HMGB1与RAGE水平在急性主动脉夹层肺损伤患者中的变化及临床意义
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摘要
目的:探讨急性主动脉夹层(AAD)患者血清高迁移率族蛋白B1(HMGB1)与晚期糖基化终产物受体(RAGE)水平与继发急性肺损伤的关系。方法:选取2016年3月—2018年5月经全主动脉CTA以及超声心动图等影像学检查明确诊断的AAD患者56例为研究对象。按静态吸氧状态下氧合指数(PaO_2/FiO_2)大小将患者分为肺损伤组(21例)与非肺损伤组(35例)。随机选取健康体检人员30例为对照组。AAD患者入院后每4小时抽血次,对照组受试者仅抽取1次清晨空腹肘静脉血。采用ELISA法检测血清HMGB1、RAGE水平,同时检测PaO_2、计算PaO_2/FiO_2。结果:与健康对照组比较,两组AAD患者入院后24 h的HMGB1、RAGE水平均明显高于健康对照组,且两者在肺损伤组均明显高于非肺损伤组(均P<0.05)。两组AAD患者入院后HMGB1、RAGE水平不断上升,而PaO_2/FiO_2逐渐降低,并均入院后48～60h达到峰值,肺损伤组的3项指标的变化幅度均明显大于非肺损伤组(均P<0.05);随着发病时间的推移,HMGB1、RAGE水平达到峰值后下降,PaO_2/FiO_2逐渐回升。AAD患者中,HMGB1与RAGE水平与PaO_2/FiO_2均呈明显负相关(r=-0.940、-0.794)。结论:HMGB1/RAGE信号通路可能在AAD肺损伤中发挥着重要的作用,随着HMGB1、RAGE水平的升高,肺损伤程度逐渐加重,监测HMGB1、RAGE水平可以对AAD并发肺损伤的风险进行评估;对HMGB1/RAGE信号通路深入研究可能会为AAD肺损伤的干预提供靶点。
Objective: To investigate the association of the serum levels of high mobility group protein B1(HMGB1) and advanced glycosylation end-product receptor(RAGE) in patients with acute lung injury secondary to acute aortic Methods: From March 2016 to May 2018, 56 consecutive patients with AAD who were diagnosed by CTA of the whole aorta and echocardiography were enrolled. According to the values of oxygenation index(PaO_2/FiO_2) during oxygen inhalation in a resting state, the patients were divided into lung injury group(21 cases) and non-lung injury group(35 cases), and 30 individuals undergoing health maintenance examination were randomly selected as control group. Blood samples were drawn once per 4 h in the AAD patients after admission, and in the control group, fasting blood samples were taken only once from the elbow vein in the morning. The serum levels of HMGB1 and RAGE were measured by ELISA and PaO_2 values were detected for calculating PaO_2/FiO_2.Results: In both groups of AAD patients, the serum levels of HMGB1 and RAGE at 24 h after admission were significantly higher than those in the healthy control group, and which were also significantly higher in lung injury group than those in non-lung injury group(all P<0.05). In both groups of AAD patients, the serum levels of HMGB1 and RAGE were continuously increased, while the PaO_2/FiO_2 values were gradually decreased, and all reached a peak value within 48-60 h after admission. The changing amplitudes of the 3 variables were all significantly greater in lung injury group than those in non-lung injury group(all P<0.05). After they reached the peak values, the HMGB1 and RAGE levels gradually decreased, while the PaO_2/FiO_2 values correspondingly increased as time elapsed. In AAD patients, both HMGB1 and RAGE levels presented a significantly negative correlation with PaO_2/FiO_2 value(r=–0.940, –0.794). Conclusion: The HMGB1/RAGE signaling pathway may play an important role in the occurrence of lung injury in AAD, and lung injury may be worsened with the increase of HMGB1 and RAGE levels. Monitoring of the HMGB1 and RAGE levels can help to evaluate the risk of lung injury after AAD. Further investigations of the HMGB1/RAGE signaling pathway may provide interventional targets for lung injury after AAD.
