Change in amount of serum cell-free mitochondrial DNA and clinical relevance in trauma patients

doi:10.16139/j.1007-9610.2020.04.010

Abstract

Abstract:

Objective To investigate change in amount of serum cell-free mitochondrial DNA (cf-mtDNA) related with inflammatory response and to explore clinical relevance to trauma patients. Methods Thirty-seven trauma patients as trauma group were divided as multiple trauma subgroup or single trauma subgroup, and as shock subgroup or non-shock subgroup. Ten healthy volunteers were as control group. The amount of cf-mtDNA in serum at 4 h, 24 h, 72 h, 7 d post-injury was compared between trauma group and control group and among subgroups. The association of serum cf-mtDNA with injury severity score (ISS), systemic inflammatory response syndrome (SIRS) score, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were analyzed respectively. The receiver operating characteristic (ROC) curve of serum cf-mtDNA post-injury were constructed to evaluate role in diagnosing SIRS. Results Serum cf-mtDNA in trauma patients at 24 h, 72 h post-injury were significantly higher than those in control group (P<0.05). Serum cf-mtDNA of patients in multiple trauma subgroup were significantly higher than those in single trauma subgroup at 4 h, 24 h, 72 h, 7 d post-injury (P<0.05, P<0.01, P<0.01, P<0.05). The amount of serum cf-mtDNA in shock subgroup were significantly higher than that in non-shock subgroup at 24 h post-injury (P<0.01), and that in group of organ dysfunction higher than in group without organ dysfunction at 4 h, 24 h post-injury (P<0.05). The peak of serum cf-mtDNA in dead patients was hi-gher than survived patients without statistical significance (P>0.05). Amounts of TNF-α, IL-6 and CRP in serum increased with serum cf-mtDNA post-injury. Amount of serum cf-mtDNA correlated positively with ISS at 24 h post-injury (r=0.454, P=0.004), with SIRS score and serum IL-6 at 4 h-7 d post-injury respectively(r=0.458, P=0.000 1; r=0.252, P=0.005), but did not correlate with serum TNF-α (r=-0.058, P=0.511), and with CRP at 4-24 h post-injury positively (r=0.264, P=0.028). The area under ROC curve of serum cf-mtDNA was 0.752 at 4 h-7 d post-injury (P=0.000 01), with 95% confidence interval of 0.668-0.836. According to maximum Youden index, the optimal cutoff value of serum cf-mtDNA was 0.075 2 with the sensitivity 63.6% and specificity 85.5% for diagnosis of SIRS. Conclusions The amount of serum cf-mtDNA increased in trauma patients at early stage, indicating severe trauma and inflammation, and more amount of serum cf-mtDNA would be helpful to diagnose SIRS.

Key words: Trauma, Cell-free mitochondrial DNA, C-reactive protein, Systemic inflammatory response syndrome, Cytokine

CLC Number:

R641

GUO Enwei, REN Dali, ZHANG Bingyu, YANG feng, YAO Yulan, JIA Ling, YU Lin, FENG Gang. Change in amount of serum cell-free mitochondrial DNA and clinical relevance in trauma patients[J]. Journal of Surgery Concepts & Practice, 2020, 25(04): 315-321.

