平。

结果

与对照相比，SiO2组上清液中TGF-β1、TNF-α、HMGB1水平明显升高（P<0.05），RFL-6细胞中α-SMA、Vimentin蛋白含量升高，E-cad蛋白含量降低，NR8338细胞中(Cleaved-) Caspase-1、IL-1β、 IL-18 mRNA及蛋白表达水平均升高（P<0.05）；与SiO2组相比，SiO2+药物组、SiO2+Bel组和SiO2+药物+Bel组上清液中TGF-β1、TNF-α、HMGB1水平明显降低（P<0.05），RFL-6细胞中α-SMA、Vimentin蛋白含量降低，E-cad蛋白含量升高，NR8338细胞中(Cleaved-) Caspase-1、IL-1β、 IL-18 mRNA及蛋白表达水平均降低（P<0.05）。

结论

ASV联合QUE可能通过抑制共培养体系中暴露于SiO2的巨噬细胞的焦亡水平来降低炎性因子的分泌，进而抑制成纤维细胞的纤维化水平。

细胞焦亡  /  黄芪甲苷  /  槲皮素  /  矽肺  /  巨噬细胞
Objective

To investigate the molecular mechanism by which Astragal side IV (ASV) combined with Quercetin (QUE) inhibits silica (SiO2)-induced macrophage proptosis activation.

Methods

An in vitro co-culture system was established using rat alveolar macrophages (NR8383) and rat fibroblasts (RFL-6). The experiment was divided into six groups: control group, drug group, SiO2 group, SiO2 + drug group, SiO2 + Balmacaan (Bel) group, and SiO2 + drug + Bel group. After 24 hours of intervention, cell and supernatant samples were collected. The levels of transforming growth factor β1 (TGF-β1), tumor necrosis factor alpha (TNF-α), and high mobility group box-1 (HMGB1) in the supernatant were measured using ELISA. The protein levels of α-SMA,Vimentin, and E-Cadherin (E-cad) in RFL-6 cells were detected using Western blot. The mRNA and protein expression levels of Caspase-1, interleukin-1β (IL-1β), and IL-18 in NR8383 cells were assessed using PCR and Western blot, respectively.

Results

Compared to the control group, the levels of TGF-β1, TNF-α, and HMGB1 in the supernatant of the SiO2 group were significantly increased (P<0.05), the protein levels of α-SMA and Vimentin in RFL-6 cells were elevated, while E-cad protein levels were reduced. The expression levels of (Cleaved-) Caspase-1, IL-1β, and IL-18 mRNA and protein in NR8383 cells were also significantly increased (P<0.05). Compared to the SiO2 group, the levels of TGF-β1, TNF-α, and HMGB1 in the supernatants of the SiO2 + drug group, SiO2 + Bel group, and SiO2 + drug + Bel group were significantly decreased (P<0.05). The protein levels of α-SMA and Vimentin in RFL-6 cells were reduced, and E-cad protein levels were elevated. The expression levels of (Cleaved-) Caspase-1, IL-1β, and IL-18 mRNA and protein in NR8383 cells were also significantly decreased (P<0.05).

Conclusion

ASV combined with QUE may reduce the secretion of inflammatory factors by inhibiting the proptosis levels of macrophages exposed to SiO2 in the co-culture system, thereby suppressing the fibrosis levels in fibroblasts.