Objective: To investigate the association of the serum levels of high mobility group protein B1(HMGB1) and advanced glycosylation end-product receptor(RAGE) in patients with acute lung injury secondary to acute aortic Methods: From March 2016 to May 2018, 56 consecutive patients with AAD who were diagnosed by CTA of the whole aorta and echocardiography were enrolled. According to the values of oxygenation index(PaO_2/FiO_2) during oxygen inhalation in a resting state, the patients were divided into lung injury group(21 cases) and non-lung injury group(35 cases), and 30 individuals undergoing health maintenance examination were randomly selected as control group. Blood samples were drawn once per 4 h in the AAD patients after admission, and in the control group, fasting blood samples were taken only once from the elbow vein in the morning. The serum levels of HMGB1 and RAGE were measured by ELISA and PaO_2 values were detected for calculating PaO_2/FiO_2.Results: In both groups of AAD patients, the serum levels of HMGB1 and RAGE at 24 h after admission were significantly higher than those in the healthy control group, and which were also significantly higher in lung injury group than those in non-lung injury group(all P<0.05). In both groups of AAD patients, the serum levels of HMGB1 and RAGE were continuously increased, while the PaO_2/FiO_2 values were gradually decreased, and all reached a peak value within 48-60 h after admission. The changing amplitudes of the 3 variables were all significantly greater in lung injury group than those in non-lung injury group(all P<0.05). After they reached the peak values, the HMGB1 and RAGE levels gradually decreased, while the PaO_2/FiO_2 values correspondingly increased as time elapsed. In AAD patients, both HMGB1 and RAGE levels presented a significantly negative correlation with PaO_2/FiO_2 value(r=–0.940, –0.794). Conclusion: The HMGB1/RAGE signaling pathway may play an important role in the occurrence of lung injury in AAD, and lung injury may be worsened with the increase of HMGB1 and RAGE levels. Monitoring of the HMGB1 and RAGE levels can help to evaluate the risk of lung injury after AAD. Further investigations of the HMGB1/RAGE signaling pathway may provide interventional targets for lung injury after AAD.
引文
[1]Wu Z,Ruan Y,Chang J,et al.Angiotensin II is related to the acute aortic dissection complicated with lung injury through mediating the release of MMP9 from macrophages[J].Am J Transl Res,2016,8(3):1426-1436.
[2]马志高,金沐,程卫平,等.急性主动脉夹层并发急性肺损伤的研究进展[J].心肺血管病杂志,2015,34(4):319-321.doi:10.3969/j.issn.1007-5062.2015.04.019.Ma ZG,Jin M,Cheng WP,et al.Research advances in acute aortic dissection complicated with acute lung injury[J].Journal of Cardiovascular and Pulmonary Diseases,2015,34(4):319-321.doi:10.3969/j.issn.1007-5062.2015.04.019.
[3]景赫,卢家凯,金沐,等.急性主动脉夹层围术期急性肺损伤与炎性细胞因子的相关性研究[J].心肺血管病杂志,2015,34(4):287-290.doi:10.3969/j.issn.1007-5062.2015.04.011.Jing H,Lu JK,Jin M,et al.Correlative study of perioperative acute lung injury and inflammatory reaction in surgical treatment for Standford A acute aortic dissection[J].Journal of Cardiovascular and Pulmonary Diseases,2015,34(4):287-290.doi:10.3969/j.issn.1007-5062.2015.04.011.
[4]Huebener P,Pradere JP,Hernandez C,et al.The HMGB1/RAGEaxis triggers neutrophil-mediated injury amplification following necrosis[J].J Clin Invest,2015,125(2):539-550.doi:10.1172/JCI76887.
[5]Jhun JY,Lee S H,Kim HY,et al.HMGB1/RAGE induces IL-17expression to exaggerate inflammation in peripheral blood cells of hepatitis B patients[J].J Transl Med,2015,13:310.doi:10.1186/s12967-015-0663-1.
[6]Weber DJ,Allette YM,Wilkes DS,et al.The HMGB1-RAGEInflammatory Pathway:Implications for Brain Injury-Induced Pulmonary Dysfunction[J].Antioxid Redox Signal,2015,23(17):1316-1328.doi:10.1089/ars.2015.6299.
[7]段旭洲,徐志云.炎性反应在急性A型主动脉夹层并发肺损伤中的作用[J].中华全科医学,2015,13(2):172-174.Duan XZ,Xu ZY.Role of inflammation in stanford type A acute aortic dissection complicated by lung injury[J].Chinese Journal of General Practice,2015,13(2):172-174.
[8]Ware LB,Calfee CS.Biomarkers of ARDS:what’s new?[J].Intensive Care Med,2016,42(5):797-799.doi:10.1007/s00134-015-3973-0.
[9]Zhang TZ,Yang SH,Yao JF,et al.Sangxingtang inhibits the inflammation of LPS-induced acute lung injury in mice by downregulating the MAPK/NF-κB pathway[J].Chin J Nat Med,2015,13(12):889-895.doi:10.1016/S1875-5364(15)30094-7.
