纳米塑料诱导肺泡Ⅱ型上皮细胞DNA损伤加重重症哮喘

doi:10.3969/j.issn.1674-8115.2024.11.006

上海交通大学学报（医学版） ›› 2024, Vol. 44 ›› Issue (11): 1391-1405.doi: 10.3969/j.issn.1674-8115.2024.11.006

• 论著 · 基础研究 • 上一篇

纳米塑料诱导肺泡Ⅱ型上皮细胞DNA损伤加重重症哮喘

施泽纶¹(), 王青¹(), 何雯¹, 傅唯佳¹, 王颖雯², 韩晓³(), 张晓波¹()

^1.复旦大学附属儿科医院呼吸科，上海 201102
^2.复旦大学附属儿科医院护理部，上海 201102
^3.复旦大学附属儿科医院儿科研究所，上海 201102

收稿日期:2024-03-11 接受日期:2024-05-21 出版日期:2024-11-28 发布日期:2024-11-28
通讯作者: 韩晓,张晓波 E-mail:21211240020@m.fudan.edu.cn;wq141269@163.com;sqhx12@126.com;zhangxiaobo0307@163.com
作者简介:施泽纶（1997—），男，硕士生；电子信箱：21211240020@m.fudan.edu.cn
王　青（1997—），女，硕士生；电子信箱：wq141269@163.com。第一联系人：施泽纶、王青为共同第一作者。
基金资助:
上海市科学技术委员会课题(22511106001);上海市2023年度科技创新行动计划(23511100600)

Nanoplastics aggravate severe asthma by inducing DNA damage of alveolar type Ⅱ epithelial cells

SHI Zelun¹(), WANG Qing¹(), HE Wen¹, FU Weijia¹, WANG Yingwen², HAN Xiao³(), ZHANG Xiaobo¹()

^1.Department of Respiratory Medicine, Children′s Hospital of Fudan University, Shanghai 201102, China
^2.Nursing Department, Children′s Hospital of Fudan University, Shanghai 201102, China
^3.Institute of Pediatrics, Children′s Hospital of Fudan University, Shanghai 201102, China

Received:2024-03-11 Accepted:2024-05-21 Online:2024-11-28 Published:2024-11-28
Contact: HAN Xiao,ZHANG Xiaobo E-mail:21211240020@m.fudan.edu.cn;wq141269@163.com;sqhx12@126.com;zhangxiaobo0307@163.com
Supported by:
Project of Science and Technology Commission of Shanghai Municipality(22511106001);2023 Annual Project of Science and Technology Innovation Action of Shanghai Municipality(23511100600)