Cell proptosis  /  Astragal side IV  /  Quercetin  /  Silicosis  /  Fibrosis  /  Macrophages
朱文文, 杜忠君, 马英华, 赵宁霞, 孙世超, 邵华. 黄芪甲苷联合槲皮素抑制二氧化硅诱导的巨噬细胞焦亡活化的机制. 现代预防医学, 2025 , 52 (7) : 1201 -1208 . DOI: 10.20043/j.cnki.MPM.202412036
Wen-wen ZHU, Zhong-jun DU, Ying-hua MA, Ning-xia ZHAO, Shi-chao SUN, Hua SHAO. Mechanism of astragal side IV combined with quercetin in inhibiting silica-induced macrophage proptosis activation[J]. Modern Preventive Medicine, 2025 , 52 (7) : 1201 -1208 . DOI: 10.20043/j.cnki.MPM.202412036
正文
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矽肺是一种由于长期暴露于游离二氧化硅粉尘引起的、以肺部炎症和不可逆的弥漫性结节性纤维化为特征的肺部疾病[1]。目前，矽肺的发病机制仍不明确，其中涉及多种促炎及促纤维化因子，以及这些因子介导的多细胞相互作用。肺泡巨噬细胞(alveolar macrophages，AMs)是肺组织中固有的免疫细胞，是维持内环境稳态的重要防线，也是局部炎症和纤维化病变的重要参与者[2]。研究表明肺泡内堆积的二氧化硅颗粒反复刺激AMs，AMs活化后可以使促炎和促纤维化因子如IL-1β，TNF-α和TGF-β1等表达升高，成纤维细胞受到作用后产生胶原蛋白，导致肺纤维化[3-4]。
细胞焦亡是一种不同于凋亡的、有炎症反应相伴的特殊的细胞程序性死亡方式，经典途径主要由Caspase-1介导，激活的Caspase-1使IL-1β和IL-18前体剪切为成熟的IL-1β和IL-18，释放到胞外发挥炎性作用[5]。研究表明，矽肺小鼠肺组织中Caspase-1、IL-1β和IL-18均有明显升高的现象，抑制Caspase-1活性可以减轻矽肺小鼠肺部炎症和纤维化水平[4，6]。黄芪甲苷（astragaloside IV， ASV）和槲皮素（quercetin， QUE）均是黄芪的重要活性单体成分，槲皮素也广泛存在于其他植物中，研究表明黄芪及其单体ASV和QUE在一定剂量下均具有减轻矽肺模型动物肺损伤和纤维化的作用[7-9]。但ASV联合QUE是否会有更好的抗炎及抗纤维化作用，其中机制如何，均尚不清楚。故本研究模拟矽肺的发病过程，根据以往的研究[10]建立大鼠肺泡巨噬细胞（rat alveolar macrophages， NR8383）和大鼠成纤维细胞（rat fibroblasts-6， RFL-6）的体外共培养细胞体系，观察ASV联合QUE对共培养体系中NR8383细胞分泌的炎性因子及FRL-6细胞中纤维化相关蛋白水平的影响，并探讨联合药物对NR8383细胞焦亡水平的影响，为临床应用黄芪甲苷联合槲皮素治疗矽肺提供理论依据。
1　材料与方法
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1.1　主要仪器和试剂
全波段酶标仪（美国Molecular Devices公司）；细胞CO2培养箱（美国Thermo Fisher Scientific公司）；Stepone plus型实时荧光定量聚合酶链式反应（real-time quantitative polymerase chain reaction， RT-PCR）仪（美国ABI公司）；双垂直电泳仪（北京六一仪器厂）；Alpha图像分析软件、灰度分析软件（美国Alpha Innotech公司）。