CN115282279B - CNR2通过介导DCs成熟及功能作为脓毒症急性肺损伤治疗靶点的应用 - Google Patents
CNR2通过介导DCs成熟及功能作为脓毒症急性肺损伤治疗靶点的应用 Download PDFInfo
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Abstract
本发明公开了CNR2通过介导DCs成熟及功能作为脓毒症急性肺损伤治疗靶点的应用。本发明依据临床样本分析了DCs中CNR2信号与脓毒症急性肺损伤疾病的关联性，并通过动物实验检测CNR2信号对脓毒症急性肺损伤小鼠中DCs成熟及功能的影响，还通过动物实验检测条件性敲除DCs中CNR2表达对脓毒症急性肺损伤小鼠中DCs成熟及功能的影响。本发明首次系统地揭示了CNR2信号通过调控DCs对脓毒症急性肺损伤的分子机制，为研究治疗脓毒症急性肺损伤提供了一个新的靶点，并且可以将CNR2作为治疗靶点用于筛选治疗脓毒症急性肺损伤的靶向药物或治疗方式中的应用。
Description
技术领域
本发明涉及生物医用技术领域，尤其涉及一种CNR2通过介导DCs成熟及功能作为脓毒症急性肺损伤治疗靶点的应用。
背景技术
脓毒症是指病原微生物经过各种途径进入体内面引发的全身炎症反应综合征，是烧伤、创伤、缺氧以及外科术后常见的并发症，病死率较高。脓毒症患者常伴发多器官功能损伤，甚至出现多器官功能衰竭。肺脏是脓毒症病情发展过程中最容易波及的器官，脓毒症患者常常在早期就出现急性肺损伤(ALI)或急性呼吸窘迫综合征(ARDS)表现。
脓毒症急性肺损伤发病机制复杂，发病率和死亡率较高，其主要原因是机体免疫反应失调导致的促炎与抗炎失衡引起的炎症因子风暴，病理表现为炎症细胞浸润、内皮细胞损伤、肺水肿和炎症细胞募集为特征的综合征，临床表现为急性呼吸窘迫综合征。由于发病机制复杂，目前仍缺乏有效的治疗手段，死亡率高达40％[1,2]。因此探索发展安全有效的脓毒症急性肺损伤治疗新策略仍是该领域亟待解决的关键科学问题。
抑制脓毒症急性肺损伤时的树突状细胞(dendritic cells,DCs)成熟和功能可减轻肺部的炎症损伤[3]。然而在脓毒症急性肺损伤早期即可出现大量DCs成熟，导致严重的炎症损伤，因此，通过介导DCs的成熟及功能对治疗脓毒症急性肺损伤有重要意义。
大麻素受体CNR2在免疫细胞尤其DCs高表达，在呼吸道感染的免疫调节中发挥重要作用，CNR2可通过调控DCs与T细胞之间抗原提呈而发挥着免疫抑制作用，从而减轻及机体的炎症反应[4,5]。CNR2的激活可保护脓毒症急性肺损伤，通过纠正肺通透性、白细胞运输和保持紧密连接，显示对急性肺损伤、药物性肺损伤、气道高反应性、咳嗽中心、肺部炎症和纤维化的保护作用[6]。
参考文献
1.Abe T,Madotto F,Pham T,Nagata I,Uchida M,Tamiya N,Kurahashi K,Bellani G,Laffey JG,Investigators L-S et al:Epidemiology and patterns oftracheostomy practice in patients with acute respiratory dist He Q,Xiao F,Yuan Q,et al.Cannabinoid receptor 2:a potential novel therapeutic target forsepsis？[J].Acta Clin Belg,2019,74(2):70-74.ress syndrome in ICUs across50countries.Crit Care 2018,22(1):195.
2.Park I,Kim M,Choe K,Song E,Seo H,Hwang Y,Ahn J,Lee SH,Lee JH,Jo YHet al:Neutrophils disturb pulmonary microcirculation in sepsis-induced acutelung injury.Eur Respir J 2019,53(3).
3.Liu J,Zhang P S,Yu Q,et al.Losartan inhibits conventional dendriticcell maturation and Th1 and Th17 polarization responses:Nuovel mechanisms ofpreventive effects on lipopolysaccharide-induced acute lung injury[J].Int JMol Med,2012,29(2):269-76.