摘要/Abstract

摘要：

目的·探讨纳米塑料（nanoplastics，NPs）对重症哮喘发生发展的影响及潜在分子机制。方法·建立屋尘螨（house dust mite，HDM）和脂多糖（lipopolysaccharide，LPS）联合诱导的重症哮喘小鼠模型，并给予聚苯乙烯纳米塑料（polystyrene nanoplastics，PS-NPs）气道滴注，收集小鼠肺泡灌洗液及制作肺组织切片。通过流式细胞术、苏木精-伊红（hematoxylin-eosin，H-E）染色、过碘酸希夫（periodic acid-Schiff，PAS）染色、免疫组织化学染色、脱氧核糖核苷酸末端转移酶介导的缺口末端标记法（terminal dexynucleotidyl transferase-mediated dUTP nick-end labeling，TUNEL）染色，观察PS-NPs对重症哮喘小鼠气道炎症、黏液分泌、肺泡结构，以及肺泡Ⅱ型上皮细胞（alveolar type Ⅱ epithelial cells，AT2 cells）增殖和凋亡的影响。采用CCK-8法及Annexin Ⅴ/PI双染色法测定PS-NPs对小鼠AT2细胞系MLE-12细胞增殖、凋亡的影响。使用γ-H2A.X免疫荧光染色检测PS-NPs对AT2细胞的DNA损伤作用。通过实时荧光定量聚合酶链反应（real-time fluorescent quantitative polymerase chain reaction，qPCR）、蛋白质印迹法（Western blotting）、酪胺信号放大（Tyramide signal amplification，TSA）多重荧光染色及免疫荧光共定位检测PS-NPs对AT2细胞ATR/Chk1/p53信号通路相关基因和蛋白表达的影响。使用ATR特异抑制剂Ceralasertib（AZD6738）与PS-NPs共同处理MLE-12细胞，以测定其对细胞增殖、凋亡的恢复作用。结果·流式细胞术显示，重症哮喘小鼠暴露于PS-NPs后，其肺泡灌洗液中炎症细胞总数及各炎症细胞数量均有增加，以中性粒细胞增多为主；肺组织H-E染色及PAS染色显示，气道炎症细胞浸润及气道黏液分泌显著增加，肺泡结构被破坏。在体外试验中，CCK-8结果显示PS-NPs显著抑制MLE-12细胞的增殖能力并呈现浓度依赖性；Annexin Ⅴ/PI双染色结果显示，PS-NPs暴露后的细胞凋亡率［（56.20±3.84）%］相比于未暴露组［（23.22±2.52）%］显著上升；免疫荧光染色显示PS-NPs能被MLE-12细胞所吞噬并定位在细胞核周围。TUNEL染色结果表明，在体内PS-NPs同样促进AT2细胞凋亡的发生。免疫荧光染色结果显示，与对照组相比，实验组DNA损伤标志物γ-H2A.X表达增加。qPCR、Western blotting、TSA多重荧光染色显示，PS-NPs诱导MLE-12细胞ATR/Chk1/p53信号通路相关基因和蛋白表达水平升高。免疫荧光共定位实验也证实在小鼠体内，PS-NPs诱导AT2细胞表达ATR、p53蛋白。而ATR特异抑制剂Ceralasertib能部分恢复由PS-NPs引起的MLE-12细胞增殖的抑制和凋亡的增强。结论·NPs暴露能够造成AT2细胞DNA损伤，激活ATR/Chk1/p53信号通路，进而加重重症哮喘小鼠气道炎症反应及肺泡结构损伤。

关键词: 重症哮喘, 纳米塑料, 肺泡Ⅱ型上皮细胞, DNA损伤, ATR/Chk1/p53信号通路

Abstract:

Objective ·To explore the effects and possible molecular mechanisms of nanoplastics (NPs) on severe asthma. Methods ·A mouse model of severe asthma was established by using house dust mite (HDM) and lipopolysaccharide (LPS) co-stimulation. Polystyrene nanoplastics (PS-NPs) were instilled into the severe asthma mice′s airways. Subsequently, bronchoalveolar lavage fluid (BALF) was collected and lung tissue sections were prepared. Flow cytometry, hematoxylin-eosin (H-E) staining, periodic acid-Schiff (PAS) staining, immunohistochemistry, and terminal dexynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, were used to observe the effects of PS-NPs on airway inflammation, mucus secretion, alveolar structure, and the proliferation and apoptosis of alveolar type Ⅱ epithelial cells (AT2 cells) in severe asthma mice. The CCK-8 assay and Annexin Ⅴ/PI double staining were performed to evaluate the effects of PS-NPs on the proliferation and apoptosis of the mouse AT2 cell line MLE-12. DNA damage in AT2 cells caused by PS-NPs was detected by using anti-γ-H2A.X immunofluorescence staining. The expression of genes in the ATR/Chk1/p53 signaling pathway was detected by real-time fluorescent quantitative polymerase chain reaction (qPCR), Western blotting, Tyramide signal amplification (TSA) multiplex immunofluorescence staining, and immunofluorescence co-localization, respectively. The ATR-specific inhibitor Ceralasertib (AZD6738) was administrated to MLE-12 cells in combination with PS-NPs to evaluate the recovery effect on cell proliferation and apoptosis. Results ·Flow cytometry revealed that exposure to PS-NPs increased the total number of inflammatory cells and the number of each type of inflammatory cells in the BALF of mice with severe asthma, with a predominance of neutrophils. H-E and PAS staining showed significant increase in airway inflammatory cell infiltration and mucus secretion, as well as disruption of alveolar structure. In vitro, the CCK-8 assay demonstrated significant, dose-dependent inhibition of MLE-12 cell proliferation by PS-NPs. The Annexin V/PI double staining assay indicated a higher apoptosis rate of (56.20±3.84)% in PS-NP-exposed cells compared to (23.22±2.52)% in the control group. Immunofluorescence staining demonstrated that PS-NPs were phagocytosed by MLE-12 cells and localized around the nucleus. TUNEL staining confirmed enhanced apoptosis in AT2 cells in vivo. The immunofluorescence assay revealed that compared to the control group, the expression of the DNA damage marker γ-H2A.X increased in the experimental group. qPCR, Western blotting, and TSA multiplex staining results showed that PS-NP-induced elevated expression of mRNA and proteins was related to the ATR/Chk1/p53 pathway in MLE-12 cells. Moreover, immunofluorescence co-localization also confirmed the induction of ATR and p53 proteins in AT2 cells in vivo. The ATR-specific inhibitor Ceralasertib partially restored the PS-NP-induced inhibition of cell proliferation and enhancement of apoptosis in MLE-12 cells. Conclusion ·NPs exposure leads to DNA damage in AT2 cells, activating the ATR/Chk1/p53 signaling pathway and exacerbating airway inflammation and alveolar damage in mice with severe asthma.