游离二氧化硅（美国Sigma-Aloric，纯度为99.00%，80.00%粒径为1～5μm）；黄芪甲苷（成都德斯特生物科技有限公司）；槲皮素（美国Sigma-Aloric）；Belnacasan（VX-765，美国Sigma公司）；F12K培养基（美国Gibco公司）；胎牛血清（上海达特希尔生物科技有限公司）；青霉素/链霉素溶液、Tryple Express（美国Gibco公司）；第一链cDNA合成试剂盒、实时荧光定量染料SYBR-Green（Thermo公司）；二辛宁可酸（Bicinchoninic acid， BCA）蛋白定量试剂盒（加拿大Millipore公司）；电化学发光试剂盒（美国Pierce公司）；大鼠TNF-α、TGF-β1酶联免疫吸附实验（Enzyme-linked immunosorbent assay， ELISA）试剂盒（杭州联科生物技术科技有限公司）；大鼠HMGB1 ELISA试剂盒、Cleaved-Caspase-1、IL-18、IL-1β抗体（英国abcam）；Vimentin、E-Cad、α-SMA、肌动蛋白（β-actin）抗体（武汉三鹰）；辣根过氧化物酶（Horseradish Peroxidase， HRP）标记的二抗（南京生兴生物技术有限公司）。
1.2　方法
1.2.1　共培养体系的建立
NR8383和RFL-6细胞购自中国科学院上海生命科学研究院细胞资源中心。配制NR8383和RFL-6细胞悬液，Transwell培养基下室每孔接种RFL-6细胞25×104个，上室接种NR8383细胞5×104个，于含20%胎牛血清和1%青霉素-链霉素的F12K完全培养基中共培养。
1.2.2　药物浓度的筛选
首先通过CCK8实验，以1×104个/ml浓度分别接种NR8383细胞和RFL-6细胞于96孔板上，每组设6个复孔，检测不同ASV+QUE联合药物浓度(10、20、40和80 μmol/L)分别对两种细胞存活力的影响，筛选出联合药物浓度范围；然后通过共培养体系，设置对照组、SiO2组及不同联合药物浓度组，每组设3个复孔，共培养24h后，通过观察不同药物浓度对RFL-6细胞α-SMA、Vimentin、E-cad蛋白水平的影响确定最终药物干预浓度。
1.2.3　分组及干预
实验分6组：对照组、药物组、SiO2组、SiO2+药物组、SiO2+Bel组、SiO2+药物+Bel组，NR8383和RFL-6细胞共培养24 h后，进行药物干预。对照组不做任何干预；药物组共培养体系中仅给予ASV及QUE终浓度为20μmol/L的混合药液；其余4组NR8383细胞（Transwell上室）均给予终浓度为100 μg/ml的SiO2混悬液，SiO2+药物组共培养体系同时给予ASV及QUE终浓度为20 μmol/L的混合药液，SiO2+Bel组同时给予终浓度为100nM的焦亡抑制剂Belnacasan，SiO2+药物+Bel组同时给予ASV及QUE终浓度为20 μmol/L的混合药液及终浓度为100nM的Belnacasan。每组设3个复孔，于37℃、体积分数为5.0% CO2培养箱中培养24h后，收集上清及细胞，保存于-80℃冰箱以备后续实验。
1.2.4　ELISA法检测细胞上清中TGF-β1、TNF-α和HMGB1含量
采用TGF-β1、TNF-α和HMGB-1 ELISA试剂盒检测细胞上清中TGF-β1、TNF-α和HMGB-1的水平。根据说明书做好样本前处理及标准品的倍比稀释。显色后于450 nm主波长及570 nm参考波长下测各孔吸光度。根据标准系列吸光度值及浓度值绘制标准曲线，然后根据标准曲线分别计算样本中TGF-β1、TNF-α和HMGB1的浓度水平。
1.2.5　Western blot法检测RFL-6细胞中α-SMA、Vimentin、E-cad蛋白含量
取收集好的RFL-6细胞，加入适量体积的RIPA（使用前数分钟内加入蛋白酶抑制剂）裂解细胞，离心收集上清总蛋白，BCA法测蛋白浓度。提取的蛋白经SDS-聚丙烯酰胺凝胶电泳分离后，转移到硝酸纤维素膜；将抗α-SMA、Vimentin、E-cad一抗稀释（1∶1 000）后，4℃孵育过夜，TBST洗涤3次，室温下与HRP标记的二抗（1∶3 000）孵育30 min，洗涤3次。对膜进行增强化学发光处理，并暴露于成像系统；采用AlphaEasefc软件对结果进行定量分析，β-actin为内参蛋白。
1.2.6　PT-PCR法检测NR8383细胞中Caspase-1、IL-1β和IL-18 mRNA表达量
