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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

Oral Hydroxychloroquine Mitigates Lipopolysaccharide-induced Lung Injury by Inhibiting Pyroptosis in Mice

Author(s): Rui Xiong*, Ning Li*, Juan Xiong*, Bohao Liu, Ruyuan He, Bo Wang and Qing Geng

Volume 16, Issue 3, 2023

Published on: 12 October, 2022

Article ID: e220822207840 Pages: 12

DOI: 10.2174/1874467215666220822110855

Price: $65

Abstract

Background and Objective: Hydroxychloroquine (HCQ) is a molecule derived from quinacrine; it displays a wide range of pharmacological properties, including anti-inflammatory, immunomodulatory, and antineoplastic. However, little is known about this molecule’s role in lung injury. This study aimed to identify HCQ’s regulatory role of HCQ in sepsis-induced lung injury and its molecular mechanism. Methods: To test the protective properties of HCQ, we established an in vivo model of lipopolysaccharide (LPS)-induced lung injury in mice. The extent of the injury was determined by evaluating histopathology, inflammatory response, oxidative stress, and apoptosis. Mechanistically, conventional nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing 3 (NLRP3) knockout mice were employed to investigate whether HCQ exerted pulmonary protection by inhibiting NLRP3-mediated pyroptosis.

Results: Our findings revealed that HCQ pretreatment significantly mitigated LPS-induced lung injury in mice in terms of histopathology, inflammatory response, oxidative stress, and apoptosis, while inhibiting LPS-induced NLRP3 inflammasome activation and pyroptosis. Additionally, the indicators of lung injury, including histopathology, inflammatory response, oxidative stress, and apoptosis, were still reduced drastically in LPS-treated NLRP3 (-/-) mice after HCQ pretreatment. Notably, HCQ pretreatment further decreased the levels of pyroptosis indicators, including IL-1β, IL-18 and Cle-GSDMD, in LPS-treated NLRP3 (-/-) mice.

Conclusion: Taken together, HCQ protects against lung injury by inhibiting pyroptosis, maybe not only through the NLRP3 pathway but also through non-NLRP3 pathway; therefore, it may be a new therapeutic strategy in the treatment of lung injury.

Keywords: Hydroxychloroquine, lung injury, NLRP3, pyroptosis inflammation, oxidative stress, apoptosis

Graphical Abstract

[1]
Spragg, R.G.; Bernard, G.R.; Checkley, W.; Curtis, J.R.; Gajic, O.; Guyatt, G.; Hall, J.; Israel, E.; Jain, M.; Needham, D.M.; Randolph, A.G.; Rubenfeld, G.D.; Schoenfeld, D.; Thompson, B.T.; Ware, L.B.; Young, D.; Harabin, A.L. Beyond mortality: Future clinical research in acute lung injury. Am. J. Respir. Crit. Care Med., 2010, 181(10), 1121-1127.
[http://dx.doi.org/10.1164/rccm.201001-0024WS] [PMID: 20224063]
[2]
Zhou, Y.; Li, P.; Goodwin, A.J.; Cook, J.A.; Halushka, P.V.; Chang, E.; Zingarelli, B.; Fan, H. Exosomes from endothelial progenitor cells improve outcomes of the lipopolysaccharide-induced acute lung injury. Crit. Care, 2019, 23(1), 44.
[http://dx.doi.org/10.1186/s13054-019-2339-3] [PMID: 30760290]
[3]
Lei, J.; Wei, Y.; Song, P.; Li, Y.; Zhang, T.; Feng, Q.; Xu, G. Cordycepin inhibits LPS-induced acute lung injury by inhibiting inflammation and oxidative stress. Eur. J. Pharmacol., 2018, 818, 110-114.
[http://dx.doi.org/10.1016/j.ejphar.2017.10.029] [PMID: 29054740]
[4]
Xie, W.; Lu, Q.; Wang, K.; Lu, J.; Gu, X.; Zhu, D.; Liu, F.; Guo, Z. miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin. J. Cell. Physiol., 2018, 233(9), 6615-6631.
[http://dx.doi.org/10.1002/jcp.26274] [PMID: 29150939]
[5]
Shi, J.; Gao, W.; Shao, F. Pyroptosis: Gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci., 2017, 42(4), 245-254.
[http://dx.doi.org/10.1016/j.tibs.2016.10.004] [PMID: 27932073]
[6]
Zhang, J.; Sun, X.; Zhong, L.; Shen, B. IL-32 exacerbates adenoid hypertrophy via activating NLRP3-mediated cell pyroptosis, which promotes inflammation. Mol. Med. Rep., 2021, 23(3), 1.
[http://dx.doi.org/10.3892/mmr.2021.11865] [PMID: 33495843]
[7]
Wang, Y.; Song, X.; Li, Z.; Liu, N.; Yan, Y.; Li, T.; Sun, W.; Guan, Y.; Li, M.; Yang, Y.; Yang, X.; Liu, B. MicroRNA-103 protects coronary artery endothelial cells against H2O2-induced oxidative stress via BNIP3-mediated end-stage autophagy and antipyroptosis pathways. Oxid. Med. Cell. Longev., 2020, 2020, 8351342.
[http://dx.doi.org/10.1155/2020/8351342] [PMID: 32190178]
[8]
Wei, Z.; Nie, G.; Yang, F.; Pi, S.; Wang, C.; Cao, H.; Guo, X.; Liu, P.; Li, G.; Hu, G.; Zhang, C. Inhibition of ROS/NLRP3/Caspase-1 mediated pyroptosis attenuates cadmium-induced apoptosis in duck renal tubular epithelial cells. Environ. Pollut., 2020, 273, 11519.
[9]
Wang, Y-C.; Liu, Q-X.; Zheng, Q.; Liu, T.; Xu, X-E.; Liu, X-H.; Gao, W.; Bai, X-J.; Li, Z-F. Dihydromyricetin alleviates sepsis-induced acute lung injury through inhibiting NLRP3 inflammasome-dependent pyroptosis in mice model. Inflammation, 2019, 42(4), 1301-1310.
[http://dx.doi.org/10.1007/s10753-019-00990-7] [PMID: 30887396]
[10]
Lamkanfi, M.; Dixit, V.M. Inflammasomes and their roles in health and disease. Annu. Rev. Cell Dev. Biol., 2012, 28(1), 137-161.
[http://dx.doi.org/10.1146/annurev-cellbio-101011-155745] [PMID: 22974247]
[11]
Shi, J.; Zhao, Y.; Wang, K.; Shi, X.; Wang, Y.; Huang, H.; Zhuang, Y.; Cai, T.; Wang, F.; Shao, F. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature, 2015, 526(7575), 660-665.
[http://dx.doi.org/10.1038/nature15514] [PMID: 26375003]
[12]
Wallace, D.J. The history of antimalarials. Lupus, 1996, 5(Suppl. 1), S2-S3.
[http://dx.doi.org/10.1177/0961203396005001021] [PMID: 8803902]
[13]
