肝细胞核因子-1b在糜烂性毒剂2-氯乙基乙基硫醚诱导急性肺支气管上皮细胞损伤中的作用及其机制

doi:10.3969/j.issn.1004-616x.2024.01.001

Abstract

Abstract: OBJECTIVE: To investigate the involvement of hepatocyte nuclear factor-1b(HNF-1b) in human lung bronchial epithelial cell injury induced by a blister agent, 2-chloroethyl ethyl sulfide(CEES).METHODS: The human BEAS-2B cells were treated in culture with various concentrations(0, 0.4, 0.6, 0.8, 1.0 and 1.2 mmol/L) of CEES for 24 h. The CCK-8 method was used to detect cell viability, and cell morphology was observed under light microscope. The DCFH-DA and MitoSOX fluorescent probes were used to detect total reactive oxygen species(ROS) and mitochondrial ROS levels, respectively. The protein expression of HNF-1b was assessed by Western blot. A BEAS-2B cell line which overexpresses HNF-1b was constructed by lentiviral infection. After exposure to 1 mmol/L CEES for 24 h, cell viability was determined by the CCK-8 method; apoptosis rate was detected by Annexin V-FITC/PI double staining method; mitochondrial ROS and whole-cell ROS levels were measured by MitoSOX and DHE probes, and mitochondrial membrane potential was detected by JC-1 staining. RESULTS: After exposure of BEAS-2B to 0.6-1.2 mmol/L CEES and compared to the controls, cell viability was reduced(P<0.01), cell morphology showed damage, the levels of total ROS and mitochondrial ROS were increased(P<0.01), and HNF-1b protein expression was significantly down-regulated(P<0.01). After exposure of the cells with over-expressed HNF-1b, the cell viability was significantly increased(P<0.01), apoptosis rate was decreased(P<0.01), mitochondrial membrane potential damage was relieved, and the levels of mitochondrial ROS and total whole-cell ROS were significantly decreased(P<0.01). CONCLUSION: Exposure of the regular BEAS-2B cells to CEES reduced the expression of HNF-1b and caused extensive damage. However, overexpression of HNF-1b in the BEAS-2B cells reduced the CEES-induced cellular damage, apoptosis and mitochondrial dysfunction. These results suggest that the protective effect of HNF-1b may mediated by antioxidation, and activation of HNF-1b may be a new strategy for the treatment of blister agent toxicity.

Key words: blister agent, 2-chloroethyl ethyl sulfide, hepatocyte nuclear factor-1b, BEAS-2B cells, oxidative stress

CLC Number:

R994.7

KONG Deqin, LIU Sijia, LIU Jianhao, MA Yao, MA Chengfei, ZHAO Yushun, ZHOU Jiaheng, SHI Minjie, LI Jia, LIU Jiangzheng. Involvement of hepatocyte nuclear factor-1b in lung bronchial epithelial cell injury induced by 2-chloroethyl ethyl sulfide[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2024, 36(1): 1-8.