TRIzol试剂盒提取NR8383细胞总RNA，使用逆转录酶第一链cDNA合成试剂盒将其逆转录为cDNA。用Premier 6.0设计Caspase-1、IL-1β和IL-18引物，引物序列见表1。PCR反应条件如下：95℃ 30s预变性；95℃ 15s变性，60℃ 30s退火，60℃ 30s延伸，共40次循环；熔解曲线：65℃→95℃，每升温0.5℃采集一次荧光信号。以GAPDH为内参照，采用2-ΔΔCt方法计算mRNA相对表达量。
1.2.7　Western blot法检测NR8383细胞中Cleaved-Caspase-1、IL-18和IL-1β蛋白含量
取收集好的NR8383细胞，提取总蛋白并测定蛋白浓度。蛋白经电泳分离后转移到硝酸纤维素膜，将抗Cleaved-Caspase-1、IL-1β、IL-18一抗稀释（1∶1 000）后，4℃孵育过夜，TBST洗涤3次，室温下与HRP标记的二抗（1∶3 000）孵育30 min，洗涤3次。对膜进行增强化学发光处理，并暴露于成像系统。采用AlphaEasefc软件对结果进行定量分析，β-actin为内参蛋白。
1.3　统计学分析
采用SPSS 27.0统计软件，符合正态性的计量资料以（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LSD检验。检验水准α=0.05。
2　结果
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2.1　ASV+QUE联合药物剂量的确定
如图1A、图1B所示，与对照组相比，培养24 h后，10和20 μmol/L联合药物浓度对NR8383细胞和RFL-6细胞的存活率均无显著影响（P>0.05），在40和80 μmol/L联合药物浓度下，NR8383细胞和RFL-6细胞的存活率均降低（P<0.05），故进一步对10和20 μmol/L浓度的联合药物作进一步筛选。如图1C、图1D所示，与对照组相比，SiO2组RFL-6细胞中的Vimentin和α-SMA蛋白显著增高，E-Cad水平显著降低（P<0.05），经10和20 μmol/L ASV+QUE联合药物分别干预后，与SiO2组相比，Vimentin和α-SMA蛋白水平有明显的降低，E-Cad水平明显升高（P<0.05），而且20 μmol/L浓度的联合药物要比10 μmol/L的联合药物抗纤维化作用效果好（P<0.05）。故后续共培养体系中，ASV+QUE联合药物浓度选用20 μmol/L。
2.2　细胞上清中TGF-β1、TNF-α、HMGB1含量变化
如图2所示，与对照组相比，药物组上清中TGF-β 1、TNF-α、HMGB1的含量变化差别无统计学意义（P>0.05），SiO2组上清中TGF-β1、TNF-α、HMGB1含量均显著升高（P<0.05）；与SiO2组相比，SiO2+药物组及SiO2+Bel组上清中TGF-β1、TNF-α、HMGB1水平下降（P<0.05）；与SiO2+Bel组和SiO2+药物组相比，SiO2+药物+Bel组TGF-β1、TNF-α、HMGB1水平均降低（P<0.05）。
2.3　RFL-6细胞α-SMA、Vimentin、E-cad蛋白含量变化
如图3所示，与对照组相比，药物组RFL-6细胞纤维化相关蛋白α-SMA、Vimentin、E-cad含量变化差别无统计学意义（P>0.05），SiO2组RFL-6细胞中α-SMA和Vimentin蛋白水平均显著升高，E-cad蛋白水平显著降低（P<0.05）；与SiO2组相比，SiO2+药物组及SiO2+Bel组均表现为α-SMA和Vimentin蛋白水平下降，E-cad蛋白水平升高（P<0.05）；与SiO2+药物组及SiO2+Bel组相比，SiO2+药物+Bel组α-SMA和Vimentin蛋白水平降低，E-cad蛋白水平升高（P<0.05）。
2.4　NR8383细胞中Caspase-1、IL-18和IL-1β mRNA含量变化
图4显示，与对照组相比，药物组NR8383细胞中Caspase-1、IL-18、IL-1β mRNA水平变化差异无统计学意义（P>0.05），SiO2组NR8383细胞中Caspase-1、IL-18、IL-1β mRNA水平显著升高（P<0.05）；与SiO2组相比，SiO2+药物组及SiO2+Bel组NR8383细胞中的Caspase-1、IL-18、IL-1β mRNA水平显著降低（P<0.05）；与SiO2+药物组及SiO2+Bel组相比，SiO2+药物+Bel组的Caspase-1、IL-18、IL-1β mRNA水平降低（P<0.05）。
2.5　NR8383细胞中Cleaved-Caspase-1、IL-18和IL-1β蛋白含量变化
图5显示，与对照组相比，药物组NR8383细胞中Cleaved-Caspase-1、IL-18、IL-1β蛋白表达水平差异无统计学意义（P>0.05），SiO2组Cleaved-Caspase-1、IL-18、IL-1β蛋白表达水平显著升高（P<0.05）；与SiO2组相比，SiO2+药物组及SiO2+Bel组NR8383细胞中的Cleaved-Caspase-1、IL-18、IL-1β蛋白表达水平显著降低（P<0.05）；与SiO2+药物组及SiO2+Bel组相比，SiO2+药物+Bel组Cleaved-Caspase-1、IL-18、IL-1β蛋白表达水平降低（P<0.05）。
3　讨论
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矽肺作为最重要的职业病之一，其高发病率和高病死率给患者和社会带来了沉重的负担。目前矽肺尚无有效的治疗方法，其发病机制复杂且尚不清楚[11]。AMs作为肺泡腔最丰富的固有免疫细胞，具有强大的吞噬功能，是抵御外来侵略的第一道防线[12]。研究表明，AMs在肺纤维化的发展中起着多种作用，包括炎症细胞的调节、受损组织的清除、肌成纤维细胞的募集和活化以及分泌多种细胞因子、生长因子、构建细胞的调控网络[13]。当SiO2被吸入肺部后，AMs识别SiO2颗粒上的类似病原体相关分子模式(pathogen-associated molecular patterns，PAMPs)，并与其自身表面上的模式识别受体(pattern recognition receptors，PRRs)结合，触发促炎因子和促纤维化细胞因子的释放[14]。成纤维细胞作为下游的效应细胞，在AMs细胞释放的细胞因子作用下，向肌成纤维细胞转化，介导肺纤维化的发生[15-16]。本研究选用NR8383和RFL-6细胞建立体外共培养体系，探讨ASV联合QUE对共培养体系的作用，及其中的细胞焦亡机制。本研究根据预实验及本实验室前期结果[17]，选用100 μg/ml的SiO2混悬液干预共培养体系中NR8383细胞。结果显示，SiO2干预的共培养体系上清液中，炎性因子TGF-β1、TNF-α、HMGB1的水平显著升高；而且SiO2干预的共培养体系中RFL-6细胞中的α-SMA、Vimentin蛋白水平明显升高，E-cad蛋白水平显著降低。提示SiO2颗粒被NR8383细胞吞噬后，刺激NR8383细胞分泌TGF-β1、TNF-α、HMGB1等细胞因子，这些细胞因子进入共培养液中，刺激RFL-6细胞，使α-SMA、Vimentin蛋白表达增多，E-cad蛋白表达减少。
ASV是黄芪中的主要活性单体，已被证明具有广泛的抗炎和抗纤维化作用[18]，ASV不仅能改善糖尿病引起的心肌病大鼠的心肌炎症和纤维化[19]，还能减轻PM2.5引起的肺部炎症及纤维化[20]。QUE也是黄芪中的重要活性成分，而且也广泛存在于其他植物当中。研究表明QUE具有持久的抗炎[21]和广泛的抗纤维化作用[22-23]；QUE可通过抑制TNF-a、TGF-β1、基质金属蛋白等衰老相关分泌表型的分泌，减轻矽肺小鼠肺纤维化程度[9]。有研究者通过对治疗新型冠状病毒肺炎的中药成分进行分析，发现ASV和QUE是这些中药发挥抗纤维化和抗炎作用的重要成分[24]。本研究通过参阅文献[9，25-26]和实验确定了ASV+QUE的联合用药浓度为20 μmol/L，研究结果表明，该浓度下ASV联合QUE可以明显降低共培养体系中TNF-a、TGF-β1、HMGB1的水平，进而使RFL-6细胞中α-SMA、Vimentin蛋白表达下降，E-cad蛋白表达升高。
近期，随着对细胞焦亡的研究，有研究者提出了“焦亡-炎性反应-纤维化”的轴样病理改变[27]。当吸入性二氧化硅粉尘与AMs膜上的PRRs受体识别后，激活胞内caspase-1活性，使IL-1β、IL-18前体成熟并释放，导致肺组织的炎性反应[28]。本研究结果显示，SiO2可以使共培养体系中NR8383细胞的Caspase-1、IL-1β、IL-18的mRNA水平和Cleaved-Caspase-1、IL-1β、IL-18蛋白表达水平均显著升高，说明SiO2激活了NR8383细胞的Caspase-1酶活性，使IL-1β、IL-18蛋白成熟并释放入胞外共培养体系中，进一步影响体系中RFL-6细胞的生物效应。
细胞焦亡作为一种程序性死亡方式，区别于与自噬和凋亡的是可以引起组织炎症反应，对于肺组织损伤，细胞焦亡既可以直接造成肺部细胞的死亡，亦可通过引起的炎症反应损伤邻近细胞。因此，如果能够有效的抑制细胞焦亡，对于肺疾病的防治将具有重大的意义[29]。有研究通过抑制NLRP3或Caspase-1来防止巨噬细胞的焦亡，减轻SiO2介导的肺部炎症和纤维化[30-31]。ASV就可以通过降低NLRP3、Caspase-1、IL-1β、GSDMD和GSDMD-N水平，抑制NLRP3炎症小体介导的焦亡，减轻脑缺血再灌注[32]。ASV也可以抑制PM2.5激活的肺组织焦亡水平来减轻PM2.5对肺的损伤[20]。QUE也可以通过抑制NLRP3信号通路，降低肺内促炎因子水平，减轻肺损伤，保护肺功能[33]。本实验用ASV联合QUE作用于SiO2暴露的共培养体系后，NR8383细胞表现出焦亡相关指标Caspase-1、IL-1β、IL-18的mRNA水平和Cleaved-Caspase-1、IL-1β、IL-18蛋白表达水平均降低，RFL-6细胞的α-SMA、Vimentin蛋白表达下降，E-cad蛋白表达升高，这与用焦亡抑制剂Belnacasan干预SiO2暴露的共培养体系的效果一样。
综上所述，ASV联合QUE可能通过抑制共培养体系中暴露于SiO2的巨噬细胞的焦亡水平来降低炎性因子的分泌，进而抑制成纤维细胞的纤维化水平。后续可通过动物实验进一步探究ASV联合QUE抑制焦亡通路的靶蛋白，为临床应用黄芪甲苷联合槲皮素治疗早期矽肺提供理论依据。
基金
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  • 国家重点研发计划(2022YFC2503202)
  • 山东省中医药科技项目(M-2023238)
文献
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参考文献 引证文献
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2025年第52卷第7期
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doi: 10.20043/j.cnki.MPM.202412036
  • 接收时间：2024-12-03
  • 首发时间：2026-03-18
  • 出版时间：2025-04-10
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  • 收稿日期：2024-12-03
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国家重点研发计划(2022YFC2503202)
山东省中医药科技项目(M-2023238)
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    1.山东中医药大学中医学院，山东 济南 250355
    2.山东第一医科大学（山东省医学科学院），山东省职业卫生与职业病防治研究院毒理学研究中心，山东 济南 250062
    3.康复大学青岛中心医院（青岛市中心医疗集团）重症医学科

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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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