p38MAPK inhibitor ameliorates lipopolysaccharide induced acute lung injury through regulating the balance of Treg cells and Th17 cells_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

FENG Jingjing ^1,2 , SHAO Chuan ³ , LI Junqing ^1,2 , SHI Tianyun ^1,2 , DU Yong ^1,2 ,  JIE Zhijun ^1,2 ,  SHI Jindong ^1,2

1. Department of Pulmonary and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, P. R. China;
2. Center of Community-Based Health Research, Fudan University, Shanghai 200240, P. R. China;
3. Department of Pulmonary and Critical Care Medicine, Ningbo Medical Center Lihuili Hospital, Ningbo, Zhejiang 315040, P. R. China;

Corresponding author：

JIE Zhijun, Email: shijindong@fudan.edu.cn; SHI Jindong, Email: jiezjlxh@163.com

Keywords：

p38MAPK signal path; lipopolysaccharide; acute lung injury; Treg cell; Th17 cell

DOI：

10.7507/1671-6205.202205020

Video：

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Objective To investigate whether p38 mitogen activated protein kinase (p38MAPK) inhibitor can reduce acute lung injury (ALI) caused by lipopolysaccharide (LPS) by regulating Th17/Treg balance. Methods Balb/c mice were randomly divided into a control group, an ALI group and an intervention group. The mice in the control group were injected with phosphate-buffered saline, the mice in the ALI group were intraperitoneally injected with 40 mg/kg LPS, and the mice in the intervention group were injected with SB203580 (0.5 mg/kg, 1 mg/kg, 2 mg/kg, 5 mg/kg) intraperitoneally 1 h prior to the intraperitoneal injection of LPS. All mice were killed on 12 h later respectively. Hematoxylin-eosinstin staining was used to observe the pathological changes of lung tissue, and cell classification, counting, and total protein levels in bronchoalveolar lavage fluid (BALF) were detected. Transcript expression of forkhead box p3 (Foxp3) and retinoic acid receptor-related orphan receptor-γt (RORγt) was detected by real-time polymerase chain reaction. Interleukin (IL)-6, IL-10, IL-17, IL-23 and transforming growth factor-β (TGF-β) in lung tissue and IL-6, tumor necrosis factor-α (TNF-α) in serum were measured by enzyme-linked immunosorbent assay. The Th17 and Treg subset distribution in spleen was determined by ﬂow cytometry. Results Histopathological examination showed that LPS induced inflammatory cell infiltration in lung tissue, increased cell count and protein levels in BALF (P<0.05), and increased proportion of neutrophils and monocytes in the ALI mice. SB203580 significantly attenuated tissue injury of the lungs in LPS-induced ALI mice. Serum levels of IL-6 and TNF-α in the ALI group were significantly higher than those in the control group, and inflammatory cytokines were decreased after SB203580 intervention. Compared with the ALI group, the production of inflammatory cytokines associate with Th17, including IL-17, IL-23, RORγt was inhibited, and the production of cytokines associate with Treg, such as IL-10 and Foxp3 in lung tissue was increased in the intervention group in a concentration-dependent manner with SB203580. After SB203580 intervention, Th17/Treg ratio was significantly decreased compared with the LPS group (P<0.05). Conclusion p38MAPK inhibitor can reduce LPS-induced ALI by regulating the imbalance of Treg cells and Th17 cells.

Citation： FENG Jingjing, SHAO Chuan, LI Junqing, SHI Tianyun, DU Yong, JIE Zhijun, SHI Jindong. p38MAPK inhibitor ameliorates lipopolysaccharide induced acute lung injury through regulating the balance of Treg cells and Th17 cells. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(1): 44-51. doi: 10.7507/1671-6205.202205020 Copy

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2.	Beal AL, Cerra FB. Multiple organ failure syndrome in the 1990s. Systemic inflammatory response and organ dysfunction. JAMA, 1994, 271(3): 226-233.
3.	Shao L, Meng D, Yang F, et al. Irisin-mediated protective effect on LPS-induced acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells. Biochem Biophys Res Commun, 2017, 487(2): 194-200.
4.	Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J, 2010, 429(3): 403-417.
5.	Guo S, Jiang KF, Wu HC, et al. Magnoflorine ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-κB and MAPK activation. Front Pharmacol, 2018, 9: 982.
6.	Chen IC, Wang SC, Chen YT, et al. Corylin ameliorates LPS-induced acute lung injury via suppressing the MAPKs and IL-6/STAT3 signaling pathways. Pharmaceuticals (Basel, Switzerland), 2021, 14(10): 1046.
7.	Peifer C, Wagner G, Laufer S. New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 MAP kinase. Curr Top Med Chem, 2006, 6(2): 113-149.
8.	Lin SH, Wu H, Wang CJ, et al. Regulatory T cells and acute lung injury: cytokines, uncontrolled inflammation, and therapeutic implications. Front Immunol, 2018, 9: 1545.
9.	Li MQ, Zhao Y, Qi D, et al. Tangeretin attenuates lipopolysaccharide-induced acute lung injury through Notch signaling pathway via suppressing Th17 cell response in mice. Microb Pathog, 2020, 138: 103826.
10.	Nadeem A, Al-Harbi NO, Ahmad SF, et al. Blockade of interleukin-2-inducible T-cell kinase signaling attenuates acute lung injury in mice through adjustment of pulmonary Th17/Treg immune responses and reduction of oxidative stress. Int Immunopharmacol, 2020, 83: 106369.
11.	Rudmann DG, Preston AM, Moore MW, et al. Susceptibility to Pneumocystis carinii in mice is dependent on simultaneous deletion of IFN-γ and type 1 and 2 TNF receptor genes. J Immunol, 1998, 161(1): 360-366.
12.	Badamjav R, Sonom D, Wu YH, et al. The protective effects of Thalictrum minus L. on lipopolysaccharide-induced acute lung injury. J Ethnopharmacol, 2020, 248: 112355.
13.	Williams AE, Chambers RC. The mercurial nature of neutrophils: still an enigma in ARDS?. Am J Physiol Lung Cell Mol Physiol, 2014, 306(3): L217-L230.
14.	Zhang ST, Xu LT, Li AX, et al. Effects of ergosterol, isolated from Scleroderma Plyrhizum Pers., on lipopolysaccharide-induced inflammatory responses in acute lung injury. Inflammation, 2015, 38(5): 1979-1985.
15.	Wu HC, Zhao G, Jiang KF, et al. Plantamajoside ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-κB and MAPK activation. Int Immunopharmacol, 2016, 35: 315-322.
16.	Chen Q, Zhang ES, Wang C, et al. PARP-1 inhibition repressed imbalance of Th17 and Treg cells in preterm rats with intrauterine infection-induced acute respiratory distress syndrome by reducing the expression level of IL-6. J Healthc Eng, 2022, 2022: 1255674.
17.	Bi YJ, Liu GW, Yang RF. Th17 cell induction and immune regulatory effects. J Cell Physiol, 2007, 211(2): 273-278.
18.	Yu ZX, Ji MS, Yan J, et al. The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome. Crit Care, 2015, 19: 82.
19.	Xie K, Chai YS, Lin HS, et al. Luteolin regulates the differentiation of regulatory T cells and activates IL-10-dependent macrophage polarization against acute lung injury. J Immunol Res, 2021, 2021: 8883962.
20.	D'Alessio FR, Tsushima K, Aggarwal NR, 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(10): 2898-2913.
21.	Chai YS, Chen YQ, Lin SH, et al. Curcumin regulates the differentiation of naïve CD4⁺T cells and activates IL-10 immune modulation against acute lung injury in mice. Biomed Pharmacother, 2020, 125: 109946.
22.	Toyama M, Kudo D, Aoyagi T, et al. Attenuated accumulation of regulatory T cells and reduced production of interleukin 10 lead to the exacerbation of tissue injury in a mouse model of acute respiratory distress syndrome. Microbiol Immunol, 2018, 62(2): 111-123.
23.	Xu F, Lin SH, Yang YZ, et al. The effect of curcumin on sepsis-induced acute lung injury in a rat model through the inhibition of the TGF-β1/SMAD3 pathway. Int Immunopharmacol, 2013, 16(1): 1-6.
24.	冯净净, 陈家君, 王盛美, 等. 白细胞介素23在呼吸道合胞病毒感染致Th1、Th2及Th17细胞分化中的作用及机制. 微生物与感染, 2017, 12(5): 279-286.

