Potential Role of Nrf2 Activators with Dual Antiviral and Anti-Inflammatory Properties in the Management of Viral Pneumonia
Authors Lin CY, Yao CA
Received 5 April 2020
Accepted for publication 26 May 2020
Published 11 June 2020 Volume 2020:13 Pages 1735—1741
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Professor Suresh Antony
Chih-Yin Lin,1 Chun-An Yao2
1Department of Neurology, Chang Gung Memorial Hospital, Linkou 333, Taiwan; 2Department of Dermatology, Cathay General Hospital, Taipei, Taiwan
Correspondence: Chun-An Yao
Department of Dermatology, Cathay General Hospital, 280 Renai Road Sec. 4, Taipei, Taiwan
Email [email protected]
Abstract: The outbreak of coronavirus disease 2019 (COVID-19) pandemic has already caused a huge burden to the global healthcare system, with the death toll reached tens of thousands. Although some antiviral agents were identified and used to inhibit viral replication, the management of cytokine storm is also a critical issue. In this article, we reviewed the literature on drug candidates for severe acute respiratory syndrome (SARS-CoV-1) and provided a brief overview of a class of drugs that exert antiviral and anti-inflammatory effects. These molecules mitigated inflammatory cytokine cascades induced by viral infections via Nrf2 activating capacity and might have additional anti-fibrotic and anti-remodeling properties. Besides, their effects on the regulation of scavenger receptors expression by macrophages may offer some benefits to the pulmonary antibacterial defense system after viral infection. The potential roles of these agents assessed on the basis of the pathophysiology of viral pneumonia and acute respiratory distress syndrome were also discussed. Further research is needed to ascertain whether Nrf2 activators are useful in the management of viral pneumonia.
Keywords: COVID-19, viral pneumonia, Nrf2 activators, curcumin, sulforaphane, macrolide
The coronavirus disease 2019 (COVID-19) pandemic has already caused a tremendous burden on the healthcare system globally and poses a threat to all human beings. Scientists and doctors have been desperately trying to find possible treatments since the outbreak of the disease. Some potential treatment options, including nucleoside analogs, protease inhibitors, and interferon, were proposed and tested.1 Besides the existing antiviral drug options, naturally occurring phytochemicals might also have a role in combating viral pneumonia. In an in vitro study of severe acute respiratory syndrome coronavirus (SARS-CoV-1), several compounds with antiviral activity, including diterpenes, sesquiterpenes, lupane-type triterpenes, lignoids, and curcumin were identified.2 Interestingly, curcumin and some triterpenoids were proven to be nuclear factor erythroid 2-related factor 2 (Nrf2) activators, and the potential role of Nrf2 activators in the management of respiratory viral infection has drawn some scientists’ attention.3,4 The Nrf2-antioxidant response element (ARE) pathway is known to maintain the redox balance in cells and reduces inflammation. These groups of plant-derived chemicals and their analogs might provide a class of drugs that possesses both antiviral and anti-inflammatory properties and might help tackle the pathophysiological changes in viral pneumonia and acute respiratory distress syndrome (ARDS).3
Among the Nrf2 activators, curcumin is the most extensively studied and widely used product with established safety profile and biological effects.5–7 Curcumin has been proven to have broad-spectrum antiviral properties against many RNA viruses, including influenza A virus, respiratory syncytial virus (RSV), and norovirus.5 Animal experiments, mostly using influenza A virus, showed decreased pulmonary viral titers, decreased production of cytokines (such as TNF-α, IL-1β, and IL-6) and matrix metalloproteinase-2 and 9 (MMP-2,9), decreased infiltration of inflammatory cells, decreased pulmonary histopathological injury score, and increased animal survival.8–11 Interestingly, although curcumin did not affect the clearance of reovirus in a mouse model, it reduced collagen deposition in lung tissue and decreased the expression of myofibroblast phenotype.8 The observed anti-fibrotic and anti-remodeling effects might offer additional benefits if they translate into clinical practice because CT images of COVID-19 pneumonia patients showed ground glass opacities with partial consolidation and were absorbed with formation of fibrotic stripes after improvement.12 Whether the observed pulmonary fibrosis is a temporary phenomenon or may affect the functional recovery of patients remain to be studied. In another study, it was demonstrated that curcumin reduced the lipopolysaccharide (LPS)-induced mucin 5AC secretion in a mouse model.13 Moreover, it is also known that Nrf2, a key mediator that combats oxidative stress, can be upregulated by curcumin.4 Nrf2/ARE pathway targets more than 500 genes, including genes which regulate oxidative stress (HO-1, GCLM, and GCLC), and reduces inflammation by decreasing NF-κB and TGF-β. Many studies have demonstrated the protective effect of Nrf2 activators in hyperoxia- or LPS-induced ARDS models.3 Besides their function in the lung tissue, Nrf2 activators also have a renoprotective effect.14 Whether Nrf2 activating drugs are useful in acute kidney injury induced by ARDS remains to be further studied.
