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beas-2b, cxcl3, hpaec, inflammation, lipopolysaccharide, mapks, sepsis
Background: CXCL3 (C-X-C motif chemokine ligand 3) is a member of chemokines family, which binds to the receptor to recruit neutrophils to lungs, thus participating in the pathogenesis of asthmatic lung. The role of CXCL3 in sepsis-induced acute lung injury is investigated here.
Methods: Human lung epithelial cell line (BEAS-2B) and human pulmonary artery endothelial cell line (HPAEC) were treated with lipopolysaccharides (LPS). MTT and flow cytometry were performed to detect cell viability and apoptosis, respectively. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to assess the levels of inflammatory factors.
Results: Treatment with LPS resulted in the decrease of cell viability in BEAS-2B and HPAEC. CXCL3 was particularly upregulated in LPS-treated BEAS-2B and HPAE cells. Knockdown of CXCL3 enhanced viability and suppressed apoptosis i006E LPS-treated BEAS-2B and HPAE cells. Knockdown of CXCL3 also upregulated TNF-α, IL-1β, and IL-18 in LPS-treated BEAS-2B and HPAE cells. Moreover, knockdown of CXCL3 suppressed the activation of mitogen-activated protein kinases (MAPKs) signaling in LPS-treated BEAS-2B and HPAE cells through downregulation of p-ERK1/2, p-p38, and p-JNK. On the other hand, overexpression of CXCL3 caused completely opposite results in LPS-treated BEAS-2B and HPAE cells.
Conclusion: Knockdown of CXCL3 exerted antiapoptotic and anti-inflammatory effects against LPS-treated BEAS-2B and HPAE cells, at least partially, through inactivation of MAPKs signaling, suggesting a potential strategy for the intervention of sepsis-induced acute lung injury.
2. Gustot T. Multiple organ failure in sepsis: Prognosis and role of systemic inflammatory response. Curr Opin Crit Care. 2011;17(2):153–9. 10.1097/MCC.0b013e328344b446
3. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: Analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11. 10.1016/S0140-6736(19)32989-7
4. Sadowitz B, Roy S, Gatto LA, Habashi N, Nieman G. Lung injury induced by sepsis: Lessons learned from large animal models and future directions for treatment. Expert Rev Anti Infect Ther. 2011;9(12):1169–78. 10.1586/eri.11.141
5. Rittirsch D, Flierl MA, Day DE, Nadeau BA, McGuire SR, Hoesel LM, et al. Acute lung injury induced by lipopolysaccharide is independent of complement activation. J Immunol. 2008;180(11):7664–72. 10.4049/jimmunol.180.11.7664
6. Xia Y, Cao Y, Sun Y, Hong X, Tang Y, Yu J, et al. Calycosin alleviates sepsis-induced acute lung injury via the inhibition of mitochondrial ROS-mediated inflammasome activation. Front Pharmacol. 2021;12: 690549. 10.3389/fphar.2021.690549
7. Mullarkey M, Rose JR, Bristol J, Kawata T, Kimura A, Kobayashi S, et al. Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther. 2003;304(3):1093–102. 10.1124/jpet.102.044487
8. Takashima K, Matsunaga N, Yoshimatsu M, Hazeki K, Kaisho T, Uekata M, et al. Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. Br J Pharmacol. 2009;157(7):1250–62. 10.1111/j.1476-5381.2009.00297.x
9. Opal SM, Laterre P-F, Francois B, LaRosa SP, Angus DC, Mira J-P, et al. Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: The ACCESS randomized trial. JAMA. 2013;309(11):1154–62. 10.1001/jama.2013.2194
10. Tidswell M, Tillis W, LaRosa SP, Lynn M, Wittek AE, Kao R, et al. Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med. 2010;38(1):72–83. 10.1097/CCM.0b013e3181b07b78
