丹参酮ⅡA通过调控中性粒细胞胞外诱捕网保护脓毒症小鼠急性肺损伤

张晓慧; 陈聪敏; 丁新耘; 董旭鹏; 马玉清

doi:10.16016/j.2097-0927.202206077

您当前的位置：

首页 >

文章列表页 >

丹参酮ⅡA通过调控中性粒细胞胞外诱捕网保护脓毒症小鼠急性肺损伤

基础医学 | 更新时间：2026-01-09

- 丹参酮ⅡA通过调控中性粒细胞胞外诱捕网保护脓毒症小鼠急性肺损伤
- TanshinoneⅡA protects acute lung injury in septic mice by regulating neutrophil extracellular traps
- 陆军军医大学学报 2023年45卷第1期页码：38-44
- 作者机构：
  
  1.730000 兰州，兰州大学第一临床医学院
  2.730000 兰州，兰州大学第一医院麻醉科
- 作者简介：
  
  [马玉清，E-mail：myq2392466@163.comMA Yuqing, E-mail: myq2392466@163.com
- 基金信息：
  
  甘肃省自然科学基金(21JRIRA077)
- DOI：10.16016/j.2097-0927.202206077
  中图分类号： R285.5;R563.9;R631.2
- 收稿：2022-06-13，
  
  修回：2022-07-31，
  
  纸质出版：2023-01-15
- 稿件说明：
移动端阅览
张晓慧, 陈聪敏, 丁新耘, 等. 丹参酮ⅡA通过调控中性粒细胞胞外诱捕网保护脓毒症小鼠急性肺损伤[J]. 陆军军医大学学报, 2023,45(1):38-44.

Xiaohui ZHANG, Congmin CHEN, Xinyun DING, et al. TanshinoneⅡA protects acute lung injury in septic mice by regulating neutrophil extracellular traps[J]. Journal of Army Medical University, 2023, 45(1): 38-44.
张晓慧, 陈聪敏, 丁新耘, 等. 丹参酮ⅡA通过调控中性粒细胞胞外诱捕网保护脓毒症小鼠急性肺损伤[J]. 陆军军医大学学报, 2023,45(1):38-44. DOI： 10.16016/j.2097-0927.202206077.

Xiaohui ZHANG, Congmin CHEN, Xinyun DING, et al. TanshinoneⅡA protects acute lung injury in septic mice by regulating neutrophil extracellular traps[J]. Journal of Army Medical University, 2023, 45(1): 38-44. DOI： 10.16016/j.2097-0927.202206077.

摘要

目的

研究丹参酮ⅡA(tanshinoneⅡA，TanⅡA)对脓毒症小鼠急性肺损伤(acute lung injury，ALI)作用，并探讨其对中性粒细胞胞外诱捕网(neutrophil extracellular traps，NETs)的影响及可能机制。

方法

采用腹腔注射脂多糖(lipopolysaccharide，LPS)建立小鼠脓毒症模型。雄性6~8周龄C57BL/6小鼠30只，随机数字表法分为5组(

=6)：①正常组(Nor组)；②脂多糖组(LPS组，腹腔注射LPS 10 mg/kg)；③丹参酮ⅡA组(LPS+TanⅡA组，LPS前30 min腹腔注射TanⅡA 30 mg/kg)；④LY294002组(LPS+LY294002组，提前注射LY294002 30 mg/kg)；⑤二甲基亚砜组(LPS+DMSO组，提前注射给药组等量DMSO)。造模12 h取材，计算肺系数，HE染色观察肺组织病理变化，ELISA检测肺组织炎症因子IL-1β、IL-10水平和NETs标志物MPO-DNA复合物、瓜氨酸化组蛋白H3(Cit H3)水平，Western blot检测PI3K/AKT信号通路的磷酸化水平。