Although curcumin has been studied in various inflammatory and proliferative diseases, its effects on human respiratory tract infection have rarely been tested. In a clinical study, the effects of lactoferrin and curcumin in healthy children with recurrent respiratory infection were examined, and the results showed reduced infection and skewing of CD8+ T lymphocyte maturation.15 Direct clinical evidence of curcumin in human viral pneumonia is still limited. Besides, one of the major drawbacks of curcumin is its poor absorption and rapid metabolism. Several formulation and conjugation strategies were used to increase the bioavailability of oral curcumin.16 Different routes of administration, such as inhalation and intravenous routes, were also evaluated.17,18 However, turmeric infusion by a naturopathic practitioner even caused mortality and was considered to be related to the presence of PEG 40 castor oil.19 Therefore, pharmaceutical-grade preparation of intravenous curcumin should be used in medical institutions by qualified personnel.
Another group of molecules, namely terpenes, was also studied for its Nrf2 activating effect.4 Several semisynthetic and synthetic triterpenoids, including bardoxolone methyl and omaveloxolone, are currently undergoing clinical trials for kidney diseases. Some evidence indicates that bardoxolone methyl suppresses RNA viruses such as dengue virus and Zika virus.20 Although some experiments showed its positive effects in LPS-induced acute lung injury mouse model,21 its effect on respiratory tract infection is still largely unknown. Another Nrf2 activator named sulforaphane was also studied for its antiviral capacity, and could suppress respiratory viruses, such as RSV22 and influenza virus.23 In a human study using live attenuated influenza virus on human subjects, sulforaphane was found to increase granzyme B production in natural killer (NK) cells after inoculation.24 Lower granzyme B levels were related to the risk for influenza in institutionalized older adults, and serum granzyme B levels correlated with protection against influenza in older adults following vaccination.25,26 Besides, a study also showed that sulforaphane increased the expression of macrophage receptor with collagenous structure (MARCO) in alveolar macrophages, and thus, provided survival benefits in an animal model of postinfluenza bacterial pneumonia.27 However, although in vitro studies showed improved phagocytosis of bacteria by alveolar macrophages from patients with COPD,28 an in vivo study of sulforaphane failed to induce Nrf2 target gene expression in alveolar macrophages from the same disease population.29 Therefore, the effects of sulforaphane observed in healthy subjects may not be accurately extrapolated to patients with COPD. Besides, another advantage of sulforaphane over curcumin is that it has good oral bioavailability.30 The overall benefits of curcumin and sulforaphane were demonstrated by their ability to increase survival rates in influenza and sepsis animal models.10,11,27,31–33 However, in many experiments animals were pretreated with drugs or drugs were used on the same day of virus inoculation; the results may be different in clinical settings because patients may be at a more advanced disease stage. Whether these agents are useful for chemoprevention or treatment remains to be elucidated.
According to a recent publication, azithromycin and hydroxychloroquine combination treatment was associated with SARS-CoV-2 viral load reduction and decreased the duration of virus carriage in a small group of patients.34 The efficacy of macrolides in respiratory viral infections and inflammatory diseases has been extensively researched,35,36 and their anti-inflammatory profiles are similar to the aforementioned Nrf2 activators. An in vitro study using human small airway epithelial cells revealed that clarithromycin decreased H2O2-induced inflammation through upregulation of Nrf2 expression.37 Another study also found that azithromycin alleviated cigarette smoke extract induced inflammation in human airway epithelial cells by activating Nrf2.38 Whether the observed effects of macrolides in viral infections are related to Nrf2 activating property remains to be clarified. Another group of antibiotics, including tetracycline, minocycline, and doxycycline, is a well-known class of antibiotics with anti-inflammatory features and was proposed as a potential repurposing candidate for the management of COVID-19 diseases.39 Although a study revealed that minocycline upregulated Nrf2 in retrovirus infected astrocytes,40 another study showed that doxycycline inhibits malondialdehyde-acetaldehyde-induced activation of Nrf2 in HEK 293 Nrf2/ARE cells.41 Therefore, the impact of different drugs of the tetracycline group on the Nrf2 pathway remains to be further clarified. The effects of Nrf2 activators on the pathophysiology of viral pneumonia/ARDS based on evidence are summarized in Table 1.
