呼吸机相关肺损伤患者血清及诱导痰液NLRP3炎症小体的表达及与其它炎症因子的相关性
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摘要
目的分析呼吸机相关肺损伤(VILI)患者血清及诱导痰液Nod样受体蛋白3(NLRP3)炎症小体及炎性因子的表达,探讨两者在VILI发病中的作用。方法测定76例VILI患者及30例健康体检者(对照组)的血清、诱导痰中NLRP3炎症小体的表达,以及血清中白介素1β(IL-1β),IL-18,IL-6和肿瘤坏死因子-α(TNF-α)等炎性指标。根据Murray肺损伤评分(LIS)将VILI患者分为两个亚组:轻、中度肺损伤组(LIS≤2.5分)、重度肺损伤组(LIS>2.5分)。分析各组NLRP3炎症小体与炎性因子的相关性。结果轻中度肺损伤组、重度肺损伤组血清、诱导痰中NLRP3炎症小体表达水平明显高于对照组[血清:106.3±29.3,131.1±37.1vs 79.2±27.3pg/ml;诱导痰:95.1±24.4,119.2±36.7vs 76.0±20.6pg/ml],重度肺损伤组上述指标亦明显高于轻中度肺损伤组(t=3.82,4.03,均P<0.05)。与对照组比较,轻中度肺损伤组、重度肺损伤组血清中IL-1β(8.7±2.4,11.6±2.7vs 5.5±1.9pg/ml),IL-18(11.3±3.4,15.6±4.7vs 4.5±1.3pg/ml),IL-6(46.4±12.1,74.6±24.8vs 6.4±1.8pg/ml),TNF-α(16.1±4.4,22.8±5.1vs 9.2±1.5ng/ml)水平明显升高;与轻中度肺损伤组比较,重度肺损伤组血清中各炎性因子水平亦明显升高(t=4.87,4.62,7.94,5.33,均P<0.05)。轻中度肺损伤组患者血清、诱导痰中NLRP3炎症小体浓度与IL-1β,IL-18均呈显著正相关(P<0.05)。重度肺损伤组患者血清、诱导痰中NLRP3炎症小体浓度与IL-1β,IL-18,IL-6,TNF-α均呈显著正相关(P<0.05)。结论 VILI患者血清、诱导痰中NLRP3表达明显上调,且与炎性因子密切相关,参与VILI的发生、发展,阻断NLRP3炎性小体的激活可能成为VILI的潜在治疗靶点。
Objective To investigate the expression of serum and phlegm NLRP3 inflammasome and inflammatory cytokines in patients with ventilator-induced lung injury(VILI),and explore the role of NLRP3 inflammasome and inflammatory cytokines in the onset of VILI.Methods The expression of NLRP3 in serum and phlegm,serum inflammatory indicators including interleukin 1β(IL-1β),IL-18,IL-6,tumor necrosis factor-α(TNF-α)in 76 patients with VILI and 30 cases of healthy physical examination(control group)were detected.These patients were divided into two groups according to the Murray lung injury score(LIS),including mild and moderate lung injury group(LIS≤2.5)and severe lung injury group(LIS>2.5).The correlation between NLRP3 inflammasome and inflammatory cytokines was analyzed in each group.Results Compared with control group,the level of NLRP3 inflammasome in serum and phlegm in mild and moderate lung injury group and severe lung injury group were increased significantly serum 106.3±29.3,131.1±37.1 vs 79.2±27.3 pg/ml,phlegm 95.1±24.4,119.2±36.7 vs 76.0±20.6 pg/ml,and these indicators were also increased significantly in severe lung injury group compared with mild and moderate lung injury group(t=3.82,4.03,all P<0.05).Compared with control group,the level of inflammatory cytokines in serum in mild and moderate lung injury group and severe lung injury group were increased significantly,and these indicators such as IL-1β(8.7±2.4,11.6±2.7 vs 5.5±1.9 pg/ml),IL-18(11.3±3.4,15.6±4.7 vs 4.5±1.3 pg/ml),IL-6(46.4±12.1,74.6±24.8 vs 6.4±1.8 pg/ml),TNF-α(16.1±4.4,22.8±5.1 vs 9.2±1.5 ng/ml)were also increased significantly in severe lung injury group compared with mild and moderate lung injury group(F=105.24,80.05,148.22 and 83.44,all P<0.05).NLRP3 inflammasome in serum and phlegm in patients with mild to moderate lung injury group were significantly positive correlated with IL-1βand IL-18(P<0.05).There was significant correlation between NLRP3 inflammasome in serum and phlegm in patients with severe lung injury group with IL-1β,bIL-18,IL-6 and TNF-α(P<0.05).Conclusion NLRP3 inflammasome in serum and phlegm of patients with VILI was over-expressed,and the expression of NLRP3 inflammasome and inflammatory cytokines was positively correlated,could be involved in the occurrence and development of VILI.Blocking the activation of NLRP3 inflammasome is expected to be as a new target in the treatment of VILI.
Objective To investigate the expression of serum and phlegm NLRP3 inflammasome and inflammatory cytokines in patients with ventilator-induced lung injury(VILI),and explore the role of NLRP3 inflammasome and inflammatory cytokines in the onset of VILI.Methods The expression of NLRP3 in serum and phlegm,serum inflammatory indicators including interleukin 1β(IL-1β),IL-18,IL-6,tumor necrosis factor-α(TNF-α)in 76 patients with VILI and 30 cases of healthy physical examination(control group)were detected.These patients were divided into two groups according to the Murray lung injury score(LIS),including mild and moderate lung injury group(LIS≤2.5)and severe lung injury group(LIS>2.5).The correlation between NLRP3 inflammasome and inflammatory cytokines was analyzed in each group.Results Compared with control group,the level of NLRP3 inflammasome in serum and phlegm in mild and moderate lung injury group and severe lung injury group were increased significantly serum 106.3±29.3,131.1±37.1 vs 79.2±27.3 pg/ml,phlegm 95.1±24.4,119.2±36.7 vs 76.0±20.6 pg/ml,and these indicators were also increased significantly in severe lung injury group compared with mild and moderate lung injury group(t=3.82,4.03,all P<0.05).Compared with control group,the level of inflammatory cytokines in serum in mild and moderate lung injury group and severe lung injury group were increased significantly,and these indicators such as IL-1β(8.7±2.4,11.6±2.7 vs 5.5±1.9 pg/ml),IL-18(11.3±3.4,15.6±4.7 vs 4.5±1.3 pg/ml),IL-6(46.4±12.1,74.6±24.8 vs 6.4±1.8 pg/ml),TNF-α(16.1±4.4,22.8±5.1 vs 9.2±1.5 ng/ml)were also increased significantly in severe lung injury group compared with mild and moderate lung injury group(F=105.24,80.05,148.22 and 83.44,all P<0.05).NLRP3 inflammasome in serum and phlegm in patients with mild to moderate lung injury group were significantly positive correlated with IL-1βand IL-18(P<0.05).There was significant correlation between NLRP3 inflammasome in serum and phlegm in patients with severe lung injury group with IL-1β,bIL-18,IL-6 and TNF-α(P<0.05).Conclusion NLRP3 inflammasome in serum and phlegm of patients with VILI was over-expressed,and the expression of NLRP3 inflammasome and inflammatory cytokines was positively correlated,could be involved in the occurrence and development of VILI.Blocking the activation of NLRP3 inflammasome is expected to be as a new target in the treatment of VILI.
引文
[1]NEEDHAM D M,COLANTUONI E,MENDEZTE-LLEZ P A,et al.Lung protective mechanical ventilation and two year survival in patients with acute lung injury:prospective cohort study[J].BMJ,2012,344:e2124.
[2]TRESCHAN T A,KAISERS W,SCHAEFER M S,et al.Ventilation with low tidal volumes during upper abdominal surgery does not improve postoperative lung function[J].Br J Anaesth,2012,109(2):263-271.
[3]赵婷婷,刘虹.呼吸机相关肺损伤的研究进展[J].临床医药文献杂志(电子版),2017,4(49):9701-9702.ZHAO Tingting,LIU Hong.Advances in research on ventilator-related lung injury[J].Journal of Clinical Medical Literature(Electronic Edition),2017,4(49):9701-9702.
[4]ZHENG F,XING S S,GONG Z S,et al.Silence of NLRP3 suppresses atherosclerosis and stabilizes plaques in apolipoprotein E-deficient mice[J].Mediators Inflamm,2014,2014(1):507208.
[5]WANG H Y,Lü C E,WANG S,et al.NLRP3inflammasome involves in the acute exacerbation of patients with chronic obstructive pulmonary disease[J].Inflammation,2018,11(6):1-13.
[6]中华医学会呼吸病学分会.急性肺损伤,急性呼吸窘迫综合征的诊断标准(草案)[J].中华结核和呼吸杂志,2000,23(4):203.Chinese Thoracic Society of Respiratory Medicine.Diagnostic criteria for acute lung injury,acute respiratory distress syndrome(draft)[J].Chinese Journal of Tuberculosis and Respiratory Diseases,2000,23(4):203.
[7]张国强,顾承东,朱宇清,等.急性生理学和慢性健康状态评分与急性肺损伤评分在重症SARS患者中的应用[J].中华流行病学杂志,2004,25(9):802-804.ZHANG Guoqiang,GU Chengdong,ZHU Yuqing,et al.Comparison between tow methods of acute physiology and chronic health evaluationⅢand acute lung injury scale to evaluate the severity and prognosis of severe acute respiratory syndrome[J].International Journal of Epidemid,2004,25(9):802-804.
[8]黄絮,詹庆元.呼吸机相关肺损伤的发生机制和处理对策[J].中华结核和呼吸杂志,2014,37(6):471-473.HUANG Xu,ZHAN Qingyuan.Mechanism and treatment of ventilator-related lung injury[J].Chinese Journal of Tuberculosis and Respiratory Diseases,2014,37(6):471-473.
[9]孟凡凡,齐晓林,黄奕江,等.乌司他丁干预对水下爆炸致兔急性肺损伤TNF-α表达的影响[J].现代检验医学杂志,2017,32(3):131-132,136.MENG Fanfan,QI Xiaolin,HUANG Yijiang,et al.Effect of ulinastatin on the expression of TNF-αin the rabbits with acute lung injury induced by underwater explosion[J].Journal of Modern Laboratory Medicine,2017,32(3):131-132,136.
[10]FUKUMOTO J,FUKUMOTO I,PARTHASARA-THY P T,et al.NLRP3deletion protects from hyperoxia-induced acute lung injury[J].Am J Physiol Cell Physiol,2013,305(2):182-189.
[11]刘文秀,尹新华.NLRP3炎性体与心血管疾病的研究进展[J].国际免疫学杂志,2014,37(2):97-100.LIU Wenxiu,YIN Xinhua.The research progress of NLRP3inflammasomes and cardiovascular diseases[J].International Journal of Immunology,2014,37(2):97-100.
[12]JONES H D,CROTHER T R,GONZALEZ-VIL-LALOBOS R A,et al.The NLRP3inflammasome is required for the development of hypoxemia in LPS/mechanical ventilation acute lung injury[J].Am JRespir Cell Mol Biol,2014,50(2):270-280.
[13]WU J B,YAN Z B,SCHWARTZ D E,et al.Activation of NLRP3inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury[J].J Immunol,2013,190(7):3590-3599.
[14]DEY N,SINHA M,GUPTA S,et al.Caspase-1/ASC inflammasome mediated activation of IL-1β-ROS-NF-κB pathway for control of Trypanosoma cruzi replication and survival is dispensable in NL-RP3-/-macrophages[J].PLoS One,2014,9(11):e111539.
[15]QIAO Y,WANG P,QI J N,et al.TLP-induced NF-kappa B activation regulates NLRP3expression in murine macrophages[J].FEBS letters,2012,586(7):1022-1026.
[16]KO Y A,YANG M C,HUANG H T,et al.NF-kappa B activation in myeloid cells mediates ventilatorinduced lung injury[J].Respir Res,2013,14(12):69-75.
[2]TRESCHAN T A,KAISERS W,SCHAEFER M S,et al.Ventilation with low tidal volumes during upper abdominal surgery does not improve postoperative lung function[J].Br J Anaesth,2012,109(2):263-271.
[3]赵婷婷,刘虹.呼吸机相关肺损伤的研究进展[J].临床医药文献杂志(电子版),2017,4(49):9701-9702.ZHAO Tingting,LIU Hong.Advances in research on ventilator-related lung injury[J].Journal of Clinical Medical Literature(Electronic Edition),2017,4(49):9701-9702.
[4]ZHENG F,XING S S,GONG Z S,et al.Silence of NLRP3 suppresses atherosclerosis and stabilizes plaques in apolipoprotein E-deficient mice[J].Mediators Inflamm,2014,2014(1):507208.
[5]WANG H Y,Lü C E,WANG S,et al.NLRP3inflammasome involves in the acute exacerbation of patients with chronic obstructive pulmonary disease[J].Inflammation,2018,11(6):1-13.
[6]中华医学会呼吸病学分会.急性肺损伤,急性呼吸窘迫综合征的诊断标准(草案)[J].中华结核和呼吸杂志,2000,23(4):203.Chinese Thoracic Society of Respiratory Medicine.Diagnostic criteria for acute lung injury,acute respiratory distress syndrome(draft)[J].Chinese Journal of Tuberculosis and Respiratory Diseases,2000,23(4):203.
[7]张国强,顾承东,朱宇清,等.急性生理学和慢性健康状态评分与急性肺损伤评分在重症SARS患者中的应用[J].中华流行病学杂志,2004,25(9):802-804.ZHANG Guoqiang,GU Chengdong,ZHU Yuqing,et al.Comparison between tow methods of acute physiology and chronic health evaluationⅢand acute lung injury scale to evaluate the severity and prognosis of severe acute respiratory syndrome[J].International Journal of Epidemid,2004,25(9):802-804.
[8]黄絮,詹庆元.呼吸机相关肺损伤的发生机制和处理对策[J].中华结核和呼吸杂志,2014,37(6):471-473.HUANG Xu,ZHAN Qingyuan.Mechanism and treatment of ventilator-related lung injury[J].Chinese Journal of Tuberculosis and Respiratory Diseases,2014,37(6):471-473.
[9]孟凡凡,齐晓林,黄奕江,等.乌司他丁干预对水下爆炸致兔急性肺损伤TNF-α表达的影响[J].现代检验医学杂志,2017,32(3):131-132,136.MENG Fanfan,QI Xiaolin,HUANG Yijiang,et al.Effect of ulinastatin on the expression of TNF-αin the rabbits with acute lung injury induced by underwater explosion[J].Journal of Modern Laboratory Medicine,2017,32(3):131-132,136.
[10]FUKUMOTO J,FUKUMOTO I,PARTHASARA-THY P T,et al.NLRP3deletion protects from hyperoxia-induced acute lung injury[J].Am J Physiol Cell Physiol,2013,305(2):182-189.
[11]刘文秀,尹新华.NLRP3炎性体与心血管疾病的研究进展[J].国际免疫学杂志,2014,37(2):97-100.LIU Wenxiu,YIN Xinhua.The research progress of NLRP3inflammasomes and cardiovascular diseases[J].International Journal of Immunology,2014,37(2):97-100.
[12]JONES H D,CROTHER T R,GONZALEZ-VIL-LALOBOS R A,et al.The NLRP3inflammasome is required for the development of hypoxemia in LPS/mechanical ventilation acute lung injury[J].Am JRespir Cell Mol Biol,2014,50(2):270-280.
[13]WU J B,YAN Z B,SCHWARTZ D E,et al.Activation of NLRP3inflammasome in alveolar macrophages contributes to mechanical stretch-induced lung inflammation and injury[J].J Immunol,2013,190(7):3590-3599.
[14]DEY N,SINHA M,GUPTA S,et al.Caspase-1/ASC inflammasome mediated activation of IL-1β-ROS-NF-κB pathway for control of Trypanosoma cruzi replication and survival is dispensable in NL-RP3-/-macrophages[J].PLoS One,2014,9(11):e111539.
[15]QIAO Y,WANG P,QI J N,et al.TLP-induced NF-kappa B activation regulates NLRP3expression in murine macrophages[J].FEBS letters,2012,586(7):1022-1026.
[16]KO Y A,YANG M C,HUANG H T,et al.NF-kappa B activation in myeloid cells mediates ventilatorinduced lung injury[J].Respir Res,2013,14(12):69-75.