利多卡因抑制基质金属蛋白酶活性改善脂多糖诱导的小鼠急性肺损伤的机制研究

郑彬彬; 张嘉男; 范轶鑫; 胡亮; 刘文涛; 王雪融

doi:10.11665/j.issn.1000-5048.20200208

利多卡因抑制基质金属蛋白酶活性改善脂多糖诱导的小鼠急性肺损伤的机制研究

南京医科大学基础医学院

基金项目: 南京医科大学“科技创新基金”重大项目资助(No.2017NJMUCX004)；江苏省自然科学基金资助项目(No.BK20161033)

计量
- 文章访问数: 437
- HTML全文浏览量: 0
- PDF下载量: 1056
出版历程
- 刊出日期: 2020-04-24

Lidocaine attenuates LPS-induced acute lung injury in mice via an inhibition on matrix metalloproteinases

摘要

摘要: 考察利多卡因对脂多糖(lipopolysaccharide，LPS)诱导急性肺损伤(ALI)小鼠模型血浆中基质金属蛋白酶MMP-9和MMP-2活性的影响，并探讨其改善LPS诱导的急性肺损伤的作用机制。小鼠尾静脉注射不同浓度的利多卡因(2，4，8 mg/kg，iv)预处理30 min，再腹腔注射LPS 10 mg/kg刺激12 h建立小鼠ALI模型，测定小鼠7 d存活率及肺组织湿/干重比；Western blot法检测肺组织中p38 MAPK的磷酸化水平；明胶酶谱法测定血浆中MMP-9和MMP-2活性。实验结果发现，利多卡因预处理可剂量依赖性提高ALI小鼠存活率，降低肺组织湿/干重比，抑制血浆中MMP-9和MMP-2活性，并下调肺组织中p38的磷酸化水平。研究结果表明，利多卡因改善LPS诱导的小鼠急性肺损伤，其机制可能与抑制基质金属蛋白酶的活化有关。
- 利多卡因 /
- 脂多糖 /
- 急性肺损伤 /
- 基质金属蛋白酶
Abstract: The aim of the present study was to investigate the effects and mechanisms of lidocaine on lipopolysaccharide(LPS)-induced matrix metalloproteinase(MMP)-9 and MMP-2 activity in plasma, and the effects of lidocaine on LPS-induced acute lung injury(ALI). Mice were pretreated with lidocaine(2, 4, 8 mg/kg )for 30 minutes, and then treated with 10 mg/kg LPS(ip)for 12 h to induce ALI. The 7-day survival rate and lung wet/dry weight ratio of mice were monitored. Phosphorylation level of p38 was measured by western blot. The activity of MMP-9 and MMP-2 in plasma was evaluated by gelatin zymography. The results showed that pretreatment with lidocaine could significantly reduce the death rate of ALI mice as well as the lung wet/dry weight ratio in a dose-dependent manner and suppress the activity of MMP-9 and MMP-2 in plasma. Moreover, lidocaine also markedly inhibited LPS-induced upregulation of p-p38 in a dose-dependent manner. In conclusion, lidocaine alleviated LPS-induced acute lung injury by suppressing MMP-9 and MMP-2 activity.
- lidocaine /
- lipopolysaccharide /
- acute lung injury /
- matrix metalloproteinases

HTML全文

参考文献(19)

[1]	Hung YL, Fang SH, Wang SC, et al. Corylin protects LPS-induced sepsis and attenuates LPS-induced inflammatory response[J].Sci Rep,2017,7:46299.
[2]	Hirano Y,Aziz M,Yang WL,et al.Neutralization of osteopontin attenuates neutrophil migration in sepsis-induced acute lung injury[J].Crit Care,2015,19(1):53.
[3]	Matthay MA,Ware LB,Zimmerman GA.The acute respiratory distress syndrome[J].J Clin Invest,2012,122(8):2731-2740.
[4]	Rhee C,Dantes R,Epstein L,et al.Incidence and trends of sepsis in US hospitals using clinical vs claims data,2009-2014[J].Jama,2017,318(13):1241-1249.
[5]	Keck T,Balcom JH,Fernández-del Castillo C,et al.Matrix metalloproteinase-9 promotes neutrophil migration and alveolar capillary leakage in pancreatitis-associated lung injury in the rat[J].Gastroenterology,2002,122(1):188-201.
[6]	Sen AI, Foronjy RF, Shiomi T, et al. Loss of MMP-13 delays inflammatory response after acute hyperoxic lung injury[J].Proc Am Thorac Soc,2008,5(3):360-361.
[7]	Zhang F, Hu L, Wu YX, et al. Doxycycline alleviates paraquat-induced acute lung injury by inhibiting neutrophil-derived matrix metalloproteinase 9[J].Int Immunopharmacol,2019,72: 243-251.
[8]	Zinter MS,Delucchi KL,Kong MY,et al.Early plasma matrix metalloproteinase profiles.A novel pathway in pediatric acute respiratory distress syndrome[J].Am J Respir Crit Care Med,2019,199(2):181-189.
[9]	Chakrabarti S,Patel KD.Matrix metalloproteinase-2(MMP-2)and MMP-9 in pulmonary pathology[J].Exp Lung Res,2005,31(6):599-621.
[10]	Fan YX,Liu HJ,Li YX,et al.Quercetin ameliorates postoperative pain by suppressing matrix metalloproteinase in microglia[J].J China Pharm Univ(中国药科大学学报),2017,48(3):343-347.
[11]	Xu XL,Ji H,Gu SY,et al.Effects of astragaloside IV on experimental ventricular remodeling in mice and its mechanism from matrix metalloproteinase aspect[J].J China Pharm Univ(中国药科大学学报),2010,41(1):70-75.
[12]	Ricou B,Nicod L,Lacraz S,et al.Matrix metalloproteinases and TIMP in acute respiratory distress syndrome[J].Am J Respir Crit Care Med,1996,154(2 Pt 1):346-352.
[13]	Fujita M,Harada E,Ikegame S,et al.Doxycycline attenuated lung injury by its biological effect apart from its antimicrobial function[J].Pulm Pharmacol Ther,2007,20(6):669-675.
[14]	Carney DE, Mccann UG, Schiller HJ, et al. Metalloproteinase inhibition prevents acute respiratory distress syndrome[J].J Surg Res,2001,99(2):245-252.
[15]	Zhang Z,Zhou J,Liao C,et al.RAGE deficiency attenuates the protective effect of Lidocaine against sepsis-induced acute lung injury[J].Inflammation,2017,40(2):601-611.
[16]	Zhang H,Sha J,Feng X,et al.Dexmedetomidine ameliorates LPS induced acute lung injury via GSK-3β/STAT3-NF-κB signaling pathway in rats[J].Int Immunopharmacol,2019,74:105717.
[17]	Vassallo A,Wood AJ,Subburayalu J,et al.The counter-intuitive role of the neutrophil in the acute respiratory distress syndrome[J].Br Med Bull,2019,131(1):43-55.
[18]	Chen LJ,Ding YB,Ma PL,et al.The protective effect of lidocaine on lipopolysaccharide-induced acute lung injury in rats through NF-κB and p38 MAPK signaling pathway and excessive inflammatory responses[J].Eur Rev Med Pharmacol Sci,2018,22(7):2099-2108.
[19]	Shang N, Zhou RB. Interpretation of the updates in the use of antiarrhythmic drugs during resuscitation of patients with VF/pVT cardiac arrest or immediately after ROSC in 2018 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations[J].Chin General Practice(中国全科医学),2019,22(20):2393-2397.