4.He Q,Xiao F,Yuan Q,et al.Cannabinoid receptor 2:a potential noveltherapeutic target for sepsis？[J].Acta Clin Belg,2019,74(2):70-74.
5.Kasten K R,Tschop J,Tschop M H,et al.The cannabinoid 2receptor as apotential therapeutic target for sepsis[J].Endocr Metab Immune Disord DrugTargets,2010,10(3):224-34.
6.Nagoor Meeran M F,Sharma C,Goyal S N,et al.CB2 receptor-selectiveagonists as candidates for targeting infection,inflammation,and immunity inSARS-CoV-2 infections[J].Drug Dev Res,2021,82(1):7-11.
发明内容
本发明的目的是提出一种CNR2通过介导DCs成熟及功能作为脓毒症急性肺损伤治疗靶点的应用。
本发明的目的将通过以下技术方案得以实现：
本发明的目的之一在于提供CNR2通过介导DCs成熟及功能作为脓毒症急性肺损伤治疗靶点的应用，CNR2作为脓毒症急性肺损伤的标志物的应用。
本发明的目的之二在于提供CNR2通过介导DCs成熟及功能作为脓毒症急性肺损伤治疗靶点的应用，其特征在于：CNR2作为脓毒症急性肺损伤的治疗靶点的应用。
本发明的目的之三在于提供CNR2通过介导DCs成熟及功能作为脓毒症急性肺损伤治疗靶点的应用，其特征在于：CNR2促进剂作为制备治疗脓毒症急性肺损伤的靶向药物或药物组合物的应用。
本发明的目的之四在于提供CNR2通过介导DCs成熟及功能作为脓毒症急性肺损伤治疗靶点的应用，其特征在于：CNR2作为标志物在制备脓毒症急性肺损伤的检测试剂或检测试剂盒中的应用。
脓毒症急性肺损伤发生时，DCs通过启动机体免疫反应，以消灭病原微生物，实现机体自我保护模式。当病原体被杀灭后，菌体裂解并释放出裂解成分进一步加剧免疫反应，引起DCs发生再次活化并迁移至炎症部位，将补体系统激活，诱发炎症反应的级联式放大形成炎症风暴造成肺实质细胞损伤是脓毒症急性肺损伤的病理基础，此时病情的发展不再依赖于病原体的存在而继续恶化，针对过度炎症反应的控制是治疗ALI的关键。因此，通过增强CNR2的表达，调节DCs的成熟，缓解脓毒症急性肺损伤的过度免疫，可降低脓毒症急性肺损伤患者的死亡率。
本发明的突出效果为：
本发明通过构建DC选择性缺失CNR2小鼠开展急性脓毒症肺损伤研究，实验结果表明，CNR2的表达水平增高可以介导DCs成熟及其功能障碍，在脓毒症急性肺损伤免疫调节中发挥关键作用，本发明首次系统地揭示了CNR2信号通过调控DCs对脓毒症急性肺损伤的分子机制，为研究治疗脓毒症急性肺损伤提供了一个新的靶点，并且可以将CNR2作为治疗靶点用于筛选治疗脓毒症急性肺损伤的靶向药物或治疗方式中的应用。
以下便结合实施例，对本发明的具体实施方式作进一步的详述，以使本发明技术方案更易于理解、掌握。
附图说明
图1为实施例1的不同分组患者外周血及肺泡灌洗液中CD11c+F4/80-CNR2+的表达水平；
图2为实施例1的脓毒症急性肺损伤患者及对照组患者外周血及肺泡灌洗液中CRN2+的mRNA表达水平；
图3为实施例1的脓毒症急性肺损伤患者与对照组患者肺泡灌洗液中CD80+、CD86+的表达水平；
图4为实施例2的H&E染色显示各组小鼠肺组织病理损伤改变；
图5为实施例2的免疫组化监测各组小鼠肺组织中CNR2、CD11c蛋白阳性表达水平；
图6为实施例2的各组小鼠肺泡灌洗液中CNR2的表达情况；