Figures/Tables 10

References 21

[1]	Soreide K. Epidemiology of major trauma[J]. Br J Surg, 2009, 96(7):697-698. doi: 10.1002/bjs.6643 URL
[2]	Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury[J]. Nature, 2010, 464(7285):104-107. doi: 10.1038/nature08780 URL
[3]	Lam NY, Rainer TH, Chiu RW, et al. Plasma mitochondrial DNA concentrations after trauma[J]. Clin Chem, 2004, 50(1):213-216. doi: 10.1373/clinchem.2003.025783 URL
[4]	Thurairajah K, Briggs GD, Balogh ZJ. The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies[J]. Eur J Trauma Emerg Surg, 2018, 44(3):325-334. doi: 10.1007/s00068-018-0954-3 URL
[5]	McIlroy DJ, Bigland M, White AE, et al. Cell necrosis-independent sustained mitochondrial and nuclear DNA release following trauma surgery[J]. J Trauma Acute Care Surg, 2015, 78(2):282-288. doi: 10.1097/TA.0000000000000519 pmid: 25602756
[6]	Yamanouchi S, Kudo D, Yamada M, et al. Plasma mitochondrial DNA levels in patients with trauma and severe sepsis: Time course and the association with clinical status[J]. J Crit Care, 2013, 28(6):1027-1031. doi: 10.1016/j.jcrc.2013.05.006 pmid: 23787023
[7]	Hu Q, Zhou Q, Wu J, et al. The role of mitochondrial DNA in the development of ischemia reperfusion injury[J]. Shock, 2019, 51(1):52-59. doi: 10.1097/SHK.0000000000001190 URL
[8]	Gu X, Yao Y, Wu G, et al. The plasma mitochondrial DNA is an independent predictor for post-traumatic systemic inflammatory response syndrome[J]. PLoS One, 2013, 8(8):e72834. doi: 10.1371/journal.pone.0072834 URL
[9]	Wang HC, Lin YJ, Tsai NW, et al. Serial plasma deo-xyribonucleic acid levels as predictors of outcome in acute traumatic brain injury[J]. J Neurotrauma, 2014, 31(11):1039-1045. doi: 10.1089/neu.2013.3070 URL
[10]	Zhang J, Chen X, Liu Z, et al. Association between plasma mitochondrial DNA and sterile systemic inflammatory response syndrome in patients with acute blunt traumatic injury[J]. Int J Clin Exp Med, 2017, 10:3254-3262.
[11]	Gu X, Wu G, Yao Y, et al. Intratracheal administration of mitochondrial DNA directly provokes lung inflammation through the TLR9-p38 MAPK pathway[J]. Free Radic Biol Med, 2015, 83:149-158. doi: 10.1016/j.freeradbiomed.2015.02.034 URL
[12]	Xie L, Liu S, Cheng J, et al. Exogenous administration of mitochondrial DNA promotes ischemia reperfusion injury via TLR9-p38 MAPK pathway[J]. Regul Toxicol Pharmacol, 2017, 89:148-154. doi: 10.1016/j.yrtph.2017.07.028 URL
[13]	West AP, Koblansky AA, Ghosh S. Recognition and signaling by toll-like receptors[J]. Annu Rev Cell Dev Biol, 2006, 22:409-437. doi: 10.1146/annurev.cellbio.21.122303.115827 URL
[14]	Zhang Q, Itagaki K, Hauser CJ. Mitochondrial DNA is released by shock and activates neutrophils via P38 map kinase[J]. Shock, 2010, 34(1):55-59. doi: 10.1097/SHK.0b013e3181cd8c08 pmid: 19997055
[15]	Zhang JZ, Liu Z, Liu J, et al. Mitochondrial DNA induces inflammation and increases TLR9/NF-κB expression in lung tissue[J]. Int J Mol Med, 2014, 33(4):817-824. doi: 10.3892/ijmm.2014.1650 URL
[16]	Timmermans K, Kox M, Scheffer GJ, et al. Plasma nuc-lear and mitochondrial DNA levels, and markers of inflammation, shock, and organ damage in patients with septic shock[J]. Shock, 2016, 45(6):607-612. doi: 10.1097/SHK.0000000000000549 pmid: 26717107
[17]	Qin C, Gu J, Liu R, et al. Release of mitochondrial DNA correlates with peak inflammatory cytokines in patients with acute myocardial infarction[J]. Anatol J Cardiol, 2017, 17(3):224-228.
[18]	Simmons JD, Lee YL, Mulekar S, et al. Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects[J]. Ann Surg, 2013, 258(4):591-598. doi: 10.1097/SLA.0b013e3182a4ea46 pmid: 23979273
[19]	Aswani A, Manson J, Itagaki K, et al. Scavenging circulating mitochondrial DNA as a potential therapeutic option for multiple organ dysfunction in trauma hemorrhage[J]. Front Immunol, 2018, 9:891. doi: 10.3389/fimmu.2018.00891 URL
[20]	Faust HE, Reilly JP, Anderson BJ, et al. Plasma mitochondrial DNA levels are associated with ARDS in trauma and sepsis patients[J]. Chest, 2020, 157(1):67-76. doi: 10.1016/j.chest.2019.09.028 URL
[21]	McIlroy DJ, Minahan K, Keely S, et al. Reduced deo-xyribonuclease enzyme activity in response to high postinjury mitochondrial DNA concentration provides a therapeutic target for systemic inflammatory response syndrome[J]. J Trauma Acute Care Surg, 2018, 85(2):354-358. doi: 10.1097/TA.0000000000001919 pmid: 30080781

组别	例数	4 h	24 h	72 h	7 d
创伤组	37	0.028(0.016,0.076)	0.100(0.028,0.262)^※△	0.043(0.018,0.119)^※	0.039(0.018,0.103)
对照组	10	0.011(0.008,0.506)	0.011(0.008,0.506)	0.011(0.008,0.506)	0.011(0.008,0.506)

组别	例数	ISS(分)	4 h	24 h	72 h	7 d
单发伤组	17	18（16,25）	0.018(0.014,0.034)	0.018(0.014,0.034)^△△	0.018(0.012,0.034)	0.02(0.008,0.057)
18~39岁	3	9(9,16)	0.018(0.007,0.019)	0.028(0.009,0.141)	0.016(0.006,0.018)	0.016(0.003,0.019)
40~59岁	8	25(16,27)	0.020(0.016,0.039)	0.042(0.023,0.094)	0.020(0.012,0.065)	0.052(0.018,0.172)
≥60岁	6	18(16,18)	0.020(0.010,0.030)	0.047(0.021,0.148)	0.034(0.008,0.050)	0.016(0.006,0.049)
多发伤组	20	28（26,36）	0.051(0.017,0.123)^★	0.209(0.069,0.486)^△△★★	0.092(0.042,0.160)^★★	0.051(0.025,0.192)^★
18~39岁	6	37(30,39)	0.129(0.088,0.265)	0.386(0.236,0.825)^△★	0.133(0.045,0.222)^★	0.219(0.018,0.898)
40~59岁	8	27(26,37)	0.056(0.030,0.123)	0.242(0.079,0.505)^★	0.116(0.042,0.165)^★	0.056(0.025,0.139)
≥60岁	6	27(21,31)	0.017(0.015,0.046)	0.065(0.063,0.138)^△	0.066(0.025,0.133)	0.043(0.024,0.082)

组别	例数	ISS（分）	4 h	24 h	72 h	7 d
创伤性休克组	15	29(25,36)	0.040(0.016,0.135)	0.255(0.079,0.493)^★★△△	0.043(0.018,0.122)	0.090(0.018,0.174)
无休克创伤组	22	23.5(17.8,27)	0.024(0.016,0.056)	0.064(0.023,0.137)^△	0.041(0.020,0.067)	0.027(0.019,0.082)

组别	例数	ISS(分)	4 h	24 h	72 h	7 d
器官功能衰竭组	13	29(25.5,37)	0.074(0.035,0.132)^★	0.242(0.073,0.389)^★△	0.048(0.028,0.108)	0.086(0.020,0.200)
无器官功能衰竭组	24	27(17.3,27)	0.017(0.014,0.047)	0.066(0.023,0.140)^△△	0.034(0.013,0.066)	0.025(0.012,0.075)

组别	例数	ISS(分)M(Q_L,Q_U)	4 h	24 h	72 h	7 d
单发伤组	17	18(16,25)	7.41 ± 4.31	10.67 ± 6.41^※	7.26 ± 4.11	9.37 ± 7.34
多发伤组	20	28(26,36)	10.83 ± 5.45^※※	17.22 ± 9.27^{△△★★※※}	13.74 ± 5.00^★★※※	12.37 ± 7.73^※
对照组	10	0(0,0)	4.67 ± 0.47	4.67 ± 0.47	4.67 ± 0.47	4.67 ± 0.47