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Article(id=1200023154757304884, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1200023152219746543, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2420.2023.0619, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1668700800000, receivedDateStr=2022-11-18, revisedDate=null, revisedDateStr=null, acceptedDate=1669564800000, acceptedDateStr=2022-11-28, onlineDate=1764037415445, onlineDateStr=2025-11-25, pubDate=1698422400000, pubDateStr=2023-10-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764037415445, onlineIssueDateStr=2025-11-25, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764037415445, creator=13701087609, updateTime=1764037415445, updator=13701087609, issue=Issue{id=1200023152219746543, tenantId=1146029695717560320, journalId=1189873630562394117, year='2023', volume='48', issue='10', pageStart='1115', pageEnd='1236', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1764037414841, creator=13701087609, updateTime=1764038706792, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200028571126301693, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1200023152219746543, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200028571126301694, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1200023152219746543, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=1144, endPage=1152, ext={EN=ArticleExt(id=1200023158888694359, articleId=1200023154757304884, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Effect and mechanism of vitamin A deficiency in regulating M1 polarization of alveolar macrophage in neonatal rats with ARDS, columnId=1190310110212751762, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Basic Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the effect and its mechanism of vitamin A (VA) deficiency (VAD) on regulating alveolar macrophage polarization in neonatal rats with acute respiratory distress syndrome (ARDS). Methods Sixty neonatal SD rats were divided into vitamin A normal control group (VAN ctrl group, n=10), normal vitamin A group (VAN group, n=10), vitamin A deficiency control group (VAD ctrl group, n=10), vitamin A deficiency group (VAD group, n=10), vitamin A rescue control group (VADR ctrl group, n=10) and vitamin A rescue group (VADR group, n=10). The VADR ctrl and VADR groups were injected with 25 µg VA at the second day after birth. All the neonatal rats were given lipopolysaccharide (LPS) to establish the neonatal rat model of ARDS, and serum and lung tissue samples were collected. The weight of newborn rats in each group was recorded before modeling, the May-Grunwald-Giemsa staining was performed to observe the number of main cells in bronchoalveolar lavage fluid (BALF), and HE staining was used to detect the pathological damage of lung tissue. The polarization of alveolar macrophages was evaluated by immunofluorescence. qRT-PCR and ELISA were performed to detected the expression of downstream markers of the polarization of alveolar macrophages inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-10 and arginase-1 (Arg-1). The content of superoxide dismutase (SOD) and malondialdehyde (MDA) in lung tissue were calculated by colorimetric method, and cell apoptosis was detected by TUNEL. Results Compared with the neonatal rats in VAN group, the neonatal rats in VAD group had lower body weight, small physique, and sparse hair, while the body weight and general condition of the newborn rats in the VADR group did not change significantly. Compared with the VAD group, the neonatal rats in VADR group gained weight and shiny hair. Compared with VAN group, the lung damage of ARDS neonatal rats in VAD group was aggravated, the number of major cells in BALF increased, the M1 polarization of alveolar macrophages activated (P<0.05), the expression levels of M1 polarization markers iNOS, IL-6, TNF-α and CD86 increased significantly (P<0.05), the content of oxidative stress marker MDA and cell apoptosis increased (P<0.05), SOD activity decreased (P<0.05), while the levels of IL-10 and Arg-1 were not statistically significant (P>0.05); Compared with VAN group, there were no significant differences in macrophage M1 polarization, TNF-α, IL-6, SOD, MDA, IL-10 and Arg-1 in newborn rats in VADR group (P>0.05). Compared with VAD group, the lung damage of ARDS neonatal rats in VADR group was significantly reduced, the number of alveolar macrophages and the polarization of alveolar macrophages M1 decreased (P<0.05), the expression levels of M1 polarization markers iNOS, IL-6, TNF-α and CD86 decreased (P<0.05), the content of the oxidative stress marker MDA and cell apoptosis decreased (P<0.05), and the SOD activity enhanced (P<0.05). Conclusion VAD could regulate the M1 polarization of alveolar macrophages, up-regulated the expression of inflammatory markers downstream of M1 polarization, increased pulmonary oxidative stress and apoptosis, and aggravated ARDS in neonatal rats.