Table 1 Summary of the Effects of Nrf2 Activators and Macrolides on the Pathophysiology of Viral Pneumonia/ARDS Based on Current Evidence
In conclusion, the activation of Nrf2 pathway by drugs has been researched for its antiviral and anti-oxidative mechanisms and can be the foundation for further clinical development. The Nrf2 activators and their analogs might be tested for their potential antiviral efficacy and might become drug candidates, either alone or in combination with other antiviral agents, for further clinical trials in viral pneumonia.
The authors report no conflicts of interest in this work. This work is not funded by research grants.
1. Li G, DeClercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020;19(3):149–150. doi:10.1038/d41573-020-00016-0
2. Wen CC, Kuo YH, Jan JT, et al. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J Med Chem. 2007;50(17):4087–4095. doi:10.1021/jm070295s
3. Liu Q, Gao Y, Ci X. Role of Nrf2 and its activators in respiratory diseases. Oxid Med Cell Longev. 2019;2019. doi:10.1155/2019/7090534.
4. Robledinos-Antón N, Fernández-Ginés R, Manda G, Cuadrado A. Activators and inhibitors of NRF2: A review of their potential for clinical development. Oxid Med Cell Longev. 2019;2019. doi:10.1155/2019/9372182.
5. Chen TY, Chen DY, Wen HW, et al. Inhibition of enveloped viruses infectivity by curcumin. PLoS One. 2013;8(5):1–11. doi:10.1371/journal.pone.0062482
6. Zorofchian Moghadamtousi S, Abdul Kadir H, Hassandarvish P, Tajik H, Abubakar S, Zandi K. A review on antibacterial, antiviral, and antifungal activity of curcumin. Biomed Res Int. 2014;2014. doi:10.1155/2014/186864.
7. Praditya D, Kirchhoff L, Brüning J, Rachmawati H, Steinmann J, Steinmann E. Anti-infective properties of the golden spice curcumin. Front Microbiol. 2019;10(MAY). doi:10.3389/fmicb.2019.00912
8. Avasarala S, Zhang F, Liu G, Wang R, London SD, London L. Curcumin modulates the inflammatory response and inhibits subsequent fibrosis in a mouse model of viral-induced acute respiratory distress syndrome. PLoS One. 2013;8(2):1–13. doi:10.1371/journal.pone.0057285
9. Xu Y, Liu L. Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-κB signaling pathway. Influenza Other Respi Viruses. 2017;11(5):457–463. doi:10.1111/irv.12459
10. Dai J, Gu L, Su Y, et al. Inhibition of curcumin on influenza A virus infection and influenzal pneumonia via oxidative stress, TLR2/4, p38/JNK MAPK and NF-κB pathways. Int Immunopharmacol. 2018;54(November 2017):177–187. doi:10.1016/j.intimp.2017.11.009
11. Han S, Xu J, Guo X, Huang M. Curcumin ameliorates severe influenza pneumonia via attenuating lung injury and regulating macrophage cytokines production. Clin Exp Pharmacol Physiol. 2018;45(1):84–93. doi:10.1111/1440-1681.12848
12. XuY H, Dong J-H, AnW M, et al. Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2. J Infect. 2020;80(4):394–400. doi:10.1016/j.jinf.2020.02.017
13. Lin X P, Xue C, Zhang J M, Wu W J, Chen X Y, Zeng Y M. Curcumin inhibits lipopolysaccharide-induced mucin 5AC hypersecretion and airway inflammation via nuclear factor erythroid 2-related factor 2. Chin Med J. 2018;131(14):1686–1693. doi:10.4103/0366-6999.235863
14. Shelton LM, Park BK, CoppleI M. Role of Nrf2 in protection against acute kidney injury. Kidney Int. 2013;84(6):1090–1095. doi:10.1038/ki.2013.248
15. Zuccotti GV, Trabattoni D, Morelli M, Borgonovo S, Schneider L, Clerici M. Immune modulation by lactoferrin and curcumin in children with recurrent respiratory infections. J Biol Regul Homeost Agents. 2009;23(2):119–123.
