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Article(id=1203002060213018757, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203002056400396334, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2023.06.0686, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1645459200000, receivedDateStr=2022-02-22, revisedDate=null, revisedDateStr=null, acceptedDate=1667059200000, acceptedDateStr=2022-10-30, onlineDate=1764747641851, onlineDateStr=2025-12-03, pubDate=1687881600000, pubDateStr=2023-06-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764747641851, onlineIssueDateStr=2025-12-03, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764747641851, creator=13701087609, updateTime=1764747641851, updator=13701087609, issue=Issue{id=1203002056400396334, tenantId=1146029695717560320, journalId=1189873630562394117, year='2023', volume='48', issue='6', pageStart='627', pageEnd='748', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1764747640943, creator=13701087609, updateTime=1764747714497, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1203002364979540735, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203002056400396334, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1203002364979540736, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1203002056400396334, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=686, endPage=693, ext={EN=ArticleExt(id=1203002060573728926, articleId=1203002060213018757, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Roles of histone acetyltransferase GCN5 in LPS-induced alveolar epithelial cell injuries, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the effects of GCN5-mediated histone H3 acetylation (ac) on the proliferation, apoptosis and inflammatory factors of lipopolysaccharide (LPS) -induced alveolar epithelial cells. Methods A549 cells were randomly divided into 6 groups: control group, LPS group, NC+LPS group, GCN5+LPS group, MB-3 (GCN5 inhibitor) +LPS group and GCN5+MB-3+LPS group. Expression levels of H3K9ac, H3K14ac, H3K23ac, GCN5, and cell viability, cell proliferation, apoptosis, levels of inflammatory factors were compared between different groups. Quantitative polymerase chain reaction (qPCR) was used to detect the GCN5 mRNA expression; CCK-8 kit was used to detect cell viability; Cell proliferation was detected by EdU assay; apoptosis was detected by flow cytometry. The expression of GCN5, H3K9ac, H3K14ac, H3K23ac, Caspase-3 and Bcl-2 proteins were detected by Western blotting. The levels of inflammatory factors [interleukin (IL) -1β, IL-6 and tumor necrosis factor (TNF) -α] were determined by enzyme-linked immunosorbent assay (ELISA). Results Compared with control group, the levels of H3K9ac, H3K14ac and H3K23ac were decreased, the mRNA and protein expression of GCN5 were down-regulated, and the cell viability and proliferation were decreased, cell apoptosis was increased, Caspase-3 protein expression was up-regulated while Bcl-2 was down-regulated, the levels of inflammatory factors were increased in LPS group (P<0.05). Compared with the LPS group, no significant changes existed in the levels of the mRNA and protein expression of GCN5 in NC+LPS group (P>0.05), the mRNA and protein expression of GCN5 were up-regulated, the levels of H3K9ac, H3K14ac and H3K23ac were increased, and the cell viability and proliferation were increased, cell apoptosis was decreased, Caspase-3 protein expression was down-regulated while Bcl-2 was up-regulated, the levels of IL-1β, IL-6 and TNF-α were decreased in GCN5+LPS group (P<0.05). Compared with GCN5+LPS group, the levels of H3K9ac, H3K14ac and H3K23ac were decreased, and the cell viability and proliferation were reduced, cell apoptosis was elevated, the levels of IL-1β, IL-6 and TNF-α were increased in GCN5+MB-3+LPS group (P<0.05). Conclusion GCN5 overexpression could resist LPS-induced injuries of alveolar epithelial cells such as abnormal proliferation and apoptosis and inflammatory factors production, which could be related to the increase of histone H3 acetylation level.

, correspAuthors=Jie Gao, authorNote=null, correspAuthorsNote=
* E-mail:
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目的 探讨组蛋白乙酰转移酶GCN5介导的组蛋白H3乙酰化对脂多糖（LPS）诱导的肺泡上皮细胞（A549细胞）增殖、凋亡及炎性因子表达的作用。方法 将A549细胞随机分为6组：对照组、LPS组、NC+LPS组、GCN5+LPS组、MB-3（GCN5抑制剂）+LPS组和GCN5+MB-3+LPS组。分别比较对照组、LPS组和GCN5+LPS组，以及LPS组、MB-3+LPS组和GCN5+MB-3+LPS组的组蛋白H3乙酰化水平、GCN5表达水平、细胞活性与增殖情况、细胞凋亡情况、炎性因子水平的差异。采用荧光定量聚合酶链反应（qPCR）检测GCN5 mRNA表达水平；CCK-8试剂盒检测细胞活性；EdU实验检测细胞增殖情况；流式细胞术检测细胞凋亡情况；Western blotting检测GCN5、H3K9ac、H3K14ac、H3K23ac、Caspase-3和Bcl-2蛋白表达水平；酶联免疫吸附试验（ELISA）检测炎性因子白细胞介素-1β（IL-1β）、IL-6和肿瘤坏死因子-α（TNF-α）表达水平。结果 与对照组A549细胞比较，LPS组的H3K9ac、H3K14ac、H3K23ac、Bcl-2蛋白及GCN5 mRNA与蛋白表达水平均明显降低（P<0.05），细胞活性和增殖能力下降（P<0.05），细胞凋亡、Caspase-3蛋白和炎性因子水平增高（P<0.05）。与LPS组比较，NC+LPS组GCN5 mRNA与蛋白表达水平差异不明显（P>0.05）；GCN5+LPS组H3K9ac、H3K14ac、H3K23ac蛋白及GCN5 mRNA与蛋白表达水平均明显增高（P<0.05），细胞活性和增殖能力增高（P<0.05），细胞凋亡和炎性因子水平降低（P<0.05）。与GCN5+LPS组比较，GCN5+MB-3+LPS组的H3K9ac、H3K14ac、H3K23ac蛋白表达水平及细胞活性与增殖能力均降低（P<0.05），细胞凋亡和炎性因子水平增高（P<0.05）。结论 GCN5过表达可抵抗LPS诱导的肺泡上皮细胞增殖与凋亡异常及炎性因子分泌，这可能与其提高组蛋白H3乙酰化水平有关。