[10]Zhang X,Li C,Li J,et al.Protective effects of protocatechuic acid on acute lung injury induced by lipopolysaccharide in mice via p38MAPK and NF-κB signal pathways[J].Int Immunopharmacol,2015,26(1):229-236.doi:10.1016/j.intimp.2015.03.031.
[11]史旻,林锦乐,张文武.HMGB1-RAGE通路及其在急性呼吸窘迫综合征中的作用[J].临床急诊杂志,2016,17(5):409-412.Shi M,Lin JL,Zhang WW.HMGB1-RAGE pathway and its role in acute respiratory distress syndrome[J].Journal of Clinical Emergency,2016,17(5):409-412.
[12]Sharma AK,Lapar DJ,Stone M L,et al.Receptor for advanced glycation end products(RAGE)on iNKT cells mediates lung ischemia-reperfusion injury[J].Am J Transplant,2013,13(9):2255-2267.doi:10.1111/ajt.12368.
[13]Li K,Yang J,Han X.Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways[J].Int Immunopharmacol,2016,34:114-128.doi:10.1016/j.intimp.2016.01.021.
[14]Entezari M,Javdan M,Antoine DJ,et al.Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury[J].Redox Biol,2014,2:314-322.doi:10.1016/j.redox.2014.01.013.e
[15]Wang G,Liu L,Zhang Y,et al.Activation of PPARγattenuates LPS-induced acute lung injury by inhibition of HMGB1-RAGElevels[J].Eur J Pharmacol,2014,726:27-32.doi:10.1016/j.ejphar.2014.01.030.
[16]Zhou M,Zhang Y,Chen X,et al.PTEN-Foxo1 signaling triggers HMGB1-mediated innate immune responses in acute lung injury[J].Immunol Res,2015,62(1):95-105.doi:10.1007/s12026-015-8639-z.
[17]Achouiti A,van der Meer AJ,Florquin S,et al.High-mobility group box 1 and the receptor for advanced glycation end products contribute to lung injury during Staphylococcus aureus pneumonia[J].Crit Care,2013,17(6):R296.doi:10.1186/cc13162.
[18]曾昭凡,武金才,戚悠飞,等.炎症反应与急性主动脉夹层肺损伤相关性研究[J].中国血管外科杂志:电子版,2018,10(3):183-187.Zeng ZF,Wu JC,Qi YF,et al.Correlation between inflammatory response and lung injury induced by acute aortic dissection[J].Chinese Journal of Vascular Surgery:Electronic Version,2018,10(3):183-187.
[19]Gil M,Kim YK,Hong SB,et al.Naringin Decreases TNF-αand HMGB1 Release from LPS-Stimulated Macrophages and Improves Survival in a CLP-Induced Sepsis Mice[J].PLoS One,2016,11(10):e0164186.doi:10.1371/journal.pone.0164186.
[20]Cheng Y,Wang D,Wang B,et al.HMGB-1 translocation and release mediate cigarette smoke-induced pulmonary inflammation in mice through a TLR-4/Myd88-depend-ent signaling pathway[J].Mol Biol Cell,2016,28(1):201-209.doi:10.1091/mbc.E16-02-0126.
[21]Sa?di H,Bras M,Formaglio P,et al.HMGB1 Is Involved in IFN-αProduction and TRAIL Expression by HIV-1-Exposed Plasmacytoid Dendritic Cells:Impact of the Crosstalk with NK Cells[J].PLoSPathog,2016,12(1):e1005407.doi:10.1371/journal.ppat.1005407.
[22]Fu Y,Lei J,Zhuang Y,et al.Overexpression of HMGB-1 a-box reduced Ll-l beta-induced mmp expression and the production of inflammatory mediators in human chondrocytes[J].Exp Cell Res,2016,349(1):184-190.doi:10.1016/j.yexcr.2016.10.014.
[23]Gao XJ,Qu YY,Liu XW,et al.Immune complexes induce TNF-alpha and baff production from U937 cells by HMGB-1 and rage[J].Eur Rev Med Pharmacol Sci,2017,21(8):1810-1819.
[24]Imbalzano E,Quartuccio S,Di Salvo E,et al.Association between HMGB-1 and asthma:a literature review[J].Clin Mol Allergy,2017,15:12.doi:10.1186/s12948-017-0068-1.
[25]Saleh A,Smith DR,Tessler L,et al.Receptor for advanced glycation end-products(rage)activates divergent signaling pathways to augment neurite outgrowth of adult sensory neurons[J].Exp Neurol,2013,249:149-159.doi:10.1016/j.expneurol.2013.08.018.
[26]Huang JS,Lee YH,Chuan LY,et al.Cinnamaldehyde and nitric oxide attenuate advanced glycation end products-induced the Jak/STAT signaling in human renal tubular cells[J].J Cell Biochem,2015,116(6):1028-1038.doi:10.1002/jcb.25058.