16. Jamwal R. Bioavailable curcumin formulations: A review of pharmacokinetic studies in healthy volunteers. J Integr Med. 2018;16(6):367–374. doi:10.1016/j.joim.2018.07.001
17. Hu Y, Li M, Zhang M, Jin Y. Inhalation treatment of idiopathic pulmonary fibrosis with curcumin large porous microparticles. Int J Pharm. 2018;551(1–2):212–222. doi:10.1016/j.ijpharm.2018.09.031
18. Bolger GT, Licollari A, Tan A, et al. Pharmacokinetics of liposomal curcumin (LipocurcTM) infusion: effect of co-medication in cancer patients and comparison with healthy individuals. Cancer Chemother Pharmacol. 2019;83(2):265–275. doi:10.1007/s00280-018-3730-5
19. Lasoff DR, Cantrell FL, Ly BT. Death associated with intravenous turmeric (Curcumin) preparation. Clin Toxicol. 2018;56(5):384–385. doi:10.1080/15563650.2017.1388387
20. Rothan HA, Zhong Y, Sanborn MA, et al. Small molecule grp94 inhibitors block dengue and Zika virus replication. Antiviral Res. 2019;171. doi:10.1016/j.antiviral.2019.104590
21. Chen T, Mou Y, Tan J, et al. The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice. Int Immunopharmacol. 2015;25(1):55–64. doi:10.1016/j.intimp.2015.01.011
22. ChoH Y, Imani F, Miller-DeGraff L, et al. Antiviral activity of Nrf2 in a murine model of respiratory syncytial virus disease. Am J Respir Crit Care Med. 2009;179(2):138–150. doi:10.1164/rccm.200804-535OC
23. Kesic MJ, Simmons SO, Bauer R, Jaspers I. Nrf 2 expression modifies influenza A entry and replication in nasal epithelial cells. Free Radic Biol Med. 2011;51(2):444–453. doi:10.1016/j.freeradbiomed.2011.04.027
24. Müller L, Meyer M, Bauer RN, et al. Effect of broccoli sprouts and live attenuated influenza virus on peripheral blood natural killer cells: A randomized, double-blind study. PLoS One. 2016;11:1. doi:10.1371/journal.pone.0147742
25. McElhaney JE, Gravenstein S, Upshaw CM, et al. Granzyme B: A marker of risk for influenza in institutionalized older adults. Vaccine. 2001;19(27):3744–3751. doi:10.1016/S0264-410X(01)00087-1
26. McElhaney JE, Ewen C, Zhou X, et al. Granzyme B: correlates with protection and enhanced CTL response to influenza vaccination in older adults. Vaccine. 2009;27(18):2418–2425. doi:10.1016/j.vaccine.2009.01.136
27. Wu M, Gibbons JG, DeLoid GM, et al. Immunomodulators targeting MARCO expression improve resistance to postinfluenza bacterial pneumonia. Am J Physiol Lung Cell Mol Physiol. 2017;313(1):L138–L153. doi:10.1152/ajplung.00075.2017
28. Bewley MA, Budd RC, Ryan E, et al. Opsonic phagocytosis in chronic obstructive pulmonary disease is enhanced by Nrf2 agonists. Am J Respir Crit Care Med. 2018;198(6):739–750. doi:10.1164/rccm.201705-0903OC
29. Wise RA, Holbrook JT, Criner G, et al. Lack of effect of oral sulforaphane administration on Nrf2 expression in COPD: A randomized, double-blind, placebo controlled trial. PLoS One. 2016;11:11. doi:10.1371/journal.pone.0163716
30. Houghton CA. Sulforaphane: its “coming of age” as a clinically relevant nutraceutical in the prevention and treatment of chronic disease. Oxid Med Cell Longev. 2019;2019. doi:10.1155/2019/2716870.
31. Chen L, Lu Y, Zhao L, et al. Curcumin attenuates sepsis-induced acute organ dysfunction by preventing inflammation and enhancing the suppressive function of Tregs. Int Immunopharmacol. 2018;61(October2017):1–7. doi:doi:10.1016/j.intimp.2018.04.041
32. LeeI C, Kim DY, Bae JS. Sulforaphane reduces HMGB1-mediated septic responses and improves survival rate in septic mice. Am J Chin Med. 2017;45(6):1253–1271. doi:10.1142/S0192415X17500690
33. Xiao X, Yang M, Sun D, Sun S. Curcumin protects against sepsis-induced acute lung injury in rats. J Surg Res. 2012;176:1. doi:10.1016/j.jss.2011.11.1032
34. Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020:105949. doi:10.1016/j.ijantimicag.2020.105949.