结果

相较于Nor组，LPS组肺系数增加，HE染色显示肺组织受损，肺组织IL-1β水平升高(

0.05)，IL-10水平下降(

0.05)，MPO-DNA复合物、Cit H3均显著增加(

0.05)，p-PI3K和p-AKT水平升高(

0.05)。相较于LPS组，LPS+TanⅡA组和LPS+LY294002组肺系数降低，HE染色及肺损伤Smith评分显示肺组织病理损伤情况

减轻，肺组织IL-1β水平增加(

0.05)，IL-10水平降低(

0.05)，MPO-DNA复合物、Cit H3显著减少(

0.05)，p-PI3K和p-AKT水平降低(

0.05)。

结论

丹参酮ⅡA可以减轻脓毒症ALI，其机制可能是通过抑制PI3K/AKT信号通路，调控NETs水平，减轻炎症反应。

Abstract

Objective

To observe the effect of tanshinoneⅡA (TanⅡA) on acute lung injury (ALI) in septic mice

and to explore its effect on neutrophil extracellular traps (NETs) and its possible mechanism.

Methods

A mouse model of sepsis was established by intraperitoneal injection of lipopolysaccharide (LPS) at a dose of 10 mg/kg. Thirty male C57BL/6 mice aged 6~8 weeks were randomly divided into 5 groups (n=6): Normal group (Nor group)

LPS group

LPS+TanⅡA group (30 mg/kg TanⅡA was injected intraperitoneally 30 min before LPS injection)

LPS+LY294002 group (pre-injection of 30 mg/kg LY294002)

and LPS+DMSO group (pre-injection of the same amount of DMSO). At 12 h after modeling

the lung tissues were collected

lung coefficients were calculated

and pathological changes of lung tissue were observed with HE staining. ELISA was used to detect the levels of inflammatory factors IL-1β and IL-10 and NETs markers MPO-DNA complex and citrolinated histone H3 (Cit H3) in lung tissue. Western blotting was applied to detect the phosphorylation of the PI3K/AKT signaling pathway.

Results

Compared with the Nor group

the LPS group had an increased lung coefficient

significantly damaged lung tissue

increased levels of IL-1β (

0.05) and decreased level of IL-10 (

0.05)

and elevated MPO-DNA complex and Cit H3 levels (

0.05) as well as the levels of p-PI3K and p-AKT (

0.05). While

the above conditions were much better in the LPS+TanⅡA group and the LPS+LY294002 group than the LPS group

with decreased l

ung coefficient

alleviated lung injury by HE staining and Smith scores

increased level of IL-1β and decreased IL-10 level in the lung tissue (

0.05)

reduced levels of MPO-DNA complex and Cit H3 (

0.05) and p-PI3K and p-AKT (

0.05).

Conclusion

TanⅡA can alleviate sepsis-induced ALI

and its mechanism may be through inhibiting PI3K/AKT signaling pathway

regulating the level of NETs

and thus reducing the inflammatory response.

关键词

Keywords

references

FERNANDO S M, ROCHWERG B, SEELY A J E. Clinical implications of the third international consensus definitions for sepsis and septic shock (Sepsis-3)[J]. CMAJ, 2018, 190(36): E1058-E1059. DOI:10.1503/cmaj.170149.

XIE J F, WANG H L, KANG Y, et al . The epidemiology of sepsis in Chinese ICUs: a national cross-sectional survey[J ] . Crit Care Med, 2020, 48(3): e209-e218. DOI:10.1097/CCM.0000000000004155.

KUMAR V. Pulmonary innate immune response determines the outcome of inflammation during pneumonia and sepsis-associated acute lung injury[J]. Front Immunol, 2020, 11: 1722. DOI:10.3389/fimmu.2020.01722.

DENNING N L, AZIZ M, GURIEN S D, et al . DAMPs and NETs in Sepsis[J ] . Front Immunol, 2019, 10: 2536. DOI:10.3389/fimmu.2019.02536.

DING Z, DU F, RÖNNOW C F, et al . Actin-related protein 2/3 complex regulates neutrophil extracellular trap expulsion and lung damage in abdominal sepsis[J ] . Am J Physiol Lung Cell Mol Physiol, 2022, 322(5): L662-L672. DOI:10.1152/ajplung.00318.2021.

NWAFOR E, LU P, LI J W, et al . Traditional Chinese medicine of Salvia miltiorrhiza Bunge: a review of phytochemistry, pharmacology and pharmacokinetics[J ] . Tradit Med Res, 2021, 6(4): 35. DOI:10.53388/tmr20201027204.

ZHAO J Y, PU J, FAN J, et al . Tanshinone ⅡA prevents acute lung injury by regulating macrophage polarization[J ] . J Integr Med, 2022, 20(3): 274-280. DOI:10.1016/j.joim.2022.01.006.

ZHANG S, HUANG G, YUAN K, et al . Tanshinone ⅡA ameliorates chronic arthritis in mice by modulating neutrophil activities[J ] . Clin Exp Immunol, 2017, 190(1): 29-39. DOI:10.1111/cei.12993.

LI N, SUN W J, ZHOU X, et al . Dihydroartemisinin protects against dextran sulfate sodium-induced colitis in mice through inhibiting the PI3K/AKT and NF-κ B signaling pathways[J ] . Biomed Res Int, 2019, 2019: 1415809. DOI:10.1155/2019/1415809.

TAI H, JIANG X L, SONG N, et al . Tanshinone ⅡA combined with cyclosporine A alleviates lung apoptosis induced by renal ischemia-reperfusion in obese rats[J ] . Front Med (Lausanne), 2021, 8: 617393. DOI:10.3389/fmed.2021.617393

顾冬生, 严鸣光, 罗宇维, 等. LY294002对小鼠体内调节性T细胞的影响[J]. 中国组织工程研究与临床康复, 2009, 13(31): 6085-6088. DOI:10.3969/j.issn.1673-8225.2009.31.018.

GU D S, YAN M G, LUO Y W, et al . Effect of LY294002 on regulatory T cells in mice[J ] . Chin J Tissue Eng Res, 2009, 13(31): 6085-6088. DOI:10.3969/j.issn.1673-8225.2009.31.018.

LIU L Q, YAN M J, YANG R, et al . Adiponectin attenuates lipopolysaccharide-induced apoptosis by regulating the Cx43/PI3K/AKT pathway[J ] . Front Pharmacol, 2021, 12: 644225. DOI:10.3389/fphar.2021.644225.

HU S, HU H T, WANG R, et al . MicroRNA-29b prevents renal fibrosis by attenuating renal tubular epithelial cell-mesenchymal transition through targeting the PI3K/AKT pathway[J ] . Int Urol Nephrol, 2021, 53(9): 1941-1950. DOI:10.1007/s11255-021-02836-4.

王文龙, 林胜友, 卢宏达, 等. 氧化苦参碱对放射性肺损伤模型小鼠肺纤维化的改善作用及其机制研究[J]. 中国临床药理学杂志, 2020, 36(5): 503-506. DOI:10.13699/j.cnki.1001-6821.2020.05.007.

WANG W L, LIN S Y, LU H D, et al . Effect and mechanism of oxymatrine on pulmonary fibrosis in mice with radiation-induced pulmonary injury[J ] . Chin J Clin Pharmacol, 2020, 36(5): 503-506. DOI:10.13699/j.cnki.1001-6821.2020.05.007.

SMITH K M, MROZEK J D, SIMONTON S C, et al . Prolonged partial liquid ventilation using conventional and high-frequency ventilatory techniques: gas exchange and lung pathology in an animal model of respiratory distress syndrome[J ] . Crit Care Med, 1997, 25(11): 1888-1897. DOI:10.1097/00003246-199711000-00030.

薄禄龙, 卞金俊, 邓小明. 2016年脓毒症最新定义与诊断标准: 回归本质重新出发[J]. 中华麻醉学杂志, 2016, 36(3): 259-262. DOI:10.3760/cma.j.issn.0254-1416.2016.03.002.

BO L L, BIAN J J, DENG X M. New definition and clinical criteria for Sepsis and septic shock in 2016: back to the nature, head for the future[J]. Chin J Anesthesiol, 2016, 36(3): 259-262. DOI:10.3760/cma.j.issn.0254-1416.2016.03.002.

GUO R, LI L, SU J, et al . Pharmacological activity and mechanism of tanshinone ⅡA in related diseases[J ] . Drug Des Devel Ther, 2020, 14: 4735-4748. DOI:10.2147/DDDT.S266911.

QUAN M X, LV Y N, DAI Y, et al . Tanshinone ⅡA protects against lipopolysaccharide-induced lung injury through targeting Sirt1[J ] . J Pharm Pharmacol, 2019, 71(7): 1142-1151. DOI:10.1111/jphp.13087.

JIANG L X, WANG J H, JU J R, et al . Salvianolic acid B and sodium tanshinone Ⅱ A sulfonate prevent pulmonary fibrosis through anti-inflammatory and anti-fibrotic process[J ] . Eur J Pharmacol, 2020, 883: 173352. DOI:10.1016/j.ejphar.2020.173352.

MENG W, PAUNEL-GÖRGVLV A, FLOHÉ S, et al . Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial Sepsis in mice[J ] . Crit Care, 2012, 16(4): R137. DOI:10.1186/cc11442..

WANG Y P, GUO Y, WEN P S, et al . Three ingredients of safflower alleviate acute lung injury and inhibit NET release induced by lipopolysaccharide[J ] . Mediators Inflamm, 2020, 2020: 2720369. DOI:10.1155/2020/2720369.

GU Z T, LI L, LI Q, et al . Polydatin alleviates severe traumatic brain injury induced acute lung injury by inhibiting S100B mediated NETs formation[J ] . Int Immunopharmacol, 2021, 98: 107699. DOI:10.1016/j.intimp.2021.107699.

BRINKMANN V, REICHARD U, GOOSMANN C, et al . Neutrophil extracellular traps kill bacteria[J ] . Science, 2004, 303(5663): 1532-1535. DOI:10.1126/science.1092385.

BIRON B M, CHUNG C S, O'BRIEN X M, et al . Clamidine prevents histone 3 citrullination and neutrophil extracellular trap formation, and improves survival in a murine Sepsis model[J ] . J Innate Immun, 2017, 9(1): 22-32. DOI:10.1159/000448808.

SIL P, YOO D G, FLOYD M, et al . High throughput measurement of extracellular DNA release and quantitative NET formation in human neutrophils in vitro [J ] . J Vis Exp, 2016(112): 52779. DOI:10.3791/52779..

ALHUSSIEN M N, DANG A K. JAK3 and PI3K mediates the suppressive effects of interferon tau on neutrophil extracellular traps formation during peri-implantation period[J]. J Reproductive Immunol, 2021, 145: 103321. DOI:10.1016/j.jri.2021.103321.

YANG Z J, WANG S C, YIN K, et al . miR-1696/GPx3 axis is involved in oxidative stress mediated neutrophil extracellular traps inhibition in chicken neutrophils[J ] . J Cell Physiol, 2021, 236(5): 3688-3699. DOI:10.1002/jcp.30105.

MD MOKHTAR A H, MALIK I A, ABD AZIZ N, et al . LY294002, a PI3K pathway inhibitor, prevents leptin-induced adverse effects on spermatozoa in Sprague-Dawley rats[J ] . Andrologia, 2019, 51(3): e13196. DOI:10.1111/and.13196.

HUANG J H, NONG X P, CHEN Y L, et al . 3-O-trans-caffeoyloleanolic acid improves acute lung injury via anti-inflammation and antioxidative stress-involved PI3K/AKT pathway[J ] . Chem Biol Drug Des, 2021, 98(1): 114-126. DOI:10.1111/cbdd.13856..

CAI B N, GAN X F, HE J X, et al . Morin attenuates cigarette smoke-induced lung inflammation through inhibition of PI3K/AKT/NF-κB signaling pathway[J ] . Int Immunopharmacol, 2018, 63: 198-203. DOI:10.1016/j.intimp.2018.07.035.

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

地塞米松降低胸部开放伤合并海水灌注致急性肺损伤犬模型前B细胞集落促进因子水平

地塞米松和法舒地尔对油酸致小鼠急性肺损伤伤情的影响

部分液体通气联合伊洛前列素治疗兔油酸型急性肺损伤

不同伤情血清可有效激活IEC-6细胞PI3K/Akt通路

肺上皮屏障在油酸致肺损伤后肺水肿发生中的作用