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Published in: Critical Care 1/2015

Open Access 01-12-2015 | Research

The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome

Authors: Zhi-xin Yu, Mu-sen Ji, Jun Yan, Yan Cai, Jing Liu, Hong-feng Yang, Yong Li, Zhao-chen Jin, Jin-xu Zheng

Published in: Critical Care | Issue 1/2015

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Abstract

Introduction

Recent studies have revealed that lung inflammation mediated by CD4+ T cells may contribute to the pathogenesis of acute respiratory distress syndrome (ARDS). The imbalance between CD4 + CD25 + Foxp3 + regulatory T (Treg) cells and T helper (Th)17 cells has been found in a number of different inflammation and autoimmune diseases, while the role of the Th17/Treg balance in ARDS remains largely unknown. The aim of this study was to investigate the Th17/Treg pattern and its impact on disease severity and outcomes in patients with ARDS.

Methods

This prospective, observational study enrolled 79 patients who fulfilled the Berlin definition of ARDS and 26 age- and sex-matched healthy controls. Circulation Th17 and Treg cell frequencies were analyzed by flow cytometry, and the expressions of Th17- and Treg-related cytokines in serum were measured by enzyme-linked immunosorbent assay (ELISA). Acute Physiologic and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, and the Lung Injury Score were also calculated at enrollment.

Results

Within 24 hours after the onset of ARDS, the changes of peripheral circulating Th17 and Treg cell frequencies gradually increased from mild to severe ARDS. Th17/Treg ratio was positively correlated with APACHE II score, SOFA score, and Lung Injury Score, while negatively correlated with PaO2/FiO2. The areas under the receiver operating characteristic (AUC) curves of Th17/Treg ratio for predicting 28-day mortality in ARDS patients was higher than that of APACHE II score, SOFA score, Lung injury score, as well as PaO2/FiO2. Using a Th17/Treg ratio cutoff value of >0.79 to determine 28-day mortality, the sensitivity was 87.5% with 68.1% specificity. Multivariate logistic regression showed Th17/Treg ratio >0.79 (odds ratio = 8.68, P = 0.002) was the independent predictor for 28-day mortality in patients with ARDS. Finally, cumulative survival rates at 28-day follow-up also differed significantly between patients with Th17/Treg ratio >0.79 and ≤0.79 (P <0.001).