35. Min J-Y, Jang YJ. Macrolide therapy in respiratory viral infections. Mediators Inflamm. 2012;2012:649570. doi:doi:10.1155/2012/649570
36. Zimmermann P, Ziesenitz VC, Curtis N, Ritz N. The immunomodulatory effects of macrolides a systematic review of the underlying mechanisms. Front Immunol. 2018;9:302. doi:10.3389/fimmu.2018.00302
37. Iwayama K, Kusakabe A, Ohtsu K, et al. Long-term treatment of clarithromycin at a low concentration improves hydrogen peroxide-induced oxidant/antioxidant imbalance in human small airway epithelial cells by increasing Nrf2 mRNA expression. BMC Pharmacol Toxicol. 2017;18(1):15. doi:10.1186/s40360-017-0119-8
38. Yang Y, Cuevas S, Armando I, Jose P. Azithromycin induces sestrin2 expression through Nrf2 signaling pathway in lung epithelial cells stimulated with cigarette smoke extract (869.11). FASEB J. 2014;28(1_supplement):
39. Conforti C, Giuffrida R, Zalaudek I, DiMeo N. Doxycycline, a widely used antibiotic in dermatology with a possible anti‐inflammatory action against IL ‐6 in COVID ‐19 outbreak. Dermatol Ther. 2020. doi:10.1111/dth.13437
40. Kuang X, Scofield VL, Yan M, Stoica G, Liu N, Wong PKY. Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirus-induced neurodegeneration in mice. Brain Res. 2009;1286:174–184. doi:10.1016/j.brainres.2009.06.007
41. Clemens DL, Duryee MJ, Sarmiento C, et al. Novel antioxidant properties of doxycycline. Int J Mol Sci. 2018;19:12. doi:10.3390/ijms19124078
42. Sun Z, Niu Z, Wu S, Shan S. Protective mechanism of sulforaphane in Nrf2 and anti-lung injury in ARDS rabbits. Exp Ther Med. 2018;15(6):4911–4915. doi:10.3892/etm.2018.6036
43. Takahashi E, IndalaoI L, Sawabuchi T, et al. Clarithromycin suppresses induction of monocyte chemoattractant protein-1 and matrix metalloproteinase-9 and improves pathological changes in the lungs and heart of mice infected with influenza A virus. Comp Immunol Microbiol Infect Dis. 2018;56:6–13. doi:10.1016/j.cimid.2017.11.002
44. Qi T, Xu F, Yan X, Li S, Li H. Sulforaphane exerts anti-inflammatory effects against lipopolysaccharide-induced acute lung injury in mice through the Nrf2/ARE pathway. Int J Mol Med. 2016;37(1):182–188. doi:10.3892/ijmm.2015.2396
45. Kumari A, Singh DK, Dash D, Singh R. Intranasal curcumin protects against LPS-induced airway remodeling by modulating toll-like receptor-4 (TLR-4) and matrixmetalloproteinase-9 (MMP-9) expression via affecting MAP kinases in mouse model. Inflammopharmacology. 2019;27(4):731–748. doi:10.1007/s10787-018-0544-3
46. Li Q, Zhou X, Yu H, Nie X, Xu X. Regulation of neutrophil elastase-induced muc5ac expression by nuclear factor erythroid-2 related factor 2 in human airway epithelial cells. J Investig Med. 2010;58(5):730–736. doi:10.231/JIM.0b013e3181d88fde
47. Inoue D, Kubo H, Sasaki T, et al. Erythromycin attenuates MUC5AC synthesis and secretion in cultured human tracheal cells infected with RV14. Respirology. 2008;13(2):215–220. doi:10.1111/j.1440-1843.2007.01227.x
48. Zingg J-M, Nakagawa K, Azzi A, Meydani M. Modulation of CD36 scavenger receptor expression by curcumin and vitamin E affects cellular uptake of lipids and bacteria (639.1). FASEB J. 2014;28(1_supplement):
49. Harvey CJ, Thimmulappa RK, Sethi S, et al. Targeting Nrf2 signaling improves bacterial clearance by alveolar macrophages in patients with COPD and in a mouse model. Sci Transl Med. 2011;3(78):78ra32. doi:10.1126/scitranslmed.3002042
50. Ishimatsu Y, Harada T, Hara A, et al. The preventive effect of macrolide antibiotics on postinfluenza bacterial pneumonia in COPD model mice. In:
51. Simonis FD, deIudicibus G, Cremer OL, et al. Macrolide therapy is associated with reduced mortality in acute respiratory distress syndrome (ARDS) patients. Ann Transl Med. 2018;6(2):24. doi:10.21037/atm.2017.12.25
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF]