Knockdown of THBS1 inhibits inflammatory damage and oxidative stress in in vitro pneumonia model by regulating NF-κB signaling pathway
Main Article Content
Keywords
pneumonia, LPS, inflammation, oxidative stress, NF-κB
Abstract
Pneumonia is an acute lower respiratory tract infection in children and the elderly. Recent studies have identified the significance of thrombospondin1 (THBS1) in inflammation. Nonetheless, the specific mechanisms by which THBS1 operates in pneumonia remain unclear. We treated 16HBE cells as an in vitro pneumonia model with lipopolysaccharide (LPS) and conducted a series of experiments to examine markers of inflammation and oxidative stress. LPS induces an increase in THBS1 expression in 16HBE cells. Knockdown of THBS1 reversed LPS-induced release of inflammatory factors [tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β]. Knocking down THBS1 reversed the LPS-induced increase in ROS and MDA and the decrease in SOD and GSH-Px. Inhibition of LPS led to the reversal of NF-κB pathway activation in response to LPS. Suppression of THBS1 hindered the NF-κB signaling cascade, resulting in a decrease in inflammation and oxidative stress triggered by LPS.
References
2 Furman CD, Leinenbach A, Usher R, Elikkottil J, Arnold FW. Pneumonia in older adults. Curr. Opin. Infect. Dis. 2021;34(2):135–41. 10.1097/QCO.0000000000000718
3 Chebib N, Cuvelier C, Malezieux-Picard A, Parent T, Roux X, Fassier T, et al. Pneumonia prevention in the elderly patients: The other sides. Aging Clin. Exp. Res. 2021;33(4):1091–100. 10.1007/s40520-019-01437-7
4 Teramoto S. The current definition, epidemiology, animal models and a novel therapeutic strategy for aspiration pneumonia. Respir. Investig. 2022;60(1):45–55. 10.1016/j.resinv.2021.09.012
5 Miyashita N. Atypical pneumonia: Pathophysiology, diagnosis, and treatment. Respir. Investig. 2022;60(1):56–67. 10.1016/j.resinv.2021.09.009
6 Luo T, Yan H, Li X, Deng Y, Huang J, Li L, et al. Proteomic analysis identified potential age-associated prognostic biomarkers in pneumonia-derived paediatric sepsis. Proteomics Clin. Appl. 2022;16(3):e2100036. 10.1002/prca.202100036
7 Vanhoutte D, Schips TG, Vo A, Grimes KM, Baldwin TA, Brody MJ, et al. Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy. Nat. Commun. 2021;12(1):3928. 10.1038/s41467-021-24215-4
8 Omatsu M, Nakanishi Y, Iwane K, Aoyama N, Duran A, Muta Y, et al. THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer. Nat. Commun. 2023;14(1):5534. 10.1038/s41467-023-41095-y
9 Sun J, Ge X, Wang Y, Niu L, Tang L, Pan S. USF2 knockdown downregulates THBS1 to inhibit the TGF-beta signaling pathway and reduce pyroptosis in sepsis-induced acute kidney injury. Pharmacol. Res. 2022;176:105962. 10.1016/j.phrs.2021.105962
10 Hassan HM, Liang X, Xin J, Lu Y, Cai Q, Shi D, et al. Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure. BMC Med. 2024;22(1):95. 10.1186/s12916-024-03318-x
11 Penaloza HF, Olonisakin TF, Bain WG, Qu Y, van der Geest R, Zupetic J, et al. Thrombospondin-1 restricts interleukin-36gamma-mediated neutrophilic inflammation during pseudomonas aeruginosa pulmonary infection. mBio. 2021;12(2):e03336–20. 10.1128/mBio.03336-20
12 Liu G, Wan Q, Li J, Hu X, Gu X, Xu S. Circ_0038467 regulates lipopolysaccharide-induced inflammatory injury in human bronchial epithelial cells through sponging miR-338-3p. Thorac. Cancer. 2020;11(5):1297–308. 10.1111/1759-7714.13397
13 Hespanhol V and Barbara C. Pneumonia mortality, comorbidities matter? Pulmonology. 2020;26(3):123–9. 10.1016/j.pulmoe.2019.10.003
14 Liu X and Meng J. Luteolin alleviates LPS-induced bronchopneumonia injury in vitro and in vivo by down-regulating microRNA-132 expression. Biomed. Pharmacother. 2018; 106:1641–9. 10.1016/j.biopha.2018.07.094
15 Stotts C, Corrales-Medina VF, Rayner KJ. Pneumonia-induced inflammation, resolution and cardiovascular disease: Causes, consequences and clinical opportunities. Circ. Res. 2023;132(6):751–74. 10.1161/CIRCRESAHA.122.321636
16 Hamldar S, Kiani SJ, Khoshmirsafa M, Nahand JS, Mirzaei H, Khatami A, et al. Expression profiling of inflammation-related genes including IFI-16, NOTCH2, CXCL8, THBS1 in COVID-19 patients. Biologicals. 2022;80:27–34. 10.1016/j.biologicals.2022.09.001
17 Lei Y, Jin X, Sun M, Ji Z. RNF7 induces skeletal muscle cell apoptosis and arrests cell autophagy via upregulation of THBS1 and inactivation of the PI3K/Akt signaling pathway in a rat sepsis model. Infect. Immun. 2023;91(4):e0053522. 10.1128/iai.00535-22
18 Sul OJ and Ra SW. Quercetin prevents LPS-induced oxidative stress and inflammation by modulating NOX2/ROS/NF-kB in lung epithelial cells. Molecules. 2021;26(22):6949. 10.3390/molecules26226949
19 Jomova K, Raptova R, Alomar SY, Alwasel SH, Nepovimova E, Kuca K, et al. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: Chronic diseases and aging. Arch. Toxicol. 2023;97(10):2499–574. 10.1007/s00204-023-03562-9
20 Georgieva E, Ananiev J, Yovchev Y, Arabadzhiev G, Abrashev H, Abrasheva D, et al. COVID-19 Complications: Oxidative stress, inflammation, and mitochondrial and endothelial dysfunction. Int. J. Mol. Sci. 2023;24(19):14876. 10.3390/ijms241914876
21 Ming S, Tian J, Ma K, Pei C, Li L, Wang Z, et al. Oxalate-induced apoptosis through ERS-ROS-NF-kappaB signalling pathway in renal tubular epithelial cell. Mol. Med. 2022;28(1):88. 10.1186/s10020-022-00494-5
22 Lin L, Yu H, Li L, Yang W, Chen X, Gong Y, et al. TRIM55 promotes noncanonical NF-kappaB signaling and B cell-mediated immune responses by coordinating p100 ubiquitination and processing. Sci. Signal. 2023;16(806):eabn5410. 10.1126/scisignal.abn5410