Conclusions

The Th17/Treg imbalance favoring a Th17 shift represents a potential therapeutic target to alleviate lung injury and a novel risk indicator in patients with early ARDS.
Literature
1.
go back to reference Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012;122:2731–40.CrossRef Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest. 2012;122:2731–40.CrossRef
2.
go back to reference Definition Task Force ARDS, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307:2526–33. Definition Task Force ARDS, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307:2526–33.
3.
go back to reference Williams AE, Chambers RC. The mercurial nature of neutrophils: still an enigma in ARDS? Am J Physiol Lung Cell Mol Physiol. 2014;306:L217–30.CrossRef Williams AE, Chambers RC. The mercurial nature of neutrophils: still an enigma in ARDS? Am J Physiol Lung Cell Mol Physiol. 2014;306:L217–30.CrossRef
4.
go back to reference Aggarwal NR, King LS, D’Alessio FR. Diverse macrophage populations mediate acute lung inflammation and resolution. Am J Physiol Lung Cell Mol Physiol. 2014;306:L709–25.CrossRef Aggarwal NR, King LS, D’Alessio FR. Diverse macrophage populations mediate acute lung inflammation and resolution. Am J Physiol Lung Cell Mol Physiol. 2014;306:L709–25.CrossRef
5.
go back to reference Liu J, Zhang PS, Yu Q, Liu L, Yang Y, Guo FM, et al. Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury. Int J Mol Med. 2012;29:269–76.CrossRef Liu J, Zhang PS, Yu Q, Liu L, Yang Y, Guo FM, et al. Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury. Int J Mol Med. 2012;29:269–76.CrossRef
6.
go back to reference Nakajima T, Suarez CJ, Lin KW, Jen KY, Schnitzer JE, Makani SS, et al. T cell pathways involving CTLA4 contribute to a model of acute lung injury. J Immunol. 2010;184:5835–41.CrossRef Nakajima T, Suarez CJ, Lin KW, Jen KY, Schnitzer JE, Makani SS, et al. T cell pathways involving CTLA4 contribute to a model of acute lung injury. J Immunol. 2010;184:5835–41.CrossRef
7.
go back to reference D’Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, et al. CD4 + CD25 + Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119:2898–913.CrossRef D’Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, et al. CD4 + CD25 + Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119:2898–913.CrossRef
8.
go back to reference Adamzik M, Broll J, Steinmann J, Westendorf AM, Rehfeld I, Kreissig C, et al. An increased alveolar CD4 + CD25 + Foxp3 + T-regulatory cell ratio in acute respiratory distress syndrome is associated with increased 30-day mortality. Intensive Care Med. 2013;39:1743–51.CrossRef Adamzik M, Broll J, Steinmann J, Westendorf AM, Rehfeld I, Kreissig C, et al. An increased alveolar CD4 + CD25 + Foxp3 + T-regulatory cell ratio in acute respiratory distress syndrome is associated with increased 30-day mortality. Intensive Care Med. 2013;39:1743–51.CrossRef
9.
go back to reference Garibaldi BT, D’Alessio FR, Mock JR, Files DC, Chau E, Eto Y, et al. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. Am J Respir Cell Mol Biol. 2013;48:35–43.CrossRef Garibaldi BT, D’Alessio FR, Mock JR, Files DC, Chau E, Eto Y, et al. Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. Am J Respir Cell Mol Biol. 2013;48:35–43.CrossRef
10.
go back to reference Wang L, Zhao L, Lv J, Yin Q, Liang X, Chu Y, et al. BLT1-dependent alveolar recruitment of CD4(+)CD25(+) Foxp3(+) regulatory T cells is important for resolution of acute lung injury. Am J Respir Crit Care Med. 2012;186:989–98.CrossRef Wang L, Zhao L, Lv J, Yin Q, Liang X, Chu Y, et al. BLT1-dependent alveolar recruitment of CD4(+)CD25(+) Foxp3(+) regulatory T cells is important for resolution of acute lung injury. Am J Respir Crit Care Med. 2012;186:989–98.CrossRef
11.
go back to reference Guo Z, Wen Z, Qin A, Zhou Y, Liao Z, Liu Z, et al. Antisense oligonucleotide treatment enhances the recovery of acute lung injury through IL-10-secreting M2-like macrophage-induced expansion of CD4+ regulatory T cells. J Immunol. 2013;190:4337–48.CrossRef Guo Z, Wen Z, Qin A, Zhou Y, Liao Z, Liu Z, et al. Antisense oligonucleotide treatment enhances the recovery of acute lung injury through IL-10-secreting M2-like macrophage-induced expansion of CD4+ regulatory T cells. J Immunol. 2013;190:4337–48.CrossRef
12.
go back to reference Hou YC, Pai MH, Liu JJ, Yeh SL. Alanyl-glutamine resolves lipopolysaccharide-induced lung injury in mice by modulating the polarization of regulatory T cells and T helper 17 cells. J Nutr Biochem. 2013;24:1555–63.CrossRef Hou YC, Pai MH, Liu JJ, Yeh SL. Alanyl-glutamine resolves lipopolysaccharide-induced lung injury in mice by modulating the polarization of regulatory T cells and T helper 17 cells. J Nutr Biochem. 2013;24:1555–63.CrossRef
13.