[27]佟昌慈,柳云恩,张玉彪,等.高迁移率族蛋白-1、糖基化终产物受体及Toll样受体-4通路对爆震伤致大鼠急性肺损伤影响研究[J].创伤与急危重病医学,2017,5(4):198-204.doi:10.16048/j.issn.2095-5561.2017.04.02.Tong CC,Liu YE,Zhang YB,et al.Effects of HMGB-1,RAGEand TLR-4 pathway on acute lung injury induced by blast in rats[J].Trauma and Critical Care Medicine,2017,5(4):198-204.doi:10.16048/j.issn.2095-5561.2017.04.02.
[2]马志高,金沐,程卫平,等.急性主动脉夹层并发急性肺损伤的研究进展[J].心肺血管病杂志,2015,34(4):319-321.doi:10.3969/j.issn.1007-5062.2015.04.019.Ma ZG,Jin M,Cheng WP,et al.Research advances in acute aortic dissection complicated with acute lung injury[J].Journal of Cardiovascular and Pulmonary Diseases,2015,34(4):319-321.doi:10.3969/j.issn.1007-5062.2015.04.019.
[3]景赫,卢家凯,金沐,等.急性主动脉夹层围术期急性肺损伤与炎性细胞因子的相关性研究[J].心肺血管病杂志,2015,34(4):287-290.doi:10.3969/j.issn.1007-5062.2015.04.011.Jing H,Lu JK,Jin M,et al.Correlative study of perioperative acute lung injury and inflammatory reaction in surgical treatment for Standford A acute aortic dissection[J].Journal of Cardiovascular and Pulmonary Diseases,2015,34(4):287-290.doi:10.3969/j.issn.1007-5062.2015.04.011.
[4]Huebener P,Pradere JP,Hernandez C,et al.The HMGB1/RAGEaxis triggers neutrophil-mediated injury amplification following necrosis[J].J Clin Invest,2015,125(2):539-550.doi:10.1172/JCI76887.
[5]Jhun JY,Lee S H,Kim HY,et al.HMGB1/RAGE induces IL-17expression to exaggerate inflammation in peripheral blood cells of hepatitis B patients[J].J Transl Med,2015,13:310.doi:10.1186/s12967-015-0663-1.
[6]Weber DJ,Allette YM,Wilkes DS,et al.The HMGB1-RAGEInflammatory Pathway:Implications for Brain Injury-Induced Pulmonary Dysfunction[J].Antioxid Redox Signal,2015,23(17):1316-1328.doi:10.1089/ars.2015.6299.
[7]段旭洲,徐志云.炎性反应在急性A型主动脉夹层并发肺损伤中的作用[J].中华全科医学,2015,13(2):172-174.Duan XZ,Xu ZY.Role of inflammation in stanford type A acute aortic dissection complicated by lung injury[J].Chinese Journal of General Practice,2015,13(2):172-174.
[8]Ware LB,Calfee CS.Biomarkers of ARDS:what’s new?[J].Intensive Care Med,2016,42(5):797-799.doi:10.1007/s00134-015-3973-0.
[9]Zhang TZ,Yang SH,Yao JF,et al.Sangxingtang inhibits the inflammation of LPS-induced acute lung injury in mice by downregulating the MAPK/NF-κB pathway[J].Chin J Nat Med,2015,13(12):889-895.doi:10.1016/S1875-5364(15)30094-7.
[10]Zhang X,Li C,Li J,et al.Protective effects of protocatechuic acid on acute lung injury induced by lipopolysaccharide in mice via p38MAPK and NF-κB signal pathways[J].Int Immunopharmacol,2015,26(1):229-236.doi:10.1016/j.intimp.2015.03.031.
[11]史旻,林锦乐,张文武.HMGB1-RAGE通路及其在急性呼吸窘迫综合征中的作用[J].临床急诊杂志,2016,17(5):409-412.Shi M,Lin JL,Zhang WW.HMGB1-RAGE pathway and its role in acute respiratory distress syndrome[J].Journal of Clinical Emergency,2016,17(5):409-412.
[12]Sharma AK,Lapar DJ,Stone M L,et al.Receptor for advanced glycation end products(RAGE)on iNKT cells mediates lung ischemia-reperfusion injury[J].Am J Transplant,2013,13(9):2255-2267.doi:10.1111/ajt.12368.
[13]Li K,Yang J,Han X.Ketamine attenuates sepsis-induced acute lung injury via regulation of HMGB1-RAGE pathways[J].Int Immunopharmacol,2016,34:114-128.doi:10.1016/j.intimp.2016.01.021.
