Resolution acute respiratory distress syndrome through reversing the imbalance of Treg/Th17 by targeting the cAMP signaling pathway

Li,Qian; Hu,Xiuping; Sun,Renhua; Tu,Yuexing; Gong,Fangxiao; Ni,Yin

doi:10.3892/mmr.2016.5222

Resolution acute respiratory distress syndrome through reversing the imbalance of Treg/Th17 by targeting the cAMP signaling pathway

Authors:
- Qian Li
- Xiuping Hu
- Renhua Sun
- Yuexing Tu
- Fangxiao Gong
- Yin Ni
View Affiliations

Affiliations: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
Published online on: May 9, 2016 https://doi.org/10.3892/mmr.2016.5222
Pages: 343-348

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acute respiratory distress syndrome (ARDS) is a severe cause of respiratory failure with a mortality rate as high as 40‑46% and without any effective pharmacological treatment available. The present study provided a novel strategy for the treatment of ARDS by specifically interfering with cyclic adenosine monophosphate (cAMP) signaling. Pre-treatment with the phosphodiesterase antagonist pentoxifyllinum (PTX) obviously attenuated lung injury and reduced the mortality of mice with cecal ligature and puncture (CLP)‑induced ARDS, while raising cAMP levels. In addition, pre‑treatment with PTX attenuated CLP‑induced increases in the number of T‑regulatory cells (Tregs) and interleukin (IL)‑17‑producing T‑helper lymphocytes (Th17) among spleen lymphocytes, while partially restoring the Treg/Th17 ratio. Correspondingly, CLP‑induced increases in the secretion of IL‑2, IL‑6, IL‑10 and IL‑17 were attenuated. Furthermore, CLP‑induced increases in forkhead box p3 and RAR‑related orphan receptor γt (RORγt) expression as well as signal transducer and activator of transcription (STAT3) activation were attenuated by PTX. The results indicated that PTX‑induced increases in cAMP may have partly restored the Treg/Th17 balance by modulating the transcription of Foxp3 and RORγt through the STAT3 pathway. In conclusion, the present study provided a novel treatment strategy for ARDS by modulating the balance of Treg/Th17 and the subsequent immune response via cAMP signaling, which requires pre-clinical and clinical validation.