11. Rice TW, Wheeler AP, Bernard GR, Vincent J-L, Angus DC, Aikawa N, et al. A randomized, double-blind, placebo--controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med. 2010;38(8):1685–94. 10.1097/CCM.0b013e3181e7c5c9
12. Esche C, Stellato C, Beck LA. Chemokines: Key Players in Innate and Adaptive Immunity. J Invest Dermatol. 2005;125(4):615–28. 10.1111/j.0022-202X.2005.23841.x
13. Meng L, Cao H, Wan C, Jiang L. MiR-539-5p alleviates sepsis-induced acute lung injury by targeting ROCK1. Folia Histochem Cytobiol. 2019;57(4):168–78. 10.5603/FHC.a2019.0019
14. Jin L, Batra S, Douda DN, Palaniyar N, Jeyaseelan S. CXCL1 contributes to host defense in polymicrobial sepsis via modulating T cell and neutrophil functions. J Immunol. 2014;193(7):3549–58. 10.4049/jimmunol.1401138
15. Strieter RM, Gomperts BN, Keane MP. The role of CXC chemokines in pulmonary fibrosis. J Clin Invest. 2007;117(3):549–56. 10.1172/JCI30562
16. Cheng Y, Ma X-l, Wei Y-q, Wei X-W. Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochim Biophys Acta Rev. 2019;1871(2):289–312. 10.1016/j.bbcan.2019.01.005
17. Sokulsky LA, Garcia-Netto K, Nguyen TH, Girkin JLN, Collison A, Mattes J, et al. A critical role for the CXCL3/CXCL5/CXCR2 neutrophilic chemotactic axis in the regulation of type 2 responses in a model of rhinoviral-induced asthma exacerbation. J Immunol. 2020;205(9):2468. 10.4049/jimmunol.1901350
18. Dong W-W, Feng Z, Zhang Y-Q, Ruan Z-S, Jiang L. Potential mechanism and key genes involved in mechanical ventilation and lipopolysaccharide-induced acute lung injury. Mol Med Rep. 2020;22(5):4265–77. 10.3892/mmr.2020.11507
19. Yan Z, Xiaoyu Z, Zhixin S, Di Q, Xinyu D, Jing X, et al. Rapamycin attenuates acute lung injury induced by LPS through inhibition of Th17 cell proliferation in mice. Sci Rep. 2016;6(1):20156. 10.1038/srep20156
20. Wang X, Zhao Z, Zhu K, Bao R, Meng Y, Bian J, et al. Effects of CXCL4/CXCR3 on the lipopolysaccharide-induced injury in human umbilical vein endothelial cells. J Cell Physiol. 2019;234(12):22378–85. 10.1002/jcp.28803
21. Tu G-W, Ju M-J, Zheng Y-J, Hao G-W, Ma G-G, Hou J-Y, et al. CXCL16/CXCR6 is involved in LPS-induced acute lung injury via P38 signalling. J Cell Mol Med. 2019;23(8):5380–9. 10.1111/jcmm.14419
22. Chen L, Xu J, Deng M, Liang Y, Ma J, Zhang L, et al. Telmisartan mitigates lipopolysaccharide (LPS)-induced production of mucin 5AC (MUC5AC) through increasing suppressor of cytokine signaling 1 (SOCS1). Bioengineered. 2021;12(1):3912–23. 10.1080/21655979.2021.1943605
23. He M, Shi W, Yu M, Li X, Xu J, Zhu J, et al. Nicorandil attenuates LPS-induced acute lung Injury by pulmonary endothelial cell protection via NF-κB and MAPK pathways. Oxid Med Cell Longev. 2019;2019:4957646. 10.1155/2019/4957646
24. Fang W, Cai SX, Wang CL, Sun XX, Li K, Yan XW, et al. Modulation of mitogen-activated protein kinase attenuates sepsis-induced acute lung injury in acute respiratory distress syndrome rats. Mol Med Rep. 2017;16(6):9652–8. 10.3892/mmr.2017.7811
25. Chen J, Xue X, Cai J, Jia L, Sun B, Zhao W. Protective effect of taurine on sepsis-induced lung injury via inhibiting the p38/MAPK signaling pathway. Mol Med Rep. 2021;24(3):653. 10.3892/mmr.2021.12292
26. Qi Y-L, Li Y, Man X-X, Sui H-Y, Zhao X-L, Zhang P-X, et al. CXCL3 overexpression promotes the tumorigenic potential of uterine cervical cancer cells via the MAPK/ERK pathway. J Cell Physiol. 2020;235(5):4756–65. 10.1002/jcp.29353
27. Kusuyama J, Komorizono A, Bandow K, Ohnishi T, Matsuguchi T. CXCL3 positively regulates adipogenic differentiation. J Lipid Res. 2016;57(10):1806–20. 10.1194/jlr.M067207