go back to reference Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014;13:668–77.CrossRef Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev. 2014;13:668–77.CrossRef
14.
go back to reference Newcomb DC, Peebles Jr RS. Th17-mediated inflammation in asthma. Curr Opin Immunol. 2013;25:755–60.CrossRef Newcomb DC, Peebles Jr RS. Th17-mediated inflammation in asthma. Curr Opin Immunol. 2013;25:755–60.CrossRef
15.
go back to reference Kononova TE, Urazova OI, Novitskii VV, Churina EG, Kolobovnikova YV, Ignatov MV, et al. Functional activity of Th-17 lymphocytes in pulmonary tuberculosis. Bull Exp Biol Med. 2014;156:743–5.CrossRef Kononova TE, Urazova OI, Novitskii VV, Churina EG, Kolobovnikova YV, Ignatov MV, et al. Functional activity of Th-17 lymphocytes in pulmonary tuberculosis. Bull Exp Biol Med. 2014;156:743–5.CrossRef
16.
go back to reference Chang SH, Mirabolfathinejad SG, Katta H, Cumpian AM, Gong L, Caetano MS, et al. T helper 17 cells play a critical pathogenic role in lung cancer. Proc Natl Acad Sci USA. 2014;111:5664–9.CrossRef Chang SH, Mirabolfathinejad SG, Katta H, Cumpian AM, Gong L, Caetano MS, et al. T helper 17 cells play a critical pathogenic role in lung cancer. Proc Natl Acad Sci USA. 2014;111:5664–9.CrossRef
17.
go back to reference Vargas-Rojas MI, Ramírez-Venegas A, Limón-Camacho L, Ochoa L, Hernández-Zenteno R, Sansores RH. Increase of Th17 cells in peripheral blood of patients with chronic obstructive pulmonary disease. Respir Med. 2011;105:1648–54.CrossRef Vargas-Rojas MI, Ramírez-Venegas A, Limón-Camacho L, Ochoa L, Hernández-Zenteno R, Sansores RH. Increase of Th17 cells in peripheral blood of patients with chronic obstructive pulmonary disease. Respir Med. 2011;105:1648–54.CrossRef
18.
go back to reference Barbi J, Pardoll D, Pan F. Metabolic control of the Treg/Th17 axis. Immunol Rev. 2013;252:52–77.CrossRef Barbi J, Pardoll D, Pan F. Metabolic control of the Treg/Th17 axis. Immunol Rev. 2013;252:52–77.CrossRef
19.
go back to reference Li C, Yang P, Sun Y, Li T, Wang C, Wang Z, et al. IL-17 response mediates acute lung injury induced by the 2009 pandemic influenza A (H1N1) virus. Cell Res. 2012;22:528–38.CrossRef Li C, Yang P, Sun Y, Li T, Wang C, Wang Z, et al. IL-17 response mediates acute lung injury induced by the 2009 pandemic influenza A (H1N1) virus. Cell Res. 2012;22:528–38.CrossRef
20.
go back to reference Halwani R, Al-Muhsen S, Hamid Q. T helper 17 cells in airway diseases: from laboratory bench to bedside. Chest. 2013;143:494–501.CrossRef Halwani R, Al-Muhsen S, Hamid Q. T helper 17 cells in airway diseases: from laboratory bench to bedside. Chest. 2013;143:494–501.CrossRef
21.
go back to reference Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29.CrossRef Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13:818–29.CrossRef
22.
go back to reference Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–10.CrossRef Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–10.CrossRef
23.
go back to reference Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720–3.CrossRef Murray JF, Matthay MA, Luce JM, Flick MR. An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis. 1988;138:720–3.CrossRef
24.
go back to reference Nguyen CQ, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB. Pathogenic effect of interleukin-17A in induction of Sjögren’s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther. 2010;12:R220.CrossRef Nguyen CQ, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB. Pathogenic effect of interleukin-17A in induction of Sjögren’s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther. 2010;12:R220.CrossRef
25.
go back to reference Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol. 2004;202:145–56.CrossRef Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol. 2004;202:145–56.CrossRef
26.
go back to reference Perl M, Lomas-Neira J, Venet F, Chung CS, Ayala A. Pathogenesis of indirect (secondary) acute lung injury. Expert Rev Respir Med. 2011;5:115–26.CrossRef Perl M, Lomas-Neira J, Venet F, Chung CS, Ayala A. Pathogenesis of indirect (secondary) acute lung injury. Expert Rev Respir Med. 2011;5:115–26.CrossRef
27.
go back to reference Kangelaris KN, Calfee CS, May AK, Zhuo H, Matthay MA, Ware LB. Is there still a role for the lung injury score in the era of the Berlin definition ARDS? Ann Intensive Care. 2014;4:4.CrossRef Kangelaris KN, Calfee CS, May AK, Zhuo H, Matthay MA, Ware LB. Is there still a role for the lung injury score in the era of the Berlin definition ARDS? Ann Intensive Care. 2014;4:4.CrossRef
Metadata
Title
The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome
Authors
Zhi-xin Yu
Mu-sen Ji
Jun Yan
Yan Cai
Jing Liu
Hong-feng Yang
Yong Li
Zhao-chen Jin
Jin-xu Zheng
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2015
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-015-0811-2

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