Dimethyl itaconate inhibits LPS-induced inflammatory release and apoptosis in alveolar type II epithelial and bronchial epithelial cells by activating pulmonary surfactant proteins A and D

Main Article Content

Yun Shi
Huai-qing Yin


dimethyl itaconate, inflammatory release, apoptosis, pulmonary surfactant protein, lung injury


Background: Injury to the lung is a common, clinically serious inflammatory disease. However, its pathogenesis remains unclear, and the existing treatments, including cytokine therapy, stem cell therapy, and hormone therapy, are not completely effective in treating this disease. Dimethyl itaconate (DMI) is a surfactant with important anti-inflammatory effects.

Objective: The present study used alveolar type II (AT II) and bronchial epithelial cells as models to determine the role of DMI in lung injury.

Material and Methods: First, the effects of DMI were established on the survival, inflammatory release, and apoptosis in lipopolysaccharide (LPS)-induced AT II and bronchial epithelial cells. The association between DMI and Sirtuin1 (SIRT1) was assessed using molecular docking. Next, by constructing interference plasmids to inhibit surfactant protein (SP)-A and SP-D expressions, the effect of DMI was observed on inflammatory release and apoptosis.

Results: The results revealed that DMI increased the survival rate and expression levels of SP-A, SP-D, and SIRT1, and inhibited inflammatory factors as well as apoptosis in LPS-induced cells. Furthermore, DMI could bind to SIRT1 to regulate SP-A and SP-D expressions. After SP-A and SP-D expressions were inhibited, the inhibitory effect of DMI was reversed on inflammatory release and apoptosis.

Conclusion: The findings of the present study revealed that DMI inhibited LPS-induced inflammatory release and apoptosis in cells by targeting SIRT1 and then activating SP-A and SP-D. This novel insight into the pharmacological mechanism of DMI lays the foundation for its later use for alleviating lung injury.

Abstract 157 | PDF Downloads 190 HTML Downloads 11 XML Downloads 8


1. Vishnupriya S, Priya Dharshini LC, Sakthivel KM, Rasmi RR. Autophagy markers as mediators of lung injury—Implication for therapeutic intervention. Life Sci. 2020 Nov 1;260:118308. 10.1016/j.lfs.2020.118308

2. Nova Z, Skovierova H, Calkovska A. Alveolar-capillary membrane-related pulmonary cells as a target in endotoxin--induced acute lung injury. Int J Mol Sci. 2019 Feb 15;20(4):831. 10.3390/ijms20040831

3. Laubach VE, Sharma AK. Mechanisms of lung ischemia--reperfusion injury. Curr Opin Organ Transplant. 2016 Jun;21(3):246–52. 10.1097/MOT.0000000000000304

4. Hughes KT, Beasley MB. Pulmonary manifestations of acute lung injury: More than just diffuse alveolar damage. Arch Pathol Lab Med. 2017 Jul;141(7):916–22. 10.5858/arpa.2016-0342-RA

5. Shafeeq H, Lat I. Pharmacotherapy for acute respiratory distress syndrome. Pharmacotherapy. 2012 Oct;32(10):943–57. 10.1002/j.1875-9114.2012.01115

6. Matthay MA, Goolaerts A, Howard JP, Lee JW. Mesenchymal stem cells for acute lung injury: Preclinical evidence. Crit Care Med. 2010 Oct;38(10 Suppl):S569–73. 10.1097/CCM.0b013e3181f1ff1d

7. Beitler JR, Malhotra A, Thompson BT. Ventilator-induced lung injury. Clin Chest Med. 2016 Dec;37(4):633–46. 10.1016/j.ccm.2016.07.004

8. Katira BH. Ventilator-induced lung injury: Classic and novel concepts. Respir Care. 2019 Jun;64(6):629–37. 10.4187/respcare.07055

9. Hanania AN, Mainwaring W, Ghebre YT, Hanania NA, Ludwig M. Radiation-induced lung injury: Assessment and management. Chest. 2019 Jul;156(1):150–62. 10.1016/j.chest.2019.03.033

10. Monsel A, Zhu YG, Gudapati V, Lim H, Lee JW. Mesenchymal stem cell-derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases. Expert Opin Biol Ther. 2016 Jul;16(7):859–71. 10.1517/14712598.2016.1170804

11. Kishore U, Greenhough TJ, Waters P, Shrive AK, Ghai R, Kamran MF, et al. Surfactant proteins SP-A and SP-D: Structure, function and receptors. Mol Immunol. 2006 Mar;43(9):1293–315. 10.1016/j.molimm.2005.08.004

12. Wu A, Song H. Regulation of alveolar type 2 stem/progenitor cells in lung injury and regeneration. Acta Biochim et Biophys Sinica. 2020 Jul 10;52(7):716–22. 10.1093/abbs/gmaa052