Key words: severe asthma, nanoplastic, alveolar type Ⅱ epithelial cell, DNA damage, ATR/Chk1/p53 signaling pathway

中图分类号:

R726.6

施泽纶, 王青, 何雯, 傅唯佳, 王颖雯, 韩晓, 张晓波. 纳米塑料诱导肺泡Ⅱ型上皮细胞DNA损伤加重重症哮喘[J]. 上海交通大学学报（医学版）, 2024, 44(11): 1391-1405.

SHI Zelun, WANG Qing, HE Wen, FU Weijia, WANG Yingwen, HAN Xiao, ZHANG Xiaobo. Nanoplastics aggravate severe asthma by inducing DNA damage of alveolar type Ⅱ epithelial cells[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(11): 1391-1405.

图/表 9

表1 qPCR引物序列

Tab 1 Primer sequences for qPCR

Gene	Forward primer (5′→3′)	Reverse primer (5′→3′)
β-actin	CACCATTGGCAATGAGCGGTTC	AGGTCTTTGCGGATGTCCACGT
Ki67	GAGGAGAAACGCCAACCAAGAG	TTTGTCCTCGGTGGCGTTATCC
Bax	AGGATGCGTCCACCAAGAAGCT	TCCGTGTCCACGTCAGCAATCA
Bcl2	CCTGTGGATGACTGAGTACCTG	AGCCAGGAGAAATCAAACAGAGG
Trp53	CCCCTGTCATCTTTTGTCCCT	AGCTGGCAGAATAGCTTATTGAG
Bid	CCACAACATTGCCAGACATCTCG	TCACCTCATCAAGGGCTTTGGC
Cdk6	ACCTCTGGAGTGTCGGTTGCAT	TTCCTCTCCTGGGAGTCCAATG
Atr	GAAAGAGGCTCCTACCAACGAG	CAACTGTCACCTGGAGACTTGC
Ccnd1	GCAGAAGGAGATTGTGCCATCC	AGGAAGCGGTCCAGGTAGTTCA

图1 BALF炎症细胞计数、肺组织病理切片及组织病理学评分结果Note： A. The flow cytometry results of the inflammatory cell counts (eosinophils, lymphocytes, macrophages and neutrophils) in the BALF of mice in each group. B. Pathological sections of mouse lung tissue: H-E staining (×200), PAS staining (×400), Ly6G immunohistochemical staining (×400). C. Eosinophil and airway inflammation scores. ①P<0.001, ④P=0.010, compared with the control group; ②P<0.001, ③P=0.025, ⑤P=0.005, ⑥P=0.023, compared with the HDM/PBS/PBS group.

Fig 1 Results of BALF inflammatory cell counts, lung tissue pathological sections and histopathological scores

图2 暴露于PS-NPs对重症哮喘小鼠BALF炎症细胞计数、肺