References

[1] 祝筱姬,朱双双,钟玉绪.芥子气肺损伤机制研究进展[J].中国药理学与毒理学杂志, 2015, 29(5):859-864.
[2] KHAZDAIR M R, BOSKABADY M H. Possible treatment approaches of sulfur mustard-induced lung disorders,experimental and clinical evidence, an updated review[J]. Front Med, 2022, 9:791914.
[3] WAHLER G, HECK D E, HEINDEL N D, et al. Antioxidant/stress response in mouse epidermis following exposure to nitrogen mustard[J]. Exp Mol Pathol, 2020, 114:104410.
[4] SABNAM S, RIZWAN H, PAL S, et al. CEES-induced ROS accumulation regulates mitochondrial complications and inflammatory response in keratinocytes[J]. Chem Biol Interact,2020, 321:109031.
[5] 肖兆铭,王玥茹,王文瑞,等.肝细胞核因子1B的研究进展[J].医学综述, 2018, 24(5):947-955.
[6] LERNER J, BAGATTIN A, VERDEGUER F, et al. Human mutations affect the epigenetic/bookmarking function of HNF1B[J]. Nucleic Acids Res, 2016, 44(17):8097-8111.
[7] WU H, YU W H, MENG F S, et al. Polychlorinated biphenyls-153 induces metabolic dysfunction through activation of ROS/NF-κB signaling via downregulation of HNF1b[J]. Redox Biol,2017, 12:300-310.
[8] SU S H, WU G Y, CHENG X D, et al. Oleanolic acid attenuates PCBs-induced adiposity and insulin resistance via HNF1b-mediated regulation of redox and PPARγ signaling[J].Free Radic Biol Med, 2018, 124:122-134.
[9] LONG Z, FAN J S, WU G Y, et al. Gestational bisphenol A exposure induces fatty liver development in male offspring mice through the inhibition of HNF1b and upregulation of PPARγ[J].Cell Biol Toxicol, 2021, 37(1):65-84.
[10] WANG X, WU H, YU W H, et al. Hepatocyte nuclear factor 1b is a novel negative regulator of white adipocyte differentiation[J]. Cell Death Differ, 2017, 24(9):1588-1597.
[11] PRESCOTT T. Accidental sulfur mustard exposure from explosive ordnance in a UK military service person[J]. BMJ Mil Health, 2021, 167(4):287-288.
[12] 赵伟明,韩信嵘,王强,等.芥子气毒性作用机制及治疗干预措施研究进展[J].解放军预防医学杂志, 2020, 38(9):153-157.
[13] AMINI H, SOLAYMANI-DODARAN M, MOUSAVI B, et al.Long-term health outcomes among survivors exposed to sulfur mustard in Iran[J]. JAMA Netw Open, 2020, 3(12):e2028894.
[14] BEIGI HARCHEGANI A, KHOR A, TAHMASBPOUR E, et al. Role of oxidative stress and antioxidant therapy in acute and chronic phases of sulfur mustard injuries:a review[J]. Cutan Ocul Toxicol, 2019, 38(1):9-17.
[15] PAROMOV V, KUMARI S, BRANNON M, et al. Protective effect of liposome-encapsulated glutathione in a human epidermal model exposed to a mustard gas analog[J]. J Toxicol,2011, 2011:109516.
[16] TEWARI-SINGH N, INTURI S, JAIN A K, et al. Catalytic antioxidant AEOL 10150 treatment ameliorates sulfur mustard analog 2-chloroethyl ethyl sulfide-associated cutaneous toxic effects[J]. Free Radic Biol Med, 2014, 72:285-295.
[17] GAMBELLA A, KALANTARI S, CADAMURO M, et al. The landscape of HNF1B deficiency:a syndrome not yet fully explored[J]. Cells, 2023, 12(2):307.
[18] KANG C Y, WANG L X, WANG D D, et al. Lung cancer A549cells suppressed with overexpressed HNF1B or PCDHA13inhibited PI3K/AKT phosphorylation[J]. Transl Cancer Res,2020, 9(6):3819-3827.
[19] YU W P, DONG X H, DAN G R, et al. Vitamin D3 protects against nitrogen mustard-induced apoptosis of the bronchial epithelial cells via activating the VDR/Nrf2/Sirt3 pathway[J].Toxicol Lett, 2022, 354:14-23.
[20] 梅逸舟,张小锐,周文霞,等.芥子气所致氧化应激相关生物标志物研究进展[J].军事医学, 2014, 38(5):392-395.
[21] LAYALI I, SHAHRIARY A, RAHMANI TALATAPPE N, et al. Sulfur mustard triggers oxidative stress through glutathione depletion and altered expression of glutathione-related enzymes in human airways[J]. Immunopharmacol Immunotoxicol, 2018, 40(4):290-296.
[22] MUKHOPADHYAY S, RAJARATNAM V, MUKHERJEE S, et al. Modulation of the expression of superoxide dismutase gene in lung injury by 2-chloroethyl ethyl sulfide, a mustard analog[J]. J Biochem Mol Toxicol, 2006, 20(3):142-149.
[23] BONDY S C. The hormesis concept:strengths and shortcomings[J]. Biomolecules, 2023, 13(10):1512.
[24] GOULD N S, WHITE C W, DAY B J. A role for mitochondrial oxidative stress in sulfur mustard analog 2-chloroethyl ethyl sulfide-induced lung cell injury and antioxidant protection[J]. J Pharmacol Exp Ther, 2009, 328(3):732-739.
[25] CLARK H, PEREIRA VERA B, ZHANG Z J, et al. MDR-1function protects oocyte mitochondria against the transgenerational effects of nitrogen mustard exposure[J]. Reprod Toxicol, 2020,98:252-259.
[26] 刘江正,宋德心,马丞飞,等.线粒体抗氧化剂MitoQ减轻氮芥诱导小鼠急性肝损伤[J].空军军医大学学报, 2023, 44(3):222-228.
[27] CASEMAYOU A, FOURNEL A, BAGATTIN A, et al.Hepatocyte nuclear factor-1β controls mitochondrial respiration in renal tubular cells[J]. J Am Soc Nephrol, 2017, 28(11):3205-3217.
[28] LIU S Q, LIU S S, HE B Y, et al. OXPHOS deficiency activates global adaptation pathways to maintain mitochondrial membrane potential[J]. EMBO Rep, 2021, 22(4):e51606.

Involvement of hepatocyte nuclear factor-1b in lung bronchial epithelial cell injury induced by 2-chloroethyl ethyl sulfide

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