[14]Entezari M,Javdan M,Antoine DJ,et al.Inhibition of extracellular HMGB1 attenuates hyperoxia-induced inflammatory acute lung injury[J].Redox Biol,2014,2:314-322.doi:10.1016/j.redox.2014.01.013.e
[15]Wang G,Liu L,Zhang Y,et al.Activation of PPARγattenuates LPS-induced acute lung injury by inhibition of HMGB1-RAGElevels[J].Eur J Pharmacol,2014,726:27-32.doi:10.1016/j.ejphar.2014.01.030.
[16]Zhou M,Zhang Y,Chen X,et al.PTEN-Foxo1 signaling triggers HMGB1-mediated innate immune responses in acute lung injury[J].Immunol Res,2015,62(1):95-105.doi:10.1007/s12026-015-8639-z.
[17]Achouiti A,van der Meer AJ,Florquin S,et al.High-mobility group box 1 and the receptor for advanced glycation end products contribute to lung injury during Staphylococcus aureus pneumonia[J].Crit Care,2013,17(6):R296.doi:10.1186/cc13162.
[18]曾昭凡,武金才,戚悠飞,等.炎症反应与急性主动脉夹层肺损伤相关性研究[J].中国血管外科杂志:电子版,2018,10(3):183-187.Zeng ZF,Wu JC,Qi YF,et al.Correlation between inflammatory response and lung injury induced by acute aortic dissection[J].Chinese Journal of Vascular Surgery:Electronic Version,2018,10(3):183-187.
[19]Gil M,Kim YK,Hong SB,et al.Naringin Decreases TNF-αand HMGB1 Release from LPS-Stimulated Macrophages and Improves Survival in a CLP-Induced Sepsis Mice[J].PLoS One,2016,11(10):e0164186.doi:10.1371/journal.pone.0164186.
[20]Cheng Y,Wang D,Wang B,et al.HMGB-1 translocation and release mediate cigarette smoke-induced pulmonary inflammation in mice through a TLR-4/Myd88-depend-ent signaling pathway[J].Mol Biol Cell,2016,28(1):201-209.doi:10.1091/mbc.E16-02-0126.
[21]Sa?di H,Bras M,Formaglio P,et al.HMGB1 Is Involved in IFN-αProduction and TRAIL Expression by HIV-1-Exposed Plasmacytoid Dendritic Cells:Impact of the Crosstalk with NK Cells[J].PLoSPathog,2016,12(1):e1005407.doi:10.1371/journal.ppat.1005407.
[22]Fu Y,Lei J,Zhuang Y,et al.Overexpression of HMGB-1 a-box reduced Ll-l beta-induced mmp expression and the production of inflammatory mediators in human chondrocytes[J].Exp Cell Res,2016,349(1):184-190.doi:10.1016/j.yexcr.2016.10.014.
[23]Gao XJ,Qu YY,Liu XW,et al.Immune complexes induce TNF-alpha and baff production from U937 cells by HMGB-1 and rage[J].Eur Rev Med Pharmacol Sci,2017,21(8):1810-1819.
[24]Imbalzano E,Quartuccio S,Di Salvo E,et al.Association between HMGB-1 and asthma:a literature review[J].Clin Mol Allergy,2017,15:12.doi:10.1186/s12948-017-0068-1.
[25]Saleh A,Smith DR,Tessler L,et al.Receptor for advanced glycation end-products(rage)activates divergent signaling pathways to augment neurite outgrowth of adult sensory neurons[J].Exp Neurol,2013,249:149-159.doi:10.1016/j.expneurol.2013.08.018.
[26]Huang JS,Lee YH,Chuan LY,et al.Cinnamaldehyde and nitric oxide attenuate advanced glycation end products-induced the Jak/STAT signaling in human renal tubular cells[J].J Cell Biochem,2015,116(6):1028-1038.doi:10.1002/jcb.25058.
[27]佟昌慈,柳云恩,张玉彪,等.高迁移率族蛋白-1、糖基化终产物受体及Toll样受体-4通路对爆震伤致大鼠急性肺损伤影响研究[J].创伤与急危重病医学,2017,5(4):198-204.doi:10.16048/j.issn.2095-5561.2017.04.02.Tong CC,Liu YE,Zhang YB,et al.Effects of HMGB-1,RAGEand TLR-4 pathway on acute lung injury induced by blast in rats[J].Trauma and Critical Care Medicine,2017,5(4):198-204.doi:10.16048/j.issn.2095-5561.2017.04.02.