图7为实施例2的各组小鼠肺泡灌洗液中主要组织相容性复合体MHCII+的表达情况；
图8为实施例2的各组小鼠肺泡灌洗液中CD86+的表达情况；
图9为实施例2的各组小鼠肺泡灌洗液中CD80+的表达情况；
图10为实施例2的各组小鼠肺泡灌洗液中CD40+的表达情况；
图11为实施例2的各组小鼠肺泡灌洗液中CCR4+的表达情况；
图12为实施例2的各组小鼠肺泡灌洗液中CCR7+的表达情况；
图13为实施例2的各组小鼠肺泡灌洗液中促炎因子IL-6、IL-12、IL-18、TNF-a、IL-1β和MCP-1的表达水平；
图14A为实施例3的qRT-PCR检测CNR2△DC小鼠来源的BMDC中的CNR2 mRNA表达水平；
图14B为实施例3的Western Blot检测CNR2△DC小鼠BMDC中CNR2蛋白表达水平；
图15为实施例3的Western blot检测方法检测MHC-II+、CD40+、CD80+、CD86+、CCR4+、CCR7+的表达水平；
图16为实施例3的ELISA不同分组间小鼠肺泡灌洗液细胞因子水平的差异。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。
实施例1 DCs中CNR2信号与脓毒症急性肺损伤疾病的关联性分析
(1)选择我院重症医学科收治的脓毒症急性患者作为实验组，健康者作为对照组。纤支镜取肺泡灌洗液，且治疗期间至少行3次纤支镜肺泡灌洗治疗。
排除标准：①年龄＜18岁；②合并有囊性纤维病等严重肺部疾病；③合并其他严重感染者或类风湿关节炎、血管炎等患者；④肺泡灌洗液收集操作不合格者；⑤气管镜肺泡灌洗≤2次者；⑥存在支气管灌洗治疗禁忌症者。
肺泡灌洗液采集和指标测定：选择右肺中叶或左上叶舌段，注入0.9％氯化钠液之后，使用合适的负压(100mmHg，1mmHg＝0.133kPa)吸取肺泡灌洗液。
(2)ELISA检测脓毒症急性肺损伤患者及健康对照者血清中内源性大麻素水平；
(3)流式检测脓毒症急性肺损伤患者及健康对照者外周血中CRN2+CD11c+F4/80-细胞率；
(4)ELISA检测脓毒症急性肺损伤患者及健康对照者肺泡灌洗液中内源性大麻素水平；
(5)流式检测脓毒症急性肺损伤患者及健康对照者肺泡灌洗液中CRN2+CD11c+F4/80-细胞率；
本实施例的临床实验结果如图1所示：
图1是急性肺损伤患者及对照者外周血及肺泡灌洗液中CRN2+CD11c+F4/80-的表达水平。为了验证CNR2在脓毒症急性肺损伤中的作用，收集了脓毒症急性肺损伤患者及非脓毒症患者的外周血和肺泡灌洗液细胞进行流式细胞仪检测。因为CD11c为成熟的DCs和巨噬细胞表面标志物，F4/80是巨噬细胞的标志物，因此CD11c+F4/80-为DCs。先圈中CD11c+细胞，再进一步进行细分。左上象限为CD11c+F4/80+CNR2-细胞、左下象限为CD11c+F4/80-CNR2-细胞、右上象限为CD11c+F4/80+CNR2+细胞、右下象限为CD11c+F4/80-CNR2+细胞即所需统计的细胞。流式细胞仪检测结果发现与非脓毒症患者相比，脓毒症急性肺损伤患者的外周血和肺泡灌洗液细胞中CD11c+F4/80-CNR2+比率分别降低至1.43％和1.87左右。
图2是qRT-PCR检测急性肺损伤患者和对照组外周血及肺泡灌洗液中CRN2+CD11c+F4/80-的mRNA表达水平。进一步验证血液及肺泡灌洗液中CRN2+CD11c+F4/80-的差异，利用qRT-PCR检测外周血及肺泡灌洗液中CRN2+CD11c+F4/80-的mRNA表达水平，结果发现，脓毒症急性肺损伤患者的外周血和肺泡灌洗液中细胞的CNR2 mRNA表达水平显著降低。因此，进一步验证了CNR2在脓毒症急性肺损伤患者中表达率低，以上临床发现以及国内外相关文献提示：在脓毒症急性肺损伤时中CNR2表达率低，而DCs表达率高。因此内源性大麻素受体可能通过介导DCs的成熟及功能在脓毒症急性肺损伤中发挥着重要的作用。