, correspAuthors=Fang Gong, authorNote=null, correspAuthorsNote=
E-mail:
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目的 探讨维生素A缺乏(VAD)调节肺泡巨噬细胞极化在新生大鼠急性呼吸窘迫综合征(ARDS)中的作用及其机制。方法 将60只新生SD大鼠分为维生素A正常对照组(VAN ctrl组，n=10)、维生素A正常组(VAN组，n=10)、维生素A缺乏对照组(VAD ctrl组，n=10)、维生素A缺乏组(VAD组，n=10)、维生素A挽救对照组(VADR ctrl组，n=10)及维生素A挽救组 (VADR组，n=10)，其中，VADR ctrl及VADR组SD大鼠于生后第2天一次性给予腹腔注射25 µg VA。6组新生大鼠分别予以脂多糖(LPS)建立ARDS新生大鼠模型并收集血清及肺组织标本。记录建模前各组新生大鼠的体重，采用May-Grunwald-Giemsa染色法检测肺泡灌洗液(BALF)中主要细胞数量，HE染色观察肺组织病理损伤情况，免疫荧光染色评估肺泡巨噬细胞极化情况，qRT-PCR、ELISA检测肺泡巨噬细胞极化下游标志物诱导型一氧化氮合酶(iNOS)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、IL-10、精氨酸酶1(Arg-1)等炎性因子的表达情况，比色法检测肺组织氧化应激标志物超氧化物歧化酶(SOD)、丙二醛(MDA)含量，TUNEL检测细胞凋亡情况。结果 与VAN组新生大鼠比较，VAD组新生大鼠体重较轻、体格偏小、毛发稀疏，而VADR组新生大鼠体重、一般情况无明显变化；与VAD组比较，VADR组新生大鼠体重增加，毛发光亮。与VAN组比较，VAD组ARDS新生大鼠肺部损伤加重，BALF中主要细胞数量增加、肺泡巨噬细胞M1极化激活(P<0.05)，M1极化标志物iNOS、IL-6、TNF-α、CD86表达水平明显升高(P<0.05)，氧化应激标志物MDA含量增多(P<0.05)，细胞凋亡增加(P<0.05)，SOD活性降低(P<0.05)，而IL-10、Arg-1水平差异无统计学意义(P>0.05)；与VAN组相比，VADR组新生大鼠巨噬细胞M1极化及TNF-α、IL-6、SOD、MDA、IL-10、Arg-1水平等差异均无统计学意义(P>0.05)；与VAD组比较，VADR组ARDS新生大鼠肺部损伤明显减轻，肺泡巨噬细胞数量及肺泡巨噬细胞M1极化减少(P<0.05)，且M1极化标志物iNOS、IL-6、TNF-α、CD86表达水平降低(P<0.05)，氧化应激标志物MDA含量及细胞凋亡减少(P<0.05)，SOD活性增加(P<0.05)。结论 VAD可通过调节肺泡巨噬细胞M1极化，上调M1极化下游炎症标志物表达，增加肺部氧化应激及细胞凋亡，从而加重新生大鼠ARDS的肺部损伤。

, correspAuthors=龚放, authorNote=null, correspAuthorsNote=
龚放，E-mail：
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曾毅文，硕士研究生，副主任医师，主要从事新生儿疾病方面的研究

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曾毅文，硕士研究生，副主任医师，主要从事新生儿疾病方面的研究

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articleId=1200023154757304884, language=CN, orderNo=5, keyword=氧化应激), Keyword(id=1200061227155157360, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=CN, orderNo=6, keyword=炎性因子)], refs=[Reference(id=1200061230258942351, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, doi=null, pmid=null, pmcid=null, year=2017, volume=5, issue=8, pageStart=657, pageEnd=666, url=null, language=null, rfNumber=[1], rfOrder=0, authorNames=de Luca D, van Kaam AH, Tingay DG, journalName=Lancet Respir Med, refType=null, unstructuredReference=de Luca D, van Kaam AH, Tingay DG, et al. 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Partial reversibility by retinoic acid, refAbstract=null), Reference(id=1200061234293862846, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, doi=null, pmid=null, pmcid=null, year=2017, volume=42, issue=11, pageStart=1192, pageEnd=1200, url=null, language=null, rfNumber=[26], rfOrder=27, authorNames=Petiz LL, Kunzler A, Bortolin RC, journalName=Physiol Appliquee Nutr Metab, refType=null, unstructuredReference=Petiz LL, Kunzler A, Bortolin RC, et al. Role of vitamin A oral supplementation on oxidative stress and inflammatory response in the liver of trained rats[J]. Physiol Appliquee Nutr Metab, 2017, 42(11): 1192-1200., articleTitle=Role of vitamin A oral supplementation on oxidative stress and inflammatory response in the liver of trained rats, refAbstract=null)], funds=[Fund(id=1200061229818540426, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, awardId=KJQN201900420, language=EN, fundingSource=Chongqing Education Commission Project(KJQN201900420), fundOrder=null, country=null), Fund(id=1200061230028255628, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, awardId=KJQN201900420, language=CN, fundingSource=重庆市教委项目(KJQN201900420), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1200061224999285062, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, xref=null, ext=[AuthorCompanyExt(id=1200061225007673671, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, companyId=1200061224999285062, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Pediatrics, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing 402160, China), AuthorCompanyExt(id=1200061225016062280, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, companyId=1200061224999285062, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=重庆医科大学附属永川医院儿科，重庆 402160)])], figs=[ArticleFig(id=1200061227360678261, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=EN, label=Fig.1, caption=Comparison of VA content and lung tissue damage in neonatal rats in each group, figureFileSmall=TExwHz+elge/ciGTiogr6w==, figureFileBig=MhR0OPA7oOgkeZkySisTig==, tableContent=null), ArticleFig(id=1200061227469730166, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=CN, label=图1, caption=各组新生大鼠VA含量及肺组织损伤情况比较

A. 血清中的维生素A(VA)含量；B. 肺组织湿干比(W/D)；C. 肺组织HE染色；*P<0.05

, figureFileSmall=TExwHz+elge/ciGTiogr6w==, figureFileBig=MhR0OPA7oOgkeZkySisTig==, tableContent=null), ArticleFig(id=1200061227612336504, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=EN, label=Fig.2, caption=Detection of cells count in the bronchoalveolar lavage fluid of neonatal rats in each group, figureFileSmall=Uira42wfv2nzpM3RXPJoVw==, figureFileBig=LRVa04HDlv9ONAhRcqyj5Q==, tableContent=null), ArticleFig(id=1200061227712999802, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=CN, label=图2, caption=各组新生大鼠BALF中细胞数量检测情况

BALF. 肺泡灌洗液；*P<0.05

, figureFileSmall=Uira42wfv2nzpM3RXPJoVw==, figureFileBig=LRVa04HDlv9ONAhRcqyj5Q==, tableContent=null), ArticleFig(id=1200061227813663099, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=EN, label=Fig.3, caption=Immunofluorescence detection of M1 marker CD86 expression in four groups of rats (×400), figureFileSmall=csrQBssFfuZ5Wq81s/yFdA==, figureFileBig=kss/6ydnnvMNvYsaaYSwrA==, tableContent=null), ArticleFig(id=1200061227901743485, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=CN, label=图3, caption=免疫荧光染色检测各组新生大鼠M1型肺泡巨噬细胞标志物CD86的表达情况(×400), figureFileSmall=csrQBssFfuZ5Wq81s/yFdA==, figureFileBig=kss/6ydnnvMNvYsaaYSwrA==, tableContent=null), ArticleFig(id=1200061227998212479, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=EN, label=Fig.4, caption=Effect of VAD on M1 and M2 polarization markers and inflammatory factors in alveolar macrophages, figureFileSmall=Q2RCsIYrYUbCReECNVVq6w==, figureFileBig=BNiGJLtw6gfPVIbfLk1PTA==, tableContent=null), ArticleFig(id=1200061228065321345, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=CN, label=图4, caption=VAD对肺泡巨噬细胞M1、M2极化标志物及炎性因子的影响

A. 各组M2极化下游标志物的mRNA表达水平；B. 各组M1极化下游标志物的mRNA表达水平；C. 各组M1极化下游标志物的蛋白表达水平；*P<0.05

, figureFileSmall=Q2RCsIYrYUbCReECNVVq6w==, figureFileBig=BNiGJLtw6gfPVIbfLk1PTA==, tableContent=null), ArticleFig(id=1200061228287619459, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=EN, label=Fig.5, caption=Comparison of oxidative stress and apoptosis of lung tissue in neonatal rats in various groups, figureFileSmall=AafyNE6dJtsZBVD3edF6FA==, figureFileBig=KHYR6EE4CXtTa019ECi+Wg==, tableContent=null), ArticleFig(id=1200061229394915717, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=CN, label=图5, caption=各组新生大鼠肺组织细胞凋亡及氧化应激的比较

A. TUNEL检测细胞凋亡情况；B. 各组肺组织凋亡指数比较；C. 各组小鼠氧化应激标志物表达情况比较；*P<0.05

, figureFileSmall=AafyNE6dJtsZBVD3edF6FA==, figureFileBig=KHYR6EE4CXtTa019ECi+Wg==, tableContent=null), ArticleFig(id=1200061229545910662, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=EN, label=Tab.1, caption=

PCR primer sequence

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
GAPDH

上游: ATGGGTGTGAACCACGAGA
下游: CAGGGATGATGTTCTGGGCA

IL-6

上游: CACAGAGGATACCACTCCCAACAGA
下游: ACAATCAGAATTGCCATTGCACAAC

TNF-α

上游: AGCACAGAAAGCATGATCCG
下游: CTGATGAGAGGGAGGCCATT

iNOS

上游: TTGGCTCCAGCATGTACCCT
下游: TCCTGCCCACTGAGTTCGTC

IL-10

上游: GCTGGACAACATACTGCTAACCG
下游: CACAGGGGAGAAATCGATGACAG

Arg-1

上游: ATCGTGTACATTGGCTTGCG
下游: CGTCGACATCAAAGCTCAGG

), ArticleFig(id=1200061229625602439, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1200023154757304884, language=CN, label=表1, caption=

PCR引物序列

, figureFileSmall=null, figureFileBig=null, tableContent=
基因引物序列(5'-3')
GAPDH

上游: ATGGGTGTGAACCACGAGA
下游: CAGGGATGATGTTCTGGGCA

IL-6

上游: CACAGAGGATACCACTCCCAACAGA
下游: ACAATCAGAATTGCCATTGCACAAC

TNF-α

上游: AGCACAGAAAGCATGATCCG
下游: CTGATGAGAGGGAGGCCATT

iNOS

上游: TTGGCTCCAGCATGTACCCT
下游: TCCTGCCCACTGAGTTCGTC

IL-10

上游: GCTGGACAACATACTGCTAACCG
下游: CACAGGGGAGAAATCGATGACAG

Arg-1

上游: ATCGTGTACATTGGCTTGCG
下游: CGTCGACATCAAAGCTCAGG

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维生素A缺乏调节肺泡巨噬细胞M1极化在新生大鼠ARDS中的作用及其机制
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曾毅文 , 龚放 *
解放军医学杂志 | 基础研究 2023,48(10): 1144-1152
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解放军医学杂志 | 基础研究 2023, 48(10): 1144-1152
维生素A缺乏调节肺泡巨噬细胞M1极化在新生大鼠ARDS中的作用及其机制
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曾毅文, 龚放*
作者信息
  • 重庆医科大学附属永川医院儿科，重庆 402160

    • 曾毅文，硕士研究生，副主任医师，主要从事新生儿疾病方面的研究

通讯作者:

龚放，E-mail：
Effect and mechanism of vitamin A deficiency in regulating M1 polarization of alveolar macrophage in neonatal rats with ARDS
Yi-Wen Zeng, Fang Gong*
Affiliations
  • Department of Pediatrics, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing 402160, China
出版时间: 2023-10-28 doi: 10.11855/j.issn.0577-7402.2420.2023.0619
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摘要
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目的 探讨维生素A缺乏(VAD)调节肺泡巨噬细胞极化在新生大鼠急性呼吸窘迫综合征(ARDS)中的作用及其机制。方法 将60只新生SD大鼠分为维生素A正常对照组(VAN ctrl组，n=10)、维生素A正常组(VAN组，n=10)、维生素A缺乏对照组(VAD ctrl组，n=10)、维生素A缺乏组(VAD组，n=10)、维生素A挽救对照组(VADR ctrl组，n=10)及维生素A挽救组 (VADR组，n=10)，其中，VADR ctrl及VADR组SD大鼠于生后第2天一次性给予腹腔注射25 µg VA。6组新生大鼠分别予以脂多糖(LPS)建立ARDS新生大鼠模型并收集血清及肺组织标本。记录建模前各组新生大鼠的体重，采用May-Grunwald-Giemsa染色法检测肺泡灌洗液(BALF)中主要细胞数量，HE染色观察肺组织病理损伤情况，免疫荧光染色评估肺泡巨噬细胞极化情况，qRT-PCR、ELISA检测肺泡巨噬细胞极化下游标志物诱导型一氧化氮合酶(iNOS)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、IL-10、精氨酸酶1(Arg-1)等炎性因子的表达情况，比色法检测肺组织氧化应激标志物超氧化物歧化酶(SOD)、丙二醛(MDA)含量，TUNEL检测细胞凋亡情况。结果 与VAN组新生大鼠比较，VAD组新生大鼠体重较轻、体格偏小、毛发稀疏，而VADR组新生大鼠体重、一般情况无明显变化；与VAD组比较，VADR组新生大鼠体重增加，毛发光亮。与VAN组比较，VAD组ARDS新生大鼠肺部损伤加重，BALF中主要细胞数量增加、肺泡巨噬细胞M1极化激活(P<0.05)，M1极化标志物iNOS、IL-6、TNF-α、CD86表达水平明显升高(P<0.05)，氧化应激标志物MDA含量增多(P<0.05)，细胞凋亡增加(P<0.05)，SOD活性降低(P<0.05)，而IL-10、Arg-1水平差异无统计学意义(P>0.05)；与VAN组相比，VADR组新生大鼠巨噬细胞M1极化及TNF-α、IL-6、SOD、MDA、IL-10、Arg-1水平等差异均无统计学意义(P>0.05)；与VAD组比较，VADR组ARDS新生大鼠肺部损伤明显减轻，肺泡巨噬细胞数量及肺泡巨噬细胞M1极化减少(P<0.05)，且M1极化标志物iNOS、IL-6、TNF-α、CD86表达水平降低(P<0.05)，氧化应激标志物MDA含量及细胞凋亡减少(P<0.05)，SOD活性增加(P<0.05)。结论 VAD可通过调节肺泡巨噬细胞M1极化，上调M1极化下游炎症标志物表达，增加肺部氧化应激及细胞凋亡，从而加重新生大鼠ARDS的肺部损伤。

维生素A缺乏  /  新生儿  /  急性呼吸窘迫综合征  /  肺泡巨噬细胞M1极化  /  氧化应激  /  炎性因子

Objective To investigate the effect and its mechanism of vitamin A (VA) deficiency (VAD) on regulating alveolar macrophage polarization in neonatal rats with acute respiratory distress syndrome (ARDS). Methods Sixty neonatal SD rats were divided into vitamin A normal control group (VAN ctrl group, n=10), normal vitamin A group (VAN group, n=10), vitamin A deficiency control group (VAD ctrl group, n=10), vitamin A deficiency group (VAD group, n=10), vitamin A rescue control group (VADR ctrl group, n=10) and vitamin A rescue group (VADR group, n=10). The VADR ctrl and VADR groups were injected with 25 µg VA at the second day after birth. All the neonatal rats were given lipopolysaccharide (LPS) to establish the neonatal rat model of ARDS, and serum and lung tissue samples were collected. The weight of newborn rats in each group was recorded before modeling, the May-Grunwald-Giemsa staining was performed to observe the number of main cells in bronchoalveolar lavage fluid (BALF), and HE staining was used to detect the pathological damage of lung tissue. The polarization of alveolar macrophages was evaluated by immunofluorescence. qRT-PCR and ELISA were performed to detected the expression of downstream markers of the polarization of alveolar macrophages inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-10 and arginase-1 (Arg-1). The content of superoxide dismutase (SOD) and malondialdehyde (MDA) in lung tissue were calculated by colorimetric method, and cell apoptosis was detected by TUNEL. Results Compared with the neonatal rats in VAN group, the neonatal rats in VAD group had lower body weight, small physique, and sparse hair, while the body weight and general condition of the newborn rats in the VADR group did not change significantly. Compared with the VAD group, the neonatal rats in VADR group gained weight and shiny hair. Compared with VAN group, the lung damage of ARDS neonatal rats in VAD group was aggravated, the number of major cells in BALF increased, the M1 polarization of alveolar macrophages activated (P<0.05), the expression levels of M1 polarization markers iNOS, IL-6, TNF-α and CD86 increased significantly (P<0.05), the content of oxidative stress marker MDA and cell apoptosis increased (P<0.05), SOD activity decreased (P<0.05), while the levels of IL-10 and Arg-1 were not statistically significant (P>0.05); Compared with VAN group, there were no significant differences in macrophage M1 polarization, TNF-α, IL-6, SOD, MDA, IL-10 and Arg-1 in newborn rats in VADR group (P>0.05). Compared with VAD group, the lung damage of ARDS neonatal rats in VADR group was significantly reduced, the number of alveolar macrophages and the polarization of alveolar macrophages M1 decreased (P<0.05), the expression levels of M1 polarization markers iNOS, IL-6, TNF-α and CD86 decreased (P<0.05), the content of the oxidative stress marker MDA and cell apoptosis decreased (P<0.05), and the SOD activity enhanced (P<0.05). Conclusion VAD could regulate the M1 polarization of alveolar macrophages, up-regulated the expression of inflammatory markers downstream of M1 polarization, increased pulmonary oxidative stress and apoptosis, and aggravated ARDS in neonatal rats.