1. Touqui L, Arbibe L. A role for phospholipase A₂ in ARDS pathogenesis. Mol Med Today, 1999, 5(6): 244-249.
2. Beal AL, Cerra FB. Multiple organ failure syndrome in the 1990s. Systemic inflammatory response and organ dysfunction. JAMA, 1994, 271(3): 226-233.
3. Shao L, Meng D, Yang F, et al. Irisin-mediated protective effect on LPS-induced acute lung injury via suppressing inflammation and apoptosis of alveolar epithelial cells. Biochem Biophys Res Commun, 2017, 487(2): 194-200.
4. Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J, 2010, 429(3): 403-417.
5. Guo S, Jiang KF, Wu HC, et al. Magnoflorine ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-κB and MAPK activation. Front Pharmacol, 2018, 9: 982.
6. Chen IC, Wang SC, Chen YT, et al. Corylin ameliorates LPS-induced acute lung injury via suppressing the MAPKs and IL-6/STAT3 signaling pathways. Pharmaceuticals (Basel, Switzerland), 2021, 14(10): 1046.
7. Peifer C, Wagner G, Laufer S. New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 MAP kinase. Curr Top Med Chem, 2006, 6(2): 113-149.
8. Lin SH, Wu H, Wang CJ, et al. Regulatory T cells and acute lung injury: cytokines, uncontrolled inflammation, and therapeutic implications. Front Immunol, 2018, 9: 1545.
9. Li MQ, Zhao Y, Qi D, et al. Tangeretin attenuates lipopolysaccharide-induced acute lung injury through Notch signaling pathway via suppressing Th17 cell response in mice. Microb Pathog, 2020, 138: 103826.
10. Nadeem A, Al-Harbi NO, Ahmad SF, et al. Blockade of interleukin-2-inducible T-cell kinase signaling attenuates acute lung injury in mice through adjustment of pulmonary Th17/Treg immune responses and reduction of oxidative stress. Int Immunopharmacol, 2020, 83: 106369.
11. Rudmann DG, Preston AM, Moore MW, et al. Susceptibility to Pneumocystis carinii in mice is dependent on simultaneous deletion of IFN-γ and type 1 and 2 TNF receptor genes. J Immunol, 1998, 161(1): 360-366.
12. Badamjav R, Sonom D, Wu YH, et al. The protective effects of Thalictrum minus L. on lipopolysaccharide-induced acute lung injury. J Ethnopharmacol, 2020, 248: 112355.
13. Williams AE, Chambers RC. The mercurial nature of neutrophils: still an enigma in ARDS?. Am J Physiol Lung Cell Mol Physiol, 2014, 306(3): L217-L230.
14. Zhang ST, Xu LT, Li AX, et al. Effects of ergosterol, isolated from Scleroderma Plyrhizum Pers., on lipopolysaccharide-induced inflammatory responses in acute lung injury. Inflammation, 2015, 38(5): 1979-1985.
15. Wu HC, Zhao G, Jiang KF, et al. Plantamajoside ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-κB and MAPK activation. Int Immunopharmacol, 2016, 35: 315-322.
16. Chen Q, Zhang ES, Wang C, et al. PARP-1 inhibition repressed imbalance of Th17 and Treg cells in preterm rats with intrauterine infection-induced acute respiratory distress syndrome by reducing the expression level of IL-6. J Healthc Eng, 2022, 2022: 1255674.
17. Bi YJ, Liu GW, Yang RF. Th17 cell induction and immune regulatory effects. J Cell Physiol, 2007, 211(2): 273-278.
18. Yu ZX, Ji MS, Yan J, et al. The ratio of Th17/Treg cells as a risk indicator in early acute respiratory distress syndrome. Crit Care, 2015, 19: 82.
19. Xie K, Chai YS, Lin HS, et al. Luteolin regulates the differentiation of regulatory T cells and activates IL-10-dependent macrophage polarization against acute lung injury. J Immunol Res, 2021, 2021: 8883962.
20. D'Alessio FR, Tsushima K, Aggarwal NR, 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(10): 2898-2913.
21. Chai YS, Chen YQ, Lin SH, et al. Curcumin regulates the differentiation of naïve CD4⁺T cells and activates IL-10 immune modulation against acute lung injury in mice. Biomed Pharmacother, 2020, 125: 109946.
22. Toyama M, Kudo D, Aoyagi T, et al. Attenuated accumulation of regulatory T cells and reduced production of interleukin 10 lead to the exacerbation of tissue injury in a mouse model of acute respiratory distress syndrome. Microbiol Immunol, 2018, 62(2): 111-123.
23. Xu F, Lin SH, Yang YZ, et al. The effect of curcumin on sepsis-induced acute lung injury in a rat model through the inhibition of the TGF-β1/SMAD3 pathway. Int Immunopharmacol, 2013, 16(1): 1-6.
24. 冯净净, 陈家君, 王盛美, 等. 白细胞介素23在呼吸道合胞病毒感染致Th1、Th2及Th17细胞分化中的作用及机制. 微生物与感染, 2017, 12(5): 279-286.

Chinese Journal of Respiratory and Critical Care Medicine

p38MAPK inhibitor ameliorates lipopolysaccharide induced acute lung injury through regulating the balance of Treg cells and Th17 cells

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