Stevens, D.M.; Crist, R.M.; Stern, S.T. Nanomedicine reformulation of chloroquine and hydroxychloroquine. Molecules, 2020, 26(1), E175.
[http://dx.doi.org/10.3390/molecules26010175] [PMID: 33396545]
[14]
Chew, C.Y.; Mar, A.; Nikpour, M.; Saracino, A.M. Hydroxychloroquine in dermatology: New perspectives on an old drug. Australas. J. Dermatol., 2020, 61(2), e150-e157.
[http://dx.doi.org/10.1111/ajd.13168] [PMID: 31612996]
[15]
Tang, T.T.; Lv, L.L.; Pan, M.M.; Wen, Y.; Wang, B.; Li, Z.L.; Wu, M.; Wang, F.M.; Crowley, S.D.; Liu, B.C. Hydroxychloroquine attenuates renal ischemia/reperfusion injury by inhibiting cathepsin mediated NLRP3 inflammasome activation. Cell Death Dis., 2018, 9(3), 351.
[http://dx.doi.org/10.1038/s41419-018-0378-3] [PMID: 29500339]
[16]
Fujita, Y.; Matsuoka, N.; Temmoku, J.; Furuya, M.Y.; Asano, T.; Sato, S.; Kobayashi, H.; Watanabe, H.; Suzuki, E.; Urano, T.; Kozuru, H.; Yatsuhashi, H.; Koga, T.; Kawakami, A.; Migita, K. Hydroxychloroquine inhibits IL-1β production from amyloid-stimulated human neutrophils. Arthritis Res. Ther., 2019, 21(1), 250.
[http://dx.doi.org/10.1186/s13075-019-2040-6] [PMID: 31775905]
[17]
Ning, L.; Wei, W.; Wenyang, J.; Rui, X.; Qing, G. Cytosolic DNA-STING-NLRP3 axis is involved in murine acute lung injury induced by lipopolysaccharide. Clin. Transl. Med., 2020, 10(7), e228.
[http://dx.doi.org/10.1002/ctm2.228] [PMID: 33252860]
[18]
Wang, R.; Xi, L.; Kukreja, R.C. PDE5 inhibitor tadalafil and hydroxychloroquine cotreatment provides synergistic protection against type 2 diabetes and myocardial infarction in mice. J. Pharmacol. Exp. Ther., 2017, 361(1), 29-38.
[http://dx.doi.org/10.1124/jpet.116.239087] [PMID: 28123046]
[19]
Jiang, T.; Liu, Y.; Meng, Q.; Lv, X.; Yue, Z.; Ding, W.; Liu, T.; Cui, X. Hydrogen sulfide attenuates lung ischemia-reperfusion injury through SIRT3-dependent regulation of mitochondrial function in type 2 diabetic rats. Surgery, 2019, 165(5), 1014-1026.
[http://dx.doi.org/10.1016/j.surg.2018.12.018] [PMID: 30824287]
[20]
Li, N.; Zhou, H.; Wu, H.; Wu, Q.; Duan, M.; Deng, W.; Tang, Q. STING-IRF3 contributes to lipopolysaccharide-induced cardiac dysfunction, inflammation, apoptosis and pyroptosis by activating NLRP3. Redox Biol., 2019, 24, 101215.
[http://dx.doi.org/10.1016/j.redox.2019.101215] [PMID: 31121492]
[21]
Matthay, M.A.; Ware, L.B.; Zimmerman, G.A. The acute respiratory distress syndrome. J. Clin. Invest., 2012, 122(8), 2731-2740.
[http://dx.doi.org/10.1172/JCI60331] [PMID: 22850883]
[22]
Li, N.; Xiong, R.; He, R.; Liu, B.; Wang, B.; Geng, Q. Mangiferin mitigates lipopolysaccharide-induced lung injury by inhibiting NLRP3 inflammasome activation. J. Inflamm. Res., 2021, 14, 2289-2300.
[http://dx.doi.org/10.2147/JIR.S304492] [PMID: 34103962]
[23]
Gao, Y.; Huang, X.; Lin, H.; Zhao, M.; Liu, W.; Li, W.; Han, L.; Ma, Q.; Dong, C.; Li, Y.; Hu, Y.; Jin, F. Adipose mesenchymal stem cell-derived antioxidative extracellular vesicles exhibit anti-oxidative stress and immunomodulatory effects under PM2.5 exposure. Toxicology, 2021, 447, 152627.
[http://dx.doi.org/10.1016/j.tox.2020.152627] [PMID: 33161053]
[24]
Chen, X.; Chen, Y.; Chen, Y.; Wang, X.; He, M. Protective effect of lutein on oxidative stress damage caused by acute PM2.5 exposure in rats. Ann. Palliat. Med., 2020, 9(4), 2028-2036.
[http://dx.doi.org/10.21037/apm-20-1138] [PMID: 32692236]
[25]
Liu, Y.; Tong, C.; Xu, Y.; Cong, P.; Liu, Y.; Shi, L.; Shi, X.; Zhao, Y.; Bi, G.; Jin, H.; Hou, M. CD28 deficiency ameliorates blast exposure-induced lung inflammation, oxidative stress, apoptosis, and T cell accumulation in the lungs via the PI3K/Akt/FoxO1 signaling pathway. Oxid. Med. Cell. Longev., 2019, 2019, 4848560.
[http://dx.doi.org/10.1155/2019/4848560] [PMID: 31565151]
[26]
Liu, Y.; Tong, C.; Tang, Y.; Cong, P.; Liu, Y.; Shi, X.; Shi, L.; Zhao, Y.; Jin, H.; Li, J.; Hou, M. Tanshinone IIA alleviates blast-induced inflammation, oxidative stress and apoptosis in mice partly by inhibiting the PI3K/Akt/FoxO1 signaling pathway. Free Radic. Biol. Med., 2020, 152, 52-60.
[http://dx.doi.org/10.1016/j.freeradbiomed.2020.02.032] [PMID: 32131025]
[27]
Kist, M.; Vucic, D. Cell death pathways: Intricate connections and disease implications. EMBO J., 2021, 40(5), e106700.
[http://dx.doi.org/10.15252/embj.2020106700] [PMID: 33439509]
[28]
Zhang, Y.; Li, X.; Grailer, J.J.; Wang, N.; Wang, M.; Yao, J.; Zhong, R.; Gao, G.F.; Ward, P.A.; Tan, D.X.; Li, X. Melatonin alleviates acute lung injury through inhibiting the NLRP3 inflammasome. J. Pineal Res., 2016, 60(4), 405-414.
[http://dx.doi.org/10.1111/jpi.12322] [PMID: 26888116]
[29]
Burmeister, R.; Rhoderick, J.F.; Holian, A. Prevention of crystalline silica-induced inflammation by the anti-malarial hydroxychloroquine. Inhal. Toxicol., 2019, 31(7), 274-284.
[http://dx.doi.org/10.1080/08958378.2019.1668091] [PMID: 31556748]
[30]
Li, Y.; Cao, F.; Li, M.; Li, P.; Yu, Y.; Xiang, L.; Xu, T.; Lei, J.; Tai, Y.Y.; Zhu, J.; Yang, B.; Jiang, Y.; Zhang, X.; Duo, L.; Chen, P.; Yu, X. Hydroxychloroquine induced lung cancer suppression by enhancing chemo-sensitization and promoting the transition of M2-TAMs to M1-like macrophages. J. Exp. Clin. Cancer Res., 2018, 37(1), 259.
[http://dx.doi.org/10.1186/s13046-018-0938-5] [PMID: 30373678]
[31]
Liu, L.; Ren, J.; He, Z.; Men, K.; Mao, Y.; Ye, T.; Chen, H.; Li, L.; Xu, B.; Wei, Y.; Wei, X. Cholesterol-modified hydroxychloroquine-loaded nanocarriers in bleomycin-induced pulmonary fibrosis. Sci. Rep., 2017, 7(1), 10737.
[http://dx.doi.org/10.1038/s41598-017-11450-3] [PMID: 28878315]
[32]
Camilli, G.; Blagojevic, M.; Naglik, J.; Richardson, J. Programmed cell death: Central player in fungal infections. Trends Cell Biol., 2020.
[PMID: 33293167]
[33]
Kovarova, M.; Hesker, P.; Jania, L.; Nguyen, M.; Snouwaert, J.; Xiang, Z.; Lommatzsch, S.; Huang, M.; Ting, J.; Koller, B. NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice. J. Immunol., 2012, 189(4), 2006-2016.
[34]
He, Y.; Xu, K.; Wang, Y.; Chao, X.; Xu, B.; Wu, J.; Shen, J.; Ren, W.; Hu, Y. AMPK as a potential pharmacological target for alleviating LPS-induced acute lung injury partly via NLRC4 inflammasome pathway inhibition. Exp. Gerontol., 2019, 125, 110661.
[http://dx.doi.org/10.1016/j.exger.2019.110661] [PMID: 31319131]
[35]
Zhang, H.; Luo, J.; Alcorn, J.; Chen, K.; Fan, S.; Pilewski, J.; Liu, A.; Chen, W.; Kolls, J.; Wang, J. AIM2 inflammasome is critical for influenza-induced lung injury and mortality. J. Immunol., 2017, 198(11), 4383-4393.

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