vitamin A deficiency  /  newborn  /  acute respiratory distress syndrome  /  alveolar macrophage M1 polarization  /  oxidative stress  /  inflammatory factors
曾毅文, 龚放. 维生素A缺乏调节肺泡巨噬细胞M1极化在新生大鼠ARDS中的作用及其机制. 解放军医学杂志, 2023 , 48 (10) : 1144 -1152 . DOI: 10.11855/j.issn.0577-7402.2420.2023.0619
Yi-Wen Zeng, Fang Gong. Effect and mechanism of vitamin A deficiency in regulating M1 polarization of alveolar macrophage in neonatal rats with ARDS[J]. Medical Journal of Chinese People’s Liberation Army, 2023 , 48 (10) : 1144 -1152 . DOI: 10.11855/j.issn.0577-7402.2420.2023.0619
正文
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新生儿急性呼吸窘迫综合征(acute respiratory distress syndrome，ARDS)是威胁新生儿生命健康的主要疾病之一[1]。在新生儿重症监护室(neonatal intensive care unit，NICU)住院治疗的患儿中，新生儿ARDS发病率为10%，病死率高达35%~46%[2]。ARDS临床表现为气促、呼吸窘迫、低氧血症、双肺透光度降低甚至白肺等[3]。维生素A(VA)作为人体代谢必需的微量营养素，可参与胎儿肺部早期的发育并影响肺部的免疫功能[4]。不同地区新生儿中维生素A缺乏(vitamin A deficiency，VAD)的发生率虽然不同，但总体均较高[5]。目前，有研究发现，发生ARDS的早产儿血清VA水平较同胎龄未发生ARDS的早产儿更低，且VAD早产儿更容易发生ARDS[6]；Elfarargy等[7]发现，VAD可加重ARDS的严重程度，并可作为新生儿ARDS发展和严重程度的预测指标。以上研究结果均提示VAD与新生儿ARDS的严重程度密切相关，但其机制尚未阐明。本课题组前期建立VAD新生大鼠ARDS模型，检测肺泡灌洗液(BALF)时发现肺泡巨噬细胞为主要的差异细胞[8]。本研究拟检测肺泡巨噬细胞M1及M2型的极化情况，探讨VAD调节ARDS的作用及其机制，旨在改善新生儿ARDS的预后，为临床防治该疾病提供参考。
1 材料与方法
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1.1 实验动物及试剂
54只180~220 g SPF级SD大鼠，其中雌鼠36只，雄鼠18只，购自重庆医科大学动物中心。RNA提取及反转录试剂盒(日本TaKaRa公司)；CD206、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)及诱导型一氧化氮合酶(iNOS)等ELISA试剂盒(美国Abcam公司)；丙二醛(MDA)测定试剂盒(南京建成科技有限公司)；超氧化物歧化酶(SOD)及TUNEL检测试剂盒(上海碧云天生物技术有限公司)；F4/80抗体(美国CST公司)；CD86抗体(武汉三鹰生物技术有限公司)；VAD饲料及VA正常(VAN)饲料(常州鼠一鼠二生物科技有限公司)，脂多糖(LPS，美国Sigma-Aldrich公司)；RNA引物(上海生物生工有限公司)。本研究已通过动物伦理委员会审查(AMUWEC20219010)，并严格按照动物伦理委员会要求完成实验。
1.2 方法
1.2.1 qRT-动物模型的制备及分组
24只SD雌鼠在孕前2周给予VAD饲料(400 U VA/kg)喂养，12只SD雌鼠则予以VAN饲料(2300 U VA/kg)喂养；雄鼠均给予普通常规饲料。将SD大鼠按照雌∶雄=2∶1的比例合笼交配12 h后取出雌鼠，随后继续分别给予VAD及VAN饲料喂养至新生大鼠生后7 d，分别获得VAD (n=40)及VAN(n=20)新生大鼠模型[8]。从VAD新生大鼠中选取20只，于生后第2天一次性给予腹腔注射VA(25 µg VA/只，相当于人体内1个月1000 U/d的剂量)，获得VAD挽救(VAD recover，VADR)新生大鼠模型。将VAD新生大鼠分为VAD ctrl组(n=10)与VAD组(n=10)，VAN新生大鼠分为VAN ctrl组(n=10)与VAN组(n=10)，VADR新生大鼠分为VADR ctrl组(n=10)与VADR组(n=10)，其中，VAD ctrl组、VAN ctrl组及VADR ctrl组新生大鼠于生后第7天给予气管内灌注磷酸盐缓冲液(phosphate buffered saline，PBS)；VAD组、VAN组及VADR组新生大鼠于生后第7天给予气管内灌注LPS(5 mg/kg)4 h，分别构建各组新生大鼠ARDS模型[9]。
1.2.2 新生大鼠一般情况、BALF中细胞计数检测及病理学形态观察
记录各组新生大鼠一般情况。建模后4 h断颈处死各组新生大鼠，并以无菌PBS灌洗并收集BALF，予以过滤器过滤除去BALF中的黏液后，在4 ℃条件下、500 r/min离心5 min，涂片后用May-Grunwald-Giemsa染色，用于细胞分类计数。建模后4 h取肺组织标本，观察各组新生大鼠肺组织出血、水肿等情况。取肺组织样本固定、包埋、切片、染色、封片后，在显微镜下观察肺组织病理损伤情况。肺组织湿干比(W/D)检测：取新生大鼠右上肺叶称重；随后将样本置于60 ℃烘箱中72 h烘干，取出后再次称重；肺叶湿重与烘干后重量的比值即为W/D[10]。
1.2.3 ELISA检测血清中的VA含量及肺组织中炎性因子的表达情况
收集各组大鼠的血液，在4 ℃条件下，3000 r/min离心10 min，取上清液，用PBS稀释后检测各组大鼠的VA含量。取出冻存的新生大鼠肺组织标本，按比例(1 mg组织：5 μl裂解液)加入组织裂解液，加入蛋白酶抑制剂，匀浆后于4 ℃、12 000×g离心10 min，取上清液，各炎性因子指标检测严格按照试剂盒说明书操作。
1.2.4 比色法检测各组氧化应激情况
在100 mg肺组织中加入PBS匀浆，样本于4 ℃条件下、1000 r/min离心10 min，取上清。(1)SOD活性检测：各组样本分别取20 μl上清液后加入200 μl工作液；继续加入20 μl稀释缓冲液及20 μl酶工作液，充分混合；混合后样本于37 ℃培养箱中培养20 min；用酶标仪在450 nm处读数[11]。(2)MDA含量检测：酶标仪预热30 min以上，将各组待测标本分别加入MDA检测工作液、样本、蒸馏水，立即混匀；混合液在100 ℃水浴中保温60 min后，置于冰浴中冷却，常温10 000×g离心10 min。吸取200 μl上清液于微量玻璃比色皿中，测定各样本在532 nm处的吸光度[12]。
1.2.5 qRT-PCR检测肺部炎性因子水平
将肺组织样本按说明书步骤提取RNA后测定其浓度；将RNA反转录为cDNA，再以cDNA为模板进行扩增。以GAPDH为内参照，计算目的基因的相对表达量。引物序列见表1。
1.2.6 TUNEL检测各组细胞凋亡情况
肺组织标本进行包埋、切片及脱蜡后，用蛋白酶K工作液修复，破膜工作液破膜；按试剂说明书步骤加入相应试剂后将样本置于37 ℃湿盒内孵育2 h；BSA封闭后加入TDT酶，再给予dUTP于37 ℃下避光孵育50 min；滴加DAPI染液，避光孵育10 min，PBS洗3次；封片后置于Eclipse Ci正置荧光显微镜下观察并采集图像[13]。
1.2.7 免疫荧光染色检测肺泡巨噬细胞极化情况
取肺组织样本包埋后行冷冻组织切片，冷丙酮固定10 min后，再用10%山羊血清封闭1 h；加入F4/80抗体(1：50)孵育2 h后加入CD86抗体(1：200)，4 ℃孵育过夜。同时设置Isotype组，加入抗体同种属、同来源、同型的免疫球蛋白作为对照，以排除假阳性。4 ℃孵育过夜后，加入羊抗兔二抗(1：100，FITC标记)孵育1 h，DAPI染色后PBS洗3次，封片后置于荧光显微镜下观察[14]。
1.3 统计学处理
采用SPSS 22.0软件进行统计分析。所有数据均为计量资料，符合正态分布且方差齐时以$\bar{x}±s$表示，多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验；方差不齐时以M(Q1，Q3)表示，组间比较采用Kruskal-Wallis非参数检验。P<0.05为差异有统计学意义。
2 结果
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2.1 各组新生大鼠一般情况、血清VA含量及肺组织损伤情况比较
取生后7 d的新生大鼠建模。建模前，VAD新生大鼠体重较VAN新生大鼠体重减轻、体格偏小、毛发稀疏；而VADR组新生大鼠一般情况较好，毛发光滑，发育良好。与VAN组比较，VAD新生大鼠血清VA含量明显降低(P<0.05)(图1A)，而VADR组无明显差异；与VAD组比较，VADR组血清VA含量明显增高(P<0.05)(图1A)。与VAN组比较，VAD组新生大鼠表现为更为严重的气促、呼吸窘迫，肺部组织水肿、充血情况更为明显，W/D明显增高(P<0.05)，而VADR组无明显差异；与VAD组比较，VADR组新生大鼠肺组织水肿、充血情况明显减轻，W/D明显降低(P<0.05)(图1B)。HE染色结果显示，VAN ctrl组、VAD ctrl组及VADR ctrl组肺组织屏障完整，炎性细胞浸润较少；与VAN组比较，VAD组新生大鼠肺组织炎性细胞浸润更严重，屏障损伤更明显；与VAD组比较，VADR组新生大鼠肺组织炎性细胞浸润减少，肺损伤减轻(图1C)。
2.2 各组新生大鼠BALF中主要细胞数量比较
BALF中，肺泡巨噬细胞含量最高，且为主要的差异细胞。与VAN组比较，VAD组BALF中细胞总数、中性粒细胞计数、淋巴细胞计数均明显增多(P<0.05)，而VADR组细胞总数、中性粒细胞计数、淋巴细胞计数差异无统计学意义；与VAD组比较，VADR组细胞总数、中性粒细胞计数、淋巴细胞计数均明显减少(P<0.05)。进一步检测BALF中肺泡巨噬细胞数量发现，与VAN组比较，VAD组BALF中巨噬细胞数增多(P<0.05)，而VADR组中巨噬细胞数差异无统计学意义；与VAD组比较，VADR组中肺泡巨噬细胞数明显减少(P<0.05)。而VAN ctrl组、VAD ctrl组及VADR ctrl组所有指标差异均无统计学意义(P>0.05)(图2)。
2.3 各组新生大鼠肺泡巨噬细胞极化及炎性因子表达情况比较
免疫荧光染色检测显示，与VAN组比较，VAD组肺泡巨噬细胞M1标志物CD86表达水平明显升高(P<0.05)，而VADR组差异无统计学意义(P>0.05)；与VAD组比较，VADR组肺泡巨噬细胞M1标志物CD86表达水平明显降低(P<0.05)。与VAN组比较，VAD组巨噬细胞M1极化免疫荧光强度增强(P<0.05)，而VADR组差异无统计学意义(P>0.05)(图3)。三组间M2极化下游标志物IL-10、Arg-1 mRNA水平差异均无统计学意义(P>0.05，图4A)。与VAN组比较，VAD组巨噬细胞M1型分泌的炎性因子iNOS、IL-6、TNF-α mRNA及蛋白表达水平均明显升高(P<0.05)，而VADR组差异无统计学意义(P>0.05)；与VAD组比较，VADR组新生大鼠iNOS、IL-6、TNF-α mRNA及蛋白表达水平均明显降低(P<0.05)(图4B、C)。而VAN ctrl组、VAD ctrl组及VADR ctrl组所有指标差异均无统计学意义(P>0.05)(图3-4)。
2.4 各组新生大鼠肺组织细胞凋亡及氧化应激标志物比较
与VAN组比较，VAD组新生大鼠肺部组织细胞凋亡指数明显增高(P<0.05)，而VADR组差异无统计学意义；与VAD组比较，VADR组新生大鼠肺部组织细胞凋亡指数明显降低(P<0.05)(图5A、B)。与VAN组比较，VAD组新生大鼠肺组织SOD活性降低、MDA含量增高(P<0.05)，而VADR组差异无统计学意义；与VAD组比较，VADR组新生大鼠肺组织SOD活性增强、MDA含量降低(P<0.05)(图5C)。而VAN ctrl组、VAD ctrl组及VADR ctrl组所有指标差异均无统计学意义(P>0.05)(图5)。
3 讨论
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ARDS是新生儿常见的临床危重症之一，早期防治对改善新生儿ARDS预后具有重要意义[15]。因此，本研究建立VAD及VADR新生大鼠ARDS模型，检测BALF中的主要细胞时发现，肺泡巨噬细胞含量最高，且为主要的差异细胞。肺泡巨噬细胞M1极化在ARDS的启动过程中发挥关键作用[16]，其极化可促进下游标志物iNOS、TNF-α、IL-6等炎性因子的表达，诱导ARDS肺部损伤[17]。Deng等[18]发现，间充质干细胞可通过增加肺泡巨噬细胞M2极化，增强肺泡巨噬细胞的吞噬能力，促进ARDS肺损伤的修复。
VA是维持人体代谢的必需营养素，但由于其难以通过胎盘进入胎儿体内，因此新生儿血清和肝脏中的VA含量明显低于母体。围产期发生的VAD不仅可影响胎儿免疫器官的发育，还可增加肺部疾病的感染风险[19]。本研究采用Antoine等[8]的方法建立VAD大鼠模型，并参考Zhen等[9]的方法建立VADR新生大鼠模型，结果显示，与VAN组比较，VAD组新生大鼠血清VA含量明显降低，且一般情况较差，毛发稀疏，体格偏小，反应欠佳；与VAD组比较，VADR组新生大鼠血清VA含量增加，一般情况改善，毛发光亮，反应尚可。提示VAD及VADR新生大鼠模型建立成功，符合现有的研究结果，且VAD可影响新生儿的生长发育及免疫功能。
VA参与了早期的肺发育、肺泡屏障形成及组织再生，在感染诱导的免疫反应中发挥重要作用。视黄酸是VA的主要活性形式，在调节早期的肺发育、促进肺泡的形成及分支形态发生、维持细胞增殖及合成肺表面活性物质中具有重要价值，还可促进肺表面活性物质蛋白C的表达，并预防ARDS的发生。与健康儿童比较，VAD患儿的呼吸道感染发病率约高2倍；反复感染的患儿VA水平降低，补充VA则可缓解新生儿肺炎链球菌诱导的肺损伤[20]。程晨等[21]发现，发生ARDS的早产儿血清VA水平较同胎龄未发生ARDS的早产儿低。Elfarargy等[7]发现，VAD可加重ARDS的严重程度，并可作为新生儿ARDS发展和严重程度的预测指标。本研究发现，与VAN组比较，VAD组新生大鼠表现为更为严重的肺部损伤，组织水肿、坏死、炎性细胞及免疫细胞聚集、屏障破坏，而补充VA则可减轻VAD新生大鼠的肺部损伤、组织水肿及炎性细胞聚集，提示VAD与儿童尤其是新生儿ARDS的严重程度密切相关。但顾志勇[22]发现，血浆VA浓度与ARDS疾病的发生无明显关系，研究结果出现争议可能与ARDS的严重程度有关，即机体存在轻度ARDS时具有自我免疫调节功能，VAD对ARDS的影响较小，而存在中重度ARDS时，VAD则可诱导免疫失衡，加重ARDS肺损伤。
此外，本研究建立VAD及VADR新生大鼠ARDS模型，检测BALF中主要细胞时发现肺泡巨噬细胞为主要的差异细胞。而Zhen等[9]发现，VAD可通过调节巨噬细胞M1与M2的平衡来参与新生儿的肺部慢性炎症，调控支气管肺部发育不良。为进一步探讨在ARDS中VAD对肺泡巨噬细胞极化的影响，本研究检测了各组大鼠M1及M2型标志物的表达情况，结果发现，与VAN组比较，VAD组新生大鼠肺泡巨噬细胞M1型极化增加，炎性因子TNF-α、IL-6及iNOS的表达水平明显升高，而VADR组新生大鼠补充VA后其肺部巨噬细胞M1型极化减轻，炎性因子表达水平明显降低。与VAN组比较，VAD组新生大鼠肺泡M2型极化及其下游标志物IL-10、Arg-1表达水平差异均无统计学意义，提示VAD主要是通过诱导巨噬细胞M1型极化来加重ARDS的肺部损伤。Gundra等[23]发现，VAD可调节单核细胞衍生巨噬细胞在替代激活过程中转化为组织驻留巨噬细胞的过程。Erkelens等[24]发现，肠道巨噬细胞通过VA和β葡聚糖受体抗体(Dectin-1)介导的信号转导来平衡炎症表达谱，调节肠道的炎症反应。Esteban-Pretel等[25]则认为，VA可影响肺泡上皮细胞和内皮细胞的发育，甚至通过调控免疫细胞来抑制炎症对内皮屏障造成的损害。从以上研究结果推测，VAD可能通过调节肺部免疫微环境，诱导巨噬细胞M1型极化，从而加重新生儿ARDS的肺部损伤。但VAD对肺泡巨噬细胞M2型极化虽有下调趋势，但差异无统计学意义，可能与LPS在诱导ARDS模型时的作用时间较短、对肺泡巨噬细胞M2极化作用影响较小有关。
视黄酸可通过增强细胞活力、促进更多细胞从G1期进入S期、抑制细胞凋亡来促进细胞增殖。在ARDS中，肺泡巨噬细胞M1极化可激活下游的炎症反应，并诱导氧化应激及细胞凋亡。Petiz等[26]发现，VA能够减轻氧化锌诱导的肝脏氧化应激，从而减轻肝脏损伤。本研究进一步检测各组新生大鼠肺组织的氧化应激及细胞凋亡情况发现，与VAN组比较，VAD组新生大鼠肺部损伤标志物MDA含量增多、SOD活性降低，且细胞凋亡增加；而VADR组新生大鼠补充VA后其肺部损伤标志物MDA含量降低、SOD活性增强，细胞凋亡减少，提示VAD可增加肺部氧化应激、炎症反应及细胞凋亡，从而加重新生大鼠ARDS肺部损伤。
综上所述，本研究发现，VAD与新生大鼠ARDS的严重程度有关，并可调节肺泡巨噬细胞M1型极化及其标志物iNOS、CD86的表达，增加肺部MDA含量，并下调SOD活性，上调炎性因子IL-6、TNF-α的表达及细胞凋亡，最终加重新生大鼠ARDS的肺部损伤。因此，在新生儿尤其是早产儿中，早期VA干预可改善新生儿ARDS的肺损伤严重程度及预后。但在复杂的机体免疫微环境中，VAD如何调节巨噬细胞M1型极化及具体分子信号通路仍有待进一步阐明。
基金
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  • 重庆市教委项目(KJQN201900420)
文献
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参考文献 引证文献
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2023年第48卷第10期
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doi: 10.11855/j.issn.0577-7402.2420.2023.0619
  • 接收时间：2022-11-18
  • 首发时间：2025-11-25
  • 出版时间：2023-10-28
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  • 收稿日期：2022-11-18
  • 录用日期：2022-11-28
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Chongqing Education Commission Project(KJQN201900420)
重庆市教委项目(KJQN201900420)
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    重庆医科大学附属永川医院儿科，重庆 402160

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龚放，E-mail：
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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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