, correspAuthors=高洁, authorNote=null, correspAuthorsNote=
高洁，E-mail：
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何宝明，副主任技师，主要从事结核病方面的研究

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何宝明，副主任技师，主要从事结核病方面的研究

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何宝明，副主任技师，主要从事结核病方面的研究

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Stem Cells, 2018, 36（12）: 1828-1838., articleTitle=Histone Acetyltransferase KAT2A Stabilizes Pluripotency with Control of Transcriptional Heterogeneity, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1203008545101931117, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, xref=1, ext=[AuthorCompanyExt(id=1203008545110319726, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, companyId=1203008545101931117, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1Department of Laboratory Medicine, Hanzhong Central Hospital, Hanzhong, Shaanxi 723000, China), AuthorCompanyExt(id=1203008545127096945, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, companyId=1203008545101931117, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1汉中市中心医院检验科，陕西汉中 723000)]), AuthorCompany(id=1203008545231954548, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, xref=2, ext=[AuthorCompanyExt(id=1203008545244537462, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, companyId=1203008545231954548, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Department of Laboratory Medicine, Disease Prevention and Control Center of Hanzhong, Hanzhong, Shaanxi 723000, China), AuthorCompanyExt(id=1203008545252926071, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, companyId=1203008545231954548, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2汉中市疾病预防控制中心检验科，陕西汉中 723000)])], figs=[ArticleFig(id=1203008547035505373, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=EN, label=Fig.1, caption=Effects of the levels of histone H3K9ac，H3K14ac and H3K23ac，and mRNA and protein of GCN5 in A549 cells treated by LPS, figureFileSmall=NX1jPgH9bOC6Fn7mQ/eGeA==, figureFileBig=dW+LNrAHQWv1tk4ZFLKuEQ==, tableContent=null), ArticleFig(id=1203008547098419939, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=CN, label=图1, caption=LPS诱导的A549细胞中组蛋白H3K9ac、H3K14ac、H3K23ac及GCN5 mRNA和蛋白表达水平的变化

LPS. 脂多糖；H3K9ac. 组蛋白H3第9位赖氨酸乙酰化；H3K14ac. 组蛋白H3第14位赖氨酸乙酰化；H3K23ac. 组蛋白H3第23位赖氨酸乙酰化；GCN5. 组蛋白乙酰转移酶；GAPDH. 磷酸甘油醛脱氢酶；A. Western blotting检测H3K9ac、H3K14ac、H3K23ac蛋白相对表达水平；B. qPCR检测GCN5 mRNA表达水平；C. Western blotting检测GCN5蛋白相对表达水平；与对照组比较，（1）P<0.05

, figureFileSmall=NX1jPgH9bOC6Fn7mQ/eGeA==, figureFileBig=dW+LNrAHQWv1tk4ZFLKuEQ==, tableContent=null), ArticleFig(id=1203008547211666152, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=EN, label=Fig.2, caption=Effects of GCN5 overexpression on the levels of histone H3K9ac，H3K14ac and H3K23ac in LPS-induced A549 cells, figureFileSmall=zwNcSjo9LBkWKp10YsPKrQ==, figureFileBig=GSO5ihk+5FKlvObL4JbJuA==, tableContent=null), ArticleFig(id=1203008547278775022, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=CN, label=图2, caption=GCN5过表达对LPS诱导的A549中组蛋白H3K9ac、H3K14ac和H3K23ac水平的影响

GCN5. 组蛋白乙酰转移酶；LPS. 脂多糖；H3K9ac. 组蛋白H3第9位赖氨酸乙酰化；H3K14ac. 组蛋白H3第14位赖氨酸乙酰化；H3K23ac. 组蛋白H3第23位赖氨酸乙酰化；GAPDH. 磷酸甘油醛脱氢酶；A. qPCR检测GCN5 mRNA表达水平；B. Western blotting检测GCN5蛋白相对表达水平；C. Western blotting检测H3K9ac、H3K14ac、H3K23ac蛋白相对表达水平；与对照组比较，（1）P<0.05；与LPS组比较，（2）P<0.05

, figureFileSmall=zwNcSjo9LBkWKp10YsPKrQ==, figureFileBig=GSO5ihk+5FKlvObL4JbJuA==, tableContent=null), ArticleFig(id=1203008547366855409, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=EN, label=Fig.3, caption=Effects of GCN5 overexpression on the cell viability and proliferation in LPS-induced A549 cells, figureFileSmall=YWd2LRCmUrXiLa7Y3LqjQQ==, figureFileBig=iLQaAGXBNDkffQeJXqFgwQ==, tableContent=null), ArticleFig(id=1203008547488490226, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=CN, label=图3, caption=GCN5过表达对LPS诱导的A549细胞活性和增殖能力的影响

LPS. 脂多糖；GCN5. 组蛋白乙酰转移酶；EdU. 胸腺嘧啶核苷类似物；DAPI. DNA荧光染料；A. CCK-8检测细胞活性；B、C. EdU检测细胞增殖能力（×100）；与对照组比较，（1）P<0.05；与LPS组比较，（2）P<0.05

, figureFileSmall=YWd2LRCmUrXiLa7Y3LqjQQ==, figureFileBig=iLQaAGXBNDkffQeJXqFgwQ==, tableContent=null), ArticleFig(id=1203008547589153531, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=EN, label=Fig.4, caption=Effects of GCN5 overexpression on cell apoptosis in LPS-induced A549 cells, figureFileSmall=YIoBSgSJhJ+6v0I/p3NrCA==, figureFileBig=VS6heb7XkuyfKKeJgI4mIw==, tableContent=null), ArticleFig(id=1203008547664651005, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=CN, label=图4, caption=GCN5过表达对LPS诱导的A549细胞凋亡的影响

LPS. 脂多糖；GCN5. 组蛋白乙酰转移酶；Caspase-3. 半胱氨酸蛋白酶-3；GAPDH. 磷酸甘油醛脱氢酶；A. 流式细胞仪检测细胞凋亡情况；B. Western blotting检测Caspase-3和Bcl-2蛋白相对表达水平；与对照组比较，（1）P<0.05；与LPS组比较，（2）P<0.05

, figureFileSmall=YIoBSgSJhJ+6v0I/p3NrCA==, figureFileBig=VS6heb7XkuyfKKeJgI4mIw==, tableContent=null), ArticleFig(id=1203008547735954178, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=EN, label=Fig.5, caption=Effects of GCN5 overexpression on histone H3 acetylation and apoptosis in LPS-induced A549 cells, figureFileSmall=0pwzsuvLG6/zwbdEyILcnQ==, figureFileBig=buUYIjHVR9B7/f3FGCMWAQ==, tableContent=null), ArticleFig(id=1203008547836617481, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=CN, label=图5, caption=GCN5过表达对LPS诱导的A549细胞组蛋白H3乙酰化水平和细胞凋亡的影响

GCN5. 组蛋白乙酰转移酶；LPS. 脂多糖；MB-3. GCN5的特异性小分子抑制剂；H3K9ac. 组蛋白H3第9位赖氨酸乙酰化；H3K14ac.组蛋白H3第14位赖氨酸乙酰化；H3K23ac. 组蛋白H3第23位赖氨酸乙酰化；Caspase-3. 半胱氨酸蛋白酶-3；GAPDH. 磷酸甘油醛脱氢酶；A. H3K9ac、H3K14ac、H3K23ac蛋白相对表达水平（Western blotting）；B. CCK-8法检测细胞活性；C. Caspase-3和Bcl-2蛋白相对表达水平（Western blotting）；与LPS组比较，（1）P<0.05；与GCN5+LPS组比较，（2）P<0.05

, figureFileSmall=0pwzsuvLG6/zwbdEyILcnQ==, figureFileBig=buUYIjHVR9B7/f3FGCMWAQ==, tableContent=null), ArticleFig(id=1203008547912114956, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=EN, label=Fig.6, caption=Effects of GCN5 overexpression on proliferation in LPS-induced A549 cells（×100）, figureFileSmall=emZla4XbylRMkECANkSt6A==, figureFileBig=7CT59eykMkgHmCkJlPOuTQ==, tableContent=null), ArticleFig(id=1203008548012778256, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=CN, label=图6, caption=GCN5过表达对LPS诱导的A549细胞增殖能力的影响（×100）

LPS. 脂多糖；GCN5. 组蛋白乙酰转移酶；MB-3. GCN5的特异性小分子抑制剂；EdU. 胸腺嘧啶核苷类似物；DAPI. DNA荧光染料

, figureFileSmall=emZla4XbylRMkECANkSt6A==, figureFileBig=7CT59eykMkgHmCkJlPOuTQ==, tableContent=null), ArticleFig(id=1203008548084081426, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=EN, label=Tab.1, caption=

Effects of GCN5 overexpression on the levels of inflammatory factors in LPS-induced A549 cells（pg/ml，$\bar{x}±s$，n=3）

, figureFileSmall=null, figureFileBig=null, tableContent=
组别IL-1βIL-6TNF-α
对照组78.54±8.89163.37±22.79151.24±20.16
LPS组226.37±35.81（1）401.24±52.32（1）505.11±68.15（1）
NC+LPS组231.24±38.36431.16±64.58510.28±75.98
GCN5+LPS组152.22±24.15（2）284.28±40.24（2）337.26±54.63（2）
), ArticleFig(id=1203008548176356117, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=CN, label=表1, caption=

GCN5过表达对LPS诱导的A549细胞炎性因子表达水平的影响（pg/ml，$\bar{x}±s$，n=3）

, figureFileSmall=null, figureFileBig=null, tableContent=
组别IL-1βIL-6TNF-α
对照组78.54±8.89163.37±22.79151.24±20.16
LPS组226.37±35.81（1）401.24±52.32（1）505.11±68.15（1）
NC+LPS组231.24±38.36431.16±64.58510.28±75.98
GCN5+LPS组152.22±24.15（2）284.28±40.24（2）337.26±54.63（2）
), ArticleFig(id=1203008548281213722, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=EN, label=Tab.2, caption=

Effects of GCN5 overexpression on the levels of inflammatory factors in LPS-induced A549 cells（pg/ml，$\bar{x}±s$，n=3）

, figureFileSmall=null, figureFileBig=null, tableContent=
组别IL-1βIL-6TNF-α
LPS组232.45±40.56424.84±70.31524.29±77.11
MB-3+LPS组324.68±54.24（1）543.61±60.38（1）693.23±94.29（1）
GCN5+LPS组155.17±30.85（1）300.91±55.97（1）350.13±60.78（1）
GCN5+MB-3+LPS组243.23±40.21（2）427.84±72.35（2）508.19±82.47（2）
), ArticleFig(id=1203008548407042845, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1203002060213018757, language=CN, label=表2, caption=

GCN5过表达对LPS诱导的A549细胞炎性因子表达水平的影响（pg/ml，$\bar{x}±s$，n=3）

, figureFileSmall=null, figureFileBig=null, tableContent=
组别IL-1βIL-6TNF-α
LPS组232.45±40.56424.84±70.31524.29±77.11
MB-3+LPS组324.68±54.24（1）543.61±60.38（1）693.23±94.29（1）
GCN5+LPS组155.17±30.85（1）300.91±55.97（1）350.13±60.78（1）
GCN5+MB-3+LPS组243.23±40.21（2）427.84±72.35（2）508.19±82.47（2）
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组蛋白乙酰转移酶GCN5对LPS诱导的肺泡上皮细胞损伤的作用
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何宝明 1 , 高洁 2, *
解放军医学杂志 | 基础研究 2023,48(6): 686-693
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解放军医学杂志 | 基础研究 2023, 48(6): 686-693
组蛋白乙酰转移酶GCN5对LPS诱导的肺泡上皮细胞损伤的作用
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何宝明1, 高洁2, *
作者信息
  • 1汉中市中心医院检验科，陕西汉中 723000
  • 2汉中市疾病预防控制中心检验科，陕西汉中 723000

    • 何宝明，副主任技师，主要从事结核病方面的研究

通讯作者:

高洁，E-mail：
Roles of histone acetyltransferase GCN5 in LPS-induced alveolar epithelial cell injuries
Bao-Ming He1, Jie Gao2, *
Affiliations
  • 1Department of Laboratory Medicine, Hanzhong Central Hospital, Hanzhong, Shaanxi 723000, China
  • 2Department of Laboratory Medicine, Disease Prevention and Control Center of Hanzhong, Hanzhong, Shaanxi 723000, China
出版时间: 2023-06-28 doi: 10.11855/j.issn.0577-7402.2023.06.0686
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目的 探讨组蛋白乙酰转移酶GCN5介导的组蛋白H3乙酰化对脂多糖（LPS）诱导的肺泡上皮细胞（A549细胞）增殖、凋亡及炎性因子表达的作用。方法 将A549细胞随机分为6组：对照组、LPS组、NC+LPS组、GCN5+LPS组、MB-3（GCN5抑制剂）+LPS组和GCN5+MB-3+LPS组。分别比较对照组、LPS组和GCN5+LPS组，以及LPS组、MB-3+LPS组和GCN5+MB-3+LPS组的组蛋白H3乙酰化水平、GCN5表达水平、细胞活性与增殖情况、细胞凋亡情况、炎性因子水平的差异。采用荧光定量聚合酶链反应（qPCR）检测GCN5 mRNA表达水平；CCK-8试剂盒检测细胞活性；EdU实验检测细胞增殖情况；流式细胞术检测细胞凋亡情况；Western blotting检测GCN5、H3K9ac、H3K14ac、H3K23ac、Caspase-3和Bcl-2蛋白表达水平；酶联免疫吸附试验（ELISA）检测炎性因子白细胞介素-1β（IL-1β）、IL-6和肿瘤坏死因子-α（TNF-α）表达水平。结果 与对照组A549细胞比较，LPS组的H3K9ac、H3K14ac、H3K23ac、Bcl-2蛋白及GCN5 mRNA与蛋白表达水平均明显降低（P<0.05），细胞活性和增殖能力下降（P<0.05），细胞凋亡、Caspase-3蛋白和炎性因子水平增高（P<0.05）。与LPS组比较，NC+LPS组GCN5 mRNA与蛋白表达水平差异不明显（P>0.05）；GCN5+LPS组H3K9ac、H3K14ac、H3K23ac蛋白及GCN5 mRNA与蛋白表达水平均明显增高（P<0.05），细胞活性和增殖能力增高（P<0.05），细胞凋亡和炎性因子水平降低（P<0.05）。与GCN5+LPS组比较，GCN5+MB-3+LPS组的H3K9ac、H3K14ac、H3K23ac蛋白表达水平及细胞活性与增殖能力均降低（P<0.05），细胞凋亡和炎性因子水平增高（P<0.05）。结论 GCN5过表达可抵抗LPS诱导的肺泡上皮细胞增殖与凋亡异常及炎性因子分泌，这可能与其提高组蛋白H3乙酰化水平有关。

H3乙酰化  /  GCN5  /  脂多糖  /  肺泡上皮细胞  /  急性肺损伤

Objective To investigate the effects of GCN5-mediated histone H3 acetylation (ac) on the proliferation, apoptosis and inflammatory factors of lipopolysaccharide (LPS) -induced alveolar epithelial cells. Methods A549 cells were randomly divided into 6 groups: control group, LPS group, NC+LPS group, GCN5+LPS group, MB-3 (GCN5 inhibitor) +LPS group and GCN5+MB-3+LPS group. Expression levels of H3K9ac, H3K14ac, H3K23ac, GCN5, and cell viability, cell proliferation, apoptosis, levels of inflammatory factors were compared between different groups. Quantitative polymerase chain reaction (qPCR) was used to detect the GCN5 mRNA expression; CCK-8 kit was used to detect cell viability; Cell proliferation was detected by EdU assay; apoptosis was detected by flow cytometry. The expression of GCN5, H3K9ac, H3K14ac, H3K23ac, Caspase-3 and Bcl-2 proteins were detected by Western blotting. The levels of inflammatory factors [interleukin (IL) -1β, IL-6 and tumor necrosis factor (TNF) -α] were determined by enzyme-linked immunosorbent assay (ELISA). Results Compared with control group, the levels of H3K9ac, H3K14ac and H3K23ac were decreased, the mRNA and protein expression of GCN5 were down-regulated, and the cell viability and proliferation were decreased, cell apoptosis was increased, Caspase-3 protein expression was up-regulated while Bcl-2 was down-regulated, the levels of inflammatory factors were increased in LPS group (P<0.05). Compared with the LPS group, no significant changes existed in the levels of the mRNA and protein expression of GCN5 in NC+LPS group (P>0.05), the mRNA and protein expression of GCN5 were up-regulated, the levels of H3K9ac, H3K14ac and H3K23ac were increased, and the cell viability and proliferation were increased, cell apoptosis was decreased, Caspase-3 protein expression was down-regulated while Bcl-2 was up-regulated, the levels of IL-1β, IL-6 and TNF-α were decreased in GCN5+LPS group (P<0.05). Compared with GCN5+LPS group, the levels of H3K9ac, H3K14ac and H3K23ac were decreased, and the cell viability and proliferation were reduced, cell apoptosis was elevated, the levels of IL-1β, IL-6 and TNF-α were increased in GCN5+MB-3+LPS group (P<0.05). Conclusion GCN5 overexpression could resist LPS-induced injuries of alveolar epithelial cells such as abnormal proliferation and apoptosis and inflammatory factors production, which could be related to the increase of histone H3 acetylation level.

H3 acetylation  /  GCN5  /  lipopolysaccharide  /  alveolar epithelial cells  /  acute lung injury
何宝明, 高洁. 组蛋白乙酰转移酶GCN5对LPS诱导的肺泡上皮细胞损伤的作用. 解放军医学杂志, 2023 , 48 (6) : 686 -693 . DOI: 10.11855/j.issn.0577-7402.2023.06.0686
Bao-Ming He, Jie Gao. Roles of histone acetyltransferase GCN5 in LPS-induced alveolar epithelial cell injuries[J]. Medical Journal of Chinese People’s Liberation Army, 2023 , 48 (6) : 686 -693 . DOI: 10.11855/j.issn.0577-7402.2023.06.0686
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急性肺损伤（acute lung injury，ALI）是发病率和病死率均较高的临床急危重症，可由多种间接或直接的肺部损伤触发，甚至诱发急性呼吸窘迫综合征（acute respiratory distress syndrome，ARDS）或低氧性呼吸衰竭，并伴持久性弥漫性肺泡损伤[1-3]。肺泡Ⅱ型上皮细胞是ALI发病过程中的重要效应细胞。脂多糖（lipopolysaccharide，LPS）是革兰阴性菌感染致ALI的重要成分，LPS诱导的肺泡上皮细胞损伤是ALI重要的病理基础[4-5]。组蛋白乙酰化是真核生物中调控染色质结构和基因表达的重要机制，参与多种疾病的发生发展[6-8]。Seiler等[9]检测LPS诱导的A/J小鼠来源的Ⅱ型肺泡上皮细胞中组蛋白的乙酰化水平，结果显示LPS处理后组蛋白H3K14和H3K23乙酰化水平降低。组蛋白乙酰转移酶GCN5（general control non-derepressible 5，GCN5）可将乙酰基转移到赖氨酸残基的游离氨基上，催化组蛋白H3多个位点（包括K9、K14和K23等）的乙酰化修饰[10]。GCN5失调在多种疾病中发挥重要作用，其中在肺癌等多种肿瘤中表达上调[11-13]，而在牙周炎、骨质疏松等疾病中表达下调[14-15]。GCN5在ALI和肺泡上皮损伤中的表达及作用均少见报道。本研究通过LPS诱导A549细胞（肺癌人类肺泡基底上皮细胞）建立体外ALI模型，探讨GCN5介导的组蛋白H3乙酰化修饰对LPS诱导的肺泡上皮细胞损伤的影响。
1 材料与方法
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1.1 细胞培养
A549细胞购自ATCC细胞库。细胞在DMEM中培养，添加10%胎牛血清、20 mmol/L HEPES缓冲液、100 U/ml青霉素和100 mg/ml链霉素，在37 ℃、5% CO2的细胞培养箱中培养。
1.2 细胞分组和转染
将A549细胞随机分为6组：对照组（正常培养）、LPS组（LPS处理）、NC+LPS组（转染pcDNA3.1空载质粒作为阴性对照，24 h后用LPS处理）、GCN5+LPS组（转染pcDNA3.1-GCN5过表达质粒，24 h后用LPS处理）、MB-3+LPS组（加入GCN5抑制剂MB-3，24 h后用LPS处理）和GCN5+MB-3+LPS组（转染pcDNA3.1-GCN5过表达质粒并加入MB-3，24 h后用LPS处理）；分别比较对照组、LPS组和GCN5+LPS组，以及LPS组、MB-3+LPS组和GCN5+MB-3+LPS组的组蛋白H3乙酰化水平、GCN5表达水平、细胞活性与增殖情况、细胞凋亡情况、炎性因子水平的差异。根据说明书，用Lipofectamine 3000（美国Invitrogen）进行质粒转染。转染48 h后进行后续相关实验。
1.3 各项指标检测
1.3.1 qPCR检测GCN5 mRNA表达水平
Trizol法提取细胞总RNA，按照SuperScript VILO cDNA合成试剂盒（美国Invitrogen）说明书，反转录生成cDNA。SYBR Premix Ex Taq Ⅱ（大连TaKaRa）检测GCN5 mRNA表达水平。反应条件为：预变性95 ℃，10 s；变性95 ℃，5 s，退火58 ℃，15 s，延伸72 ℃，15 s，循环40次。以β-actin为内参，2–ΔΔCt法分析GCN5 mRNA的相对表达水平。
1.3.2 Western blotting检测GCN5、乙酰化组蛋白H3、Caspase-3、Bcl-2蛋白表达水平
RIPA裂解液提取细胞总蛋白，BCA蛋白试剂盒进行蛋白定量。取20 μg蛋白经SDS-PAGE凝胶电泳，通过半干转方法将蛋白转移到硝酸纤维素膜上。脱脂奶粉室温封闭1 h后，将膜与一抗（1：1000）4 ℃孵育过夜。第2天，经相应二抗（1：10 000）室温孵育1 h后，采用Odyssey红外激光成像系统进行扫描并分析灰度值。一抗：兔单克隆抗体Anti-GCN5（Abcam ab217876，94 kD），兔单克隆抗体Anti-H3K9ac[Histone H3（acetyl K14），Abcam ab177177，15 kD]，兔单克隆抗体Anti-H13K14ac（Abcam ab52946，15 kD），兔单克隆抗体Anti-H3K23ac（Abcam ab177275，15 kD），小鼠单克隆抗体Anti-H3（Abcam ab10799，15 kD），小鼠单克隆抗体Anti-GAPDH（Proteintech Cat No. 60004-1-Ig，36 kD）。
1.3.3 CCK-8法检测细胞活性
将各组细胞接种到96孔板，每孔加入10 ml CCK-8溶液，在37 ℃、5%CO2细胞培养箱中孵育2 h，采用酶标仪测定450 nm处的吸光度（A）值。
1.3.4 EdU实验检测细胞增殖情况
将各组细胞接种到96孔板，根据试剂盒说明书，每孔加入50 μmol/L EdU工作液100 μl进行细胞标记2 h，经清洗、固定后进行Apollo染色、DNA染色（DAPI），随后进行荧光观察。
1.3.5 流式细胞术检测细胞凋亡情况
经0.25%胰酶（不含EDTA）消化后，离心收集各组细胞。每组加入100 μl 1×结合缓冲液悬浮细胞，然后分别加入5 μl Annexin V-FITC和5 μl荧光染料碘化丙啶（PI）染色，室温闭光孵育15 min。各组再加入400 μl 1×结合缓冲液，于1 h内进行流式细胞仪检测。
1.3.6 酶联免疫吸附试验（ELISA）检测白细胞介素-1β（IL-1β）、IL-6和肿瘤坏死因子-α（TNF-α）的表达水平
收集各组细胞上清液，分别根据试剂盒说明书检测细胞上清液中IL-1β、IL-6和TNF-α的表达水平。
1.4 统计学处理
采用GraphPad Prism 8.0软件进行统计分析。计量资料符合正态分布，以$\bar{x}±s$表示，两组间比较采用t检验；多组间比较采用单因素方差分析，进一步两两比较采用Bonferroni检验。P<0.05为差异有统计学意义。
2 结果
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2.1 LPS诱导的A549细胞中组蛋白H3乙酰化和GCN5表达水平的变化
与对照组A549细胞比较，LPS组组蛋白H3K9ac、H3K14ac、H3K23ac及GCN5 mRNA和蛋白表达水平均明显降低（P<0.05，图1）。
2.2 GCN5过表达对A549细胞中组蛋白H3乙酰化水平的影响
与LPS组比较，NC+LPS组（过表达阴性对照组）GCN5 mRNA与蛋白表达水平差异无统计学意义（P>0.05）；过表达GCN5的GCN5+LPS组GCN5 mRNA和蛋白表达水平明显增高（P<0.05），组蛋白H3K9ac、H3K14ac和H3K23ac水平也明显增高（P<0.05，图2）。
2.3 GCN5过表达对LPS诱导的A549细胞活性与增殖的影响
与对照组A549细胞比较，LPS组的细胞活性和细胞增殖能力明显降低（P<0.05）；与LPS组比较，GCN5+LPS组的细胞活性和细胞增殖能力明显增高（P<0.05，图3）。
2.4 GCN5过表达对LPS诱导的A549细胞凋亡的影响
与对照组A549细胞比较，LPS组细胞凋亡率和Caspase-3蛋白表达水平明显增高（P<0.05），Bcl-2蛋白表达水平明显下降（P<0.05）；与LPS组比较，GCN5+LPS组细胞凋亡率和Caspase-3蛋白表达水平明显降低（P<0.05），Bcl-2蛋白表达水平明显增高（P<0.05，图4）。
2.5 GCN5过表达对LPS诱导的A549细胞炎性因子IL-1β、IL-6和TNF-α表达水平的影响
与对照组A549细胞比较，LPS组IL-1β、IL-6和TNF-α表达水平明显增高（P<0.05）；与LPS组比较，GCN5+LPS组IL-1β、IL-6和TNF-α表达水平明显降低（P<0.05，表1）。
2.6 GCN5表达水平对LPS诱导的A549细胞组蛋白H3乙酰化和细胞增殖、凋亡及炎性因子表达水平的影响
与LPS组A549细胞比较，MB-3+LPS组组蛋白H3K9ac、H3K14ac和H3K23ac水平明显降低（P<0.05），而GCN5+LPS组组蛋白H3K9ac、H3K14ac和H3K23ac水平明显增高（P<0.05）；与GCN5+LPS组比较，GCN5+MB-3+LPS组H3K9ac、H3K14ac和H3K23ac水平明显降低（P<0.05）。
与LPS组A549细胞比较，MB-3+LPS组细胞活性、细胞增殖能力和Bcl-2表达水平均明显降低（P<0.05），Caspase-3、IL-1β、IL-6和TNF-α表达水平均明显增高（P<0.05）；而GCN5+LPS组细胞活性、细胞增殖能力和Bcl-2表达水平均明显增高（P<0.05），Caspase-3、IL-1β、IL-6和TNF-α表达水平则明显降低（P<0.05）。与GCN5+LPS组比较，GCN5+MB-3+LPS组细胞活性、细胞增殖能力和Bcl-2表达水平均明显降低（P<0.05），Caspase-3、IL-1β、IL-6和TNF-α表达水平均明显增高（P<0.05）（表2、图5、图6）。
3 讨论
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转录起始是真核生物基因表达的重要调控节点，涉及一般转录因子和RNA聚合酶Ⅱ在核心启动子上组装成一个功能性的起始前复合物。染色质的松散和凝聚状态是决定起始前复合物与模板DNA能否结合的重要条件，而辅激活因子是调节染色质状态的关键组分。许多转录辅激活因子是多亚基复合物，可形成不同的结构和功能模块，具有多种调节活性。近年来，GCN5被鉴定为Spt-Ada-Gcn5-acetyltransferase（SAGA）、Ada-Two-A-Containing（ATAC）等多种辅激活因子复合物的催化亚基[16]。文献报道，GCN5参与调控多种生物事件，如细胞增殖、凋亡和炎症反应等[17]。本研究观察了GCN5在LPS诱导的肺泡上皮细胞损伤中的作用。
正常情况下，肺泡上皮细胞由Ⅰ型和Ⅱ型上皮细胞构成；其中Ⅱ型肺泡上皮细胞是一种多功能细胞，能够合成及分泌表面活性物质，维持肺泡内外液体平衡，还可以分化为Ⅰ型上皮细胞。肺泡上皮细胞受损会导致低氧血症等一系列ALI的病理变化[18]。因此，探讨LPS诱导Ⅱ型肺泡上皮细胞损伤的机制具有重要意义。来源于人肺腺癌的A549细胞拥有正常Ⅱ型肺泡上皮细胞的许多特征，如分泌表面活性物质，多层胞质包含体结构等，因此，A549细胞被广泛用于研究Ⅱ型肺泡上皮细胞的功能[19]。本研究结果显示，在LPS诱导的A549细胞中，组蛋白H3K14和H3K23乙酰化水平均明显降低，与Seiler等[9]的研究一致；LPS诱导还可降低H3K9乙酰化水平，提示组蛋白H3乙酰化在肺泡上皮细胞损伤中发挥了重要作用。本研究进一步检测了组蛋白H3乙酰化相关的乙酰转移酶GCN5的表达情况，结果显示LPS诱导可下调GCN5 mRNA和蛋白表达水平，提示GCN5可能通过组蛋白H3乙酰化调控LPS诱导的肺泡上皮细胞损伤。
为了验证GCN5的生物学功能，本研究通过GCN5的过表达质粒使其过表达，结果显示可提高LPS诱导的A549细胞中组蛋白H3K9、H3K14和H3K23乙酰化水平，再次提示GCN5介导的组蛋白H3乙酰化在LPS诱导的A549细胞中具有重要的调控作用。在ALI过程中，LPS可启动并放大机体的炎症反应，促进炎性介质的过度释放及肺实质炎性细胞的弥漫性浸润，导致肺泡上皮细胞死亡，表现出染色质浓缩、DNA断裂、Bcl-2家族蛋白表达异常等细胞凋亡的特点。因此，减轻炎症反应和细胞凋亡是促进肺泡上皮细胞抵抗LPS诱导损伤的关键。在本研究中，LPS处理可显著降低A549细胞活性和增殖能力，促进细胞凋亡，上调Caspase-3蛋白表达水平且下调Bcl-2蛋白表达水平，同时提高炎性因子IL-1β、IL-6和TNF-α的表达水平，与文献报道的LPS诱导的肺泡上皮细胞损伤一致[4-5]。本研究还发现，GCN5过表达可显著提高A549细胞活性和增殖能力，降低LPS诱导的细胞凋亡和炎性因子水平。以上结果提示，GCN5过表达可促进肺泡上皮细胞抵抗LPS诱导的凋亡和炎性损伤。
为了进一步观察GCN5过表达对LPS损伤的抵抗作用是否与其提高组蛋白H3乙酰化水平相关，本研究通过GCN5特异性抑制剂MB-3抑制GCN5介导的H3乙酰化[20-21]，结果显示，MB-3处理可进一步加重LPS诱导的细胞凋亡和炎性损伤，降低细胞活性和增殖能力，提示GCN5介导的H3乙酰化与LPS损伤密切相关；而且，MB-3处理可逆转GCN5过表达对LPS损伤的抵抗作用，即抑制GCN5介导的H3乙酰化可逆转GCN5过表达对LPS损伤的抵抗作用，提示GCN5过表达对LPS损伤的抵抗作用与其提高组蛋白H3的乙酰化水平有关。
ALI发病机制复杂，目前仍缺乏有效的治疗手段。识别并靶向调控ALI的关键分子对于相关的药物研发具有重要意义。本研究显示，GCN5过表达可抑制LPS诱导的肺泡上皮细胞损伤，促进细胞增殖，减轻细胞凋亡和炎症反应的作用，这与其提高组蛋白H3乙酰化水平有关，提示GCN5是调控肺泡上皮细胞生理功能的重要因子，可能成为临床防治ALI的重要靶点。
本研究的不足之处在于仅在体外观察了GCN5对LPS诱导的肺泡上皮细胞损伤的作用。一方面，未来需要在体内、临床水平进一步探讨GCN5的作用，才能为GCN5作为ALI防治靶点提供更多的理论依据；另一方面，组蛋白H3乙酰化是调控基因转录的重要方面，未来应明确其下游的靶基因，以进一步阐明GCN5抗肺泡上皮细胞损伤的作用机制。GCN5同时具有组蛋白乙酰转移酶和赖氨酸乙酰转移酶的功能，其能否通过调控非组蛋白赖氨酸乙酰化而发挥抗肺泡上皮细胞损伤的作用，也有待进一步探讨。
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2023年第48卷第6期
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doi: 10.11855/j.issn.0577-7402.2023.06.0686
  • 接收时间：2022-02-22
  • 首发时间：2025-12-03
  • 出版时间：2023-06-28
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  • 收稿日期：2022-02-22
  • 录用日期：2022-10-30
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    1汉中市中心医院检验科，陕西汉中 723000
    2汉中市疾病预防控制中心检验科，陕西汉中 723000

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2种不同金属材料的力学参数
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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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