View Figures

View References

1	Ashbaugh DG, Bigelow DB, Petty TL and Levine BE: Acute respiratory distress in adults. Lancet. 2:319–323. 1967. View Article : Google Scholar : PubMed/NCBI
2	ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L and Slutsky AS: Acute respiratory distress syndrome: The Berlin Definition. JAMA. 307:2526–2533. 2012.PubMed/NCBI
3	Pierrakos C, Karanikolas M, Scolletta S, Karamouzos V and Velissaris D: Acute respiratory distress syndrome: Pathophysiology and therapeutic options. J Clin Med Res. 4:7–16. 2012.PubMed/NCBI
4	Curley GF and Laffey JG: Future therapies for ARDS. Intensive Care Med. 41:322–326. 2015. View Article : Google Scholar
5	Besnard AG, Togbe D, Couillin I, Tan Z, Zheng SG, Erard F, Le Bert M, Quesniaux V and Ryffel B: Inflammasome-IL-1-Th17 response in allergic lung inflammation. J Mol Cell Biol. 4:3–10. 2012. View Article : Google Scholar
6	Tsai HC, Velichko S, Hung LY and Wu R: IL-17A and Th17 cells in lung inflammation: An update on the role of Th17 cell differentiation and IL-17R signaling in host defense against infection. Clin Dev Immunol. 2013:2679712013. View Article : Google Scholar : PubMed/NCBI
7	Ji L, Zhan Y, Hua F, Li F, Zou S, Wang W, Song D, Min Z, Chen H and Cheng Y: The ratio of Treg/Th17 cells correlates with the disease activity of primary immune thrombocytopenia. PLoS One. 7:e509092012. View Article : Google Scholar : PubMed/NCBI
8	Kimura A and Kishimoto T: IL-6: Regulator of Treg/Th17 balance. Eur J Immunol. 40:1830–1835. 2010. View Article : Google Scholar : PubMed/NCBI
9	Ma L, Xue HB, Guan XH, et al: The Imbalance of Th17 cells and CD4(+) CD25(high) Foxp3(+) Treg cells in patients with atopic dermatitis. J Eur Acad Dermatol Venereol. 28:1079–1086. 2014. View Article : Google Scholar
10	Bourne HR, Lichtenstein LM, Melmon KL, Henney CS, Weinstein Y and Shearer GM: Modulation of inflammation and immunity by cyclic AMP. Science. 184:19–28. 1974. View Article : Google Scholar : PubMed/NCBI
11	Cao J, Zhang X, Wang Q, Wang X, Jin J, Zhu T, Zhang D, Wang W, Li X, Li Y, et al: Cyclic AMP suppresses TGF-β-mediated adaptive Tregs differentiation through inhibiting the activation of ERK and JNK. Cell Immunol. 285:42–48. 2013. View Article : Google Scholar : PubMed/NCBI
12	Lee J, Kim TH, Murray F, et al: Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma. Proc Natl Acad Sci USA. 112:1529–1534. 2015. View Article : Google Scholar : PubMed/NCBI
13	Ding XF, Zhou J, Hu QY, Liu SC and Chen G: The tumor suppressor pVHL down-regulates never-in-mitosis A-related kinase 8 via hypoxia-inducible factors to maintain cilia in human renal cancer cells. J Biol Chem. 290:1389–1394. 2015. View Article : Google Scholar :
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
15	Adamzik M, Broll J, Steinmann J, Westendorf AM, Rehfeld I, Kreissig C and Peters J: 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. 39:1743–1751. 2013. View Article : Google Scholar : PubMed/NCBI
16	D'Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, Pipeling MR, Brower RG, Tuder RM, McDyer JF and King LS: CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 119:2898–2913. 2009. View Article : Google Scholar : PubMed/NCBI
17	Zhang F, Fuss IJ, Yang Z and Strober W: Transcription of RORγt in developing Th17 cells is regulated by E-proteins. Mucosal Immunol. 7:521–532. 2014. View Article : Google Scholar
18	Newcomb DC and Peebles RS Jr: Th17-mediated inflammation in asthma. Curr Opin Immunol. 25:755–760. 2013. View Article : Google Scholar : PubMed/NCBI
19	Kononova TE, Urazova OI, Novitskii VV, Churina EG, Kolobovnikova YV, Ignatov MV, Zakharova PA and Pechenova OV: Functional activity of Th-17 lymphocytes in pulmonary tuberculosis. Bull Exp Biol Med. 156:743–745. 2014. View Article : Google Scholar : PubMed/NCBI
20	Vargas-Rojas MI, Ramírez-Venegas A, Limón-Camacho L, Ochoa L, Hernández-Zenteno R and Sansores RH: Increase of Th17 cells in peripheral blood of patients with chronic obstructive pulmonary disease. Respir Med. 105:1648–1654. 2011. View Article : Google Scholar : PubMed/NCBI
21	Yu ZX, Ji MS, Yan J, Cai Y, Liu J, Yang HF, Li Y, Jin ZC and Zheng JX: The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome. Crit Care. 19:822015. View Article : Google Scholar : PubMed/NCBI
22	Chen Z, Lin F, Gao Y, Li Z, Zhang J, Xing Y, Deng Z, Yao Z, Tsun A and Li B: FOXP3 and RORγt: Transcriptional regulation of Treg and Th17. Int Immunopharmacol. 11:536–542. 2011. View Article : Google Scholar
23	Chu S, Zhong X, Zhang J, Lao Q, He Z and Bai J: The expression of Foxp3 and ROR gamma t in lung tissues from normal smokers and chronic obstructive pulmonary disease patients. Int Immunopharmacol. 11:1780–1788. 2011. View Article : Google Scholar : PubMed/NCBI