图3是脓毒症急性肺损伤患者与对照组DCs成熟程度的差异。CD80+、CD86+等共刺激分子在成熟的DCs表面高表达，DCs通过共刺激分子(CD80+、CD86+、CD40+等)调控T细胞活化。流式细胞仪进一步检测两组患者肺泡灌洗液发现在脓毒症急性肺损伤患者中DCs成熟CD86+、CD80+明显增加。
综上所述，本实施例的临床实验结果发现脓毒症急性肺损伤患者肺泡灌洗液及外周血中CD11c+较对照组明显增加，且CD80+、CD86+DCs也在脓毒症急性肺损伤患者中显著增加。且与非脓毒症患者相比，脓毒症急性肺损伤患者外周血和肺泡灌洗液中CNR2的表达明显减少，提示CNR2可能通过介导DCs的成熟及功能抑制脓毒症急性肺损伤。
实施例2 CNR2通过介导DCs成熟及功能对脓毒症急性肺损伤小鼠的影响
(1)饲养C57BL/6小鼠，气管注射5mg/kg LPS，2h后尾静脉注射CNR2激动剂Hu308或拮抗剂SR144528，实验分组：①Sham；②Sham+Hu308；③Sham+SR144528；④LPS；⑤LPS+Hu308；⑥LPS+SR144528；
(2)每组小鼠经上述处理后，选择6h和24h两个时间点，收集小鼠的实验标本，收取肺泡灌洗液和外周血清。用4％多聚甲醛固定小鼠肺和肝、脾、肾等组织，将肺组织进行HE染色，并在光学显微镜下观察肺组织的病理变化，按照盲法进行肺病理损伤评分，评分内容包括肺泡水肿、肺间质水肿、炎症细胞浸润、肺泡壁的增厚程度、肺不张、透明膜形成。并使用免疫组化检测各组小鼠肺组织中CNR2、CD11c蛋白阳性表达水平；
(3)取各组小鼠肺泡灌洗液性进行流式细胞仪检测肺泡灌洗液中CD11c+F4/80-细胞率、DCs(CD11c+F4/80-)细胞CNR2+比例；MHC II+、CD40+、CD86+、CD80+比例；细胞CCR7+、CCR4+比例；ELISA检测各组小鼠肺泡灌洗液中TNF-a、IL-1β、IL-6、IL-18、MCP-1和IL-12因子表达水平；
本实施例的临床实验结果如图4-13所示：
图4是H&E染色检测C57BL/6ALI小鼠肺部病理损伤情况。构建脓毒症急性肺损伤小鼠模型，小鼠分组为①对照组(Sham)；②Sham+HU308(CNR2激动剂)；③Sham+SR144528(CNR2拮抗剂)；④脓毒症组(LPS)；⑤LPS+HU308；⑥LPS+SR144528。检测结果显示与10％DMSO的对照组相比，HU308(CNR2激动剂)组和SR144528(CNR2拮抗剂)组小鼠肺组织的肺泡排列规则，无炎症细胞浸润，证明两种药物本身不具有毒性。在LPS诱导脓毒症急性肺损伤后可以看到肺水肿、充血、肺间隔增厚且伴有炎性细胞渗出，符合脓毒症急性肺损伤的病理表现。与之相反的是，HU308给药能一定程度上减轻LPS诱导的小鼠肺组织结构损伤，炎症细胞浸润相对较少，肺间隔增厚不明显。而SR144528给药能在一定程度上加重LPS诱导的小鼠肺组织结构损伤。另外，与Sham组相比，LPS诱导小鼠脓毒症急性肺损伤后表现为肺组织病理损伤评分显著升高，而Hu308处理后能明显降低小鼠肺组织病理评分，SR144528治疗后小鼠肺组织损伤评分则明显增高。
图5是ALI小鼠不同分组之间CD11c蛋白和CNR2阳性表达水平的差异显示：未经LPS诱导的小鼠(10％DMSO组、Hu308组以及SR144528组)。前三组肺组织中CD11c阳性细胞比例接近，经LPS诱导刺激后，肺组织中CD11c阳性细胞比率显著升高。而Hu308给药能明显降低LPS诱导的急性肺损伤组织中CD11c阳性细胞比率，SR144528给药则增加LPS诱导的急性肺损伤组织中CD11c阳性细胞比率。以上结果表明脓毒症急性肺损伤发生时，肺组织内成熟的DCs明显增多，而CNR2减少，当利用CNR2激动剂后使CNR2表达增加，而CD11c蛋白表达明显减少，因此可以说明CNR2的增加可通过抑制DCs的成熟进一步减轻肺部的炎症反应。
图6是脓毒症急性肺损伤小鼠不同分组之间CNR2、CD11c蛋白阳性表达水平的差异。收集各组肺泡灌洗液中的细胞进行流式检测。CD11c+F4/80-CNR2+细胞为所需统计的细胞。结果显示与对阴性对照组相比，LPS诱导刺激后，CD11c+F4/80-CNR2+细胞降低至9％左右。而HU308能提升LPS诱导刺激肺泡灌洗液中CD11c+F4/80-CNR2+细胞比例至12％左右，与之相反的是SR144528则进一步抑制LPS诱导刺激的CD11c+F4/80-CNR2+细胞比例(5％左右)。
图7-12是不同分组间小鼠肺部经典DCs的变化。当机体受到感染或检测到肿瘤细胞时，未成熟的DC摄取抗原后分后为成熟的DCs，并将抗原提成给T细胞产生免疫反应。在适当的信号刺激下DCs分化为成熟的DCs并通过表达趋化因子受体、主要组织相容性复合体和共刺激分子及分泌细胞因子发挥免疫功能。DCs通过趋化因子受体CCR4+、CCR7+迁移至T细胞，通过MHC类分子(MHCI、MHCII)、共刺激分子(CD80+、CD86+、CD40+等)调控T细胞活化，DCs分泌细胞因子进一步调控T细胞活性。为了进一步验证脓毒症急性肺损伤时CNR2能否调节DCs的成熟及功能，是否对DCs相关免疫细胞的数量及活化产生影响，我们通过流式细胞仪检测不同分组小鼠肺部免疫细胞的比率及活化指标。根据流式结果可知，LPS诱导刺激下，趋化因子受体CCR4+、CCR7+，共刺激分子CD80+、CD86+、CD40+以及MHC-II表达升高。而HU308给药后则在一定程度上抑制了MHC-II+、CD40+、CD80+、CD86+、CCR4+、CCR7+的表达，与之相反的是，SR144528给药则进一步促进了MHC-II+、CD86+和CCR4+因子的表达，但对CD40+、CD80+和CCR7+的影响不明显。以上结果初步表明CNR2信号能够影响LPS诱导的小鼠脓毒症急性肺损伤中DCs的成熟及功能。
图13是不同分组间小鼠肺泡灌洗液细胞因子水平的差异。TNF-α能激活DCs，参与抗原提呈以诱导机体免疫应答，并协同刺激T细胞的增殖从而参与特异性免疫调节。IL-1β与抗原协同作用，可使CD4+T细胞活化，并促进B细胞生长和分化，另外促进单核-巨噬细胞的抗原能力。IL-6是活化的T细胞产生的淋巴因子。细胞因子IL-12在参与T细胞的活化和抗原提呈等的免疫应答中起到非常重要的作用。IL-18可刺激T细胞分泌多种细胞因子，加重炎症反应。MCP-1细胞表面的受体为CCR4，在参与炎症反应过程中发挥重要的作用。在本研究中发现：LPS诱导刺激下，小鼠BALF中促炎因子IL-6、IL-12、IL-18、TNF-a、IL-1β和MCP-1的表达明显升高，而激活CNR2(HU308给药)后肺泡灌洗液中的这些细胞因子显著降低，相反抑制CNR2信号(SR144528给药)后能进一步加重LPS诱导刺激下相关因子的表达(TNF-a、IL-12、IL-18进一步升高，IL-1β、IL-6和MCP-1变化不明显)。由此可见，改变CNR2信号能够影响LPS诱导的急性肺损伤相关促炎因子的释放。
因此，根据以上实验结果可以初步说明CNR2可通过介导DCs成熟及功能抑制脓毒症急性肺损伤的炎症反应。
实施例3条件性敲除DCs中CNR2表达，反向验证对脓毒症急性肺损伤小鼠中DCs成熟及功能的影响
(1)基因敲除小鼠的建立：构建了CNR2f/f小鼠，并与CD11c-Cre小鼠杂交，繁育了DC细胞中特异性缺失CNR2受体的CNR2ΔDC小鼠，并通过上述方法构建脓毒症急性肺损伤小鼠模型。将以上小鼠建立LPS诱导的ALI小鼠模型，分组：①WT；②CNR2f/f；③CNR2ΔDC；④WT+LPS；⑤CNR2f/f+LPS；⑥CNR2ΔDC+LPS；
(2)每组小鼠经上述处理后，选择6h和24h两个时间点，收集小鼠的实验标本，收取肺泡灌洗液和外周血清。用4％多聚甲醛固定小鼠肺和肝、脾、肾等组织，将肺组织进行HE染色，并在光学显微镜下观察肺组织的病理变化，按照盲法进行肺病理损伤评分，评分内容包括肺泡水肿、肺间质水肿、炎症细胞浸润、肺泡壁的增厚程度、肺不张、透明膜形成。并使用免疫组化检测各组小鼠肺组织中CNR2、CD11c蛋白阳性表达水平；
(3)取各组小鼠肺泡灌洗液性进行流式细胞仪检测肺泡灌洗液中CD11c+F4/80-细胞率、DCs(CD11c+F4/80-)细胞CNR2+比例；MHC II+、CD40+、CD86+、CD80+比例；细胞CCR7+、CCR4+比例；ELISA检测各组小鼠肺泡灌洗液中TNF-a、IL-1β、IL-6、IL-18、MCP-1和IL-12因子表达水平；
图14-16为本申请实施例提供的基因敲除小鼠的实验结果。利用条件性敲除小鼠进一步验证DCs中CNR2表达对脓毒症急性肺损伤小鼠肺组织DCs成熟及功能的影响。首先建立CNR2f/f小鼠，将CNR2f/f小鼠与CD11cCre小鼠杂交建立出特异性敲除DCs中CNR2的纯合子小鼠(CD11cCreCNR2f/f，即CNR2△DC)和CD11c-Cre重组酶阴性对照组小鼠(CNR2f/f对照)。分别取CNR2f/f小鼠和CNR2△DC小鼠的骨髓细胞，体外诱导分化为BMDC，分别采用qRT-PCR和Western blot分析CNR2的表达，相比于CNR2f/f小鼠来源的BMDC而言，CNR2△DC小鼠来源的BMDC中的CNR2 mRNA表达水平显著降低(p＜0.001)(如图14A所示)，蛋白层面的检测也提示CNR2f/f小鼠DC细胞正常表达CNR2蛋白，而CNR2ΔDC小鼠DCs中CNR2蛋白几乎不表达(如图14B所示)，表明小鼠构建成功。
图15是Western blot检测不同分组间小鼠肺部经典DCs的变化。为进一步验证在脓毒症急性肺损伤中CNR2对DCs的成熟及功能的影响，构建获得了DCs选择性缺失的CNR2小鼠(CNR2ΔDC)，用Western blot检测方法检测小鼠肺泡灌洗液中DCs成熟相关细胞因子的表达，根据蛋白表达结果可知，LPS诱导刺激下MHC-II+、CD40+、CD80+、CD86+、CCR4+、CCR7+表达升高，而CNR2△DC组则进一步促进MHC-II+、CD40+、CD80+、CD86+、CCR4+、CCR7+的表达。以上数据进一步验证了CNR2能够影响LPS诱导的脓毒症小鼠肺组织中DCs的成熟及功能。由此推断，CNR2通过调控DCs的成熟及功能影响减轻小鼠脓毒性肺的损伤。
图16是ELISA不同分组间小鼠肺泡灌洗液细胞因子水平的差异。与Sham组相比，LPS小鼠BALF中促炎因子IL-6、IL-12、TNF-a、IL-1β、IL-18和MCP-1因子表达水平明显上升，而特异性敲除DCs中CNR2表达会明显加重LPS对小鼠促炎因子的分泌，表现在小鼠肺泡灌洗液中各中促炎症因子较其他组进一步上升。证实了干预DCs中CNR2的表达会加重脓毒症急性肺损伤，加重炎症反应。
总之，通过前期发现的脓毒症急性肺损伤的临床问题，以及动物实验的结果可以证实CNR2可以通过调控DCs成熟及其功能减轻脓毒症急性肺损伤。
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员在本发明揭露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应涵盖在本发明的保护范围之内。
Claims (1)
1.体外检测DCs中CNR2表达水平的试剂在用于制备脓毒症急性肺损伤中的检测试剂中的应用。
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