13. Schicht M, Knipping S, Hirt R, Beileke S, Sel S, Paulsen F, et al. Detection of surfactant proteins A, B, C, and D in human nasal mucosa and their regulation in chronic rhinosinusitis with polyps. Am J Rhinol Allergy. 2013 Jan;27(1):24–9. 10.2500/ajra.2013.27.3838

14. Goto H, Ledford JG, Mukherjee S, Noble PW, Williams KL, Wright JR. The role of surfactant protein A in-bleomycin-induced acute lung injury. Am J Respir Crit Care Med. 2010 Jun 15;181(12):1336–44. 10.1164/rccm.200907-1002OC

15. Gu C, Zhang Q, Ni D, Xiao QF, Cao LF, Fei CY, et al. Therapeutic effects of SRT2104 on lung injury in rats with emphysema via reduction of type II alveolar epithelial cell senescence. Copd. 2020 Aug;17(4):444–51. 10.1080/15412555.2020.1797657

16. Gu L, Lin J, Wang Q, Li C, Peng X, Fan Y, et al. Dimethyl itaconate protects against fungal keratitis by activating the Nrf2/HO-1 signaling pathway. Immunol Cell Biol. 2020 Mar;98(3):229–41. 10.1111/imcb.12316

17. Zhang D, Lu Z, Zhang Z, Man J, Guo R, Liu C, et al. A likely protective effect of dimethyl itaconate on cerebral ischemia/reperfusion injury. Int Immunopharmacol. 2019 Dec;77: 105924. 10.1016/j.intimp.2019.105924

18. Zhao C, Jiang P, He Z, Yuan X, Guo J, Li Y, et al. Dimethyl itaconate protects against lippolysacchride-induced mastitis in mice by activating MAPKs and Nrf2 and inhibiting NF-κB signaling pathways. Microb Pathog. 2019 Aug;133:103541. 10.1016/j.micpath.2019.05.024

19. Pfalzgraff A, Weindl G. Intracellular lipopolysaccharide sensing as a potential therapeutic target for sepsis. Trends Pharmacol Sci. 2019 Mar;40(3):187–97. 10.1016/j.tips.2019.01.001

20. Zhang C, Zhu X, Hua Y, Zhao Q, Wang K, Zhen L, et al. YY1 mediates TGF-β1-induced EMT and pro-fibrogenesis in alveolar epithelial cells. Respir Res. 2019 Nov 8;20(1):249. 10.1186/s12931-019-1223-7

21. Pal PB, Sonowal H, Shukla K, Srivastava SK, Ramana KV. Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-α1/mTOR pathway. J Mol Endocrinol. 2019 Jul 1;63(1):11–25. 10.1530/JME-19-0080

22. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) method. Methods (San Diego). 2001 Dec;25(4):402–8. 10.1006/meth.2001.1262

23. Mills EL, Ryan DG, Prag HA, Dikovskaya D, Menon D, Zaslona Z, et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018 Apr 5;556(7699):113–7. 10.1038/nature25986

24. Domínguez-Andrés J, Novakovic B, Li Y, Scicluna BP, Gresnigt MS, Arts RJW, et al. The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab. 2019 Jan 8;29(1):211–20.e5. 10.1016/j.cmet.2018.09.003

25. Swain A, Bambouskova M, Kim H, Andhey PS, Duncan D, Auclair K, et al. Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages. Nature Metab. 2020 Jul;2(7):594–602. 10.1038/s42255-020-0210-0

26. Shen L, Li L, She H, Yue S, Li C, Luo Z. Inhibition of pulmonary surfactants synthesis during N-methyl-D-aspartate-induced lung injury. Basic Clin Pharmacol Toxicol. 2010 Sep;107(3):751–7. 10.1111/j.1742-7843.2010.00572.x

27. Zhang S, Jiao Y, Li C, Liang X, Jia H, Nie Z, et al. Dimethyl itaconate alleviates the inflammatory responses of macrophages in sepsis. Inflammation. 2021 Apr;44(2):549–57. 10.1007/s10753-020-01352-4

28. Akash MSH, Rehman K, Liaqat A. Tumor necrosis factor-alpha: Role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. J Cell Biochem. 2018 Jan;119(1):105–10. 10.1002/jcb.26174

29. Holtmann MH, Neurath MF. Differential TNF-signaling in chronic inflammatory disorders. Curr Mol Med. 2004 Jun;4(4): 439–44. 10.2174/1566524043360636

30. Jia P, Liu W, Liu S, Gao W. Therapeutic effects of Hedyotis diffusa Willd. on type II collagen-induced rheumatoid arthritis in rats. Chin J Appl Physiol (Zhongguo Ying Yong Sheng Li Xue Za Zhi). 2018 Jun 8;34(6):558–61.

31. Kang S, Tanaka T, Narazaki M, Kishimoto T. Targeting-interleukin-6 signaling in clinic. Immunity. 2019 Apr 16;50(4): 1007–23. 10.1016/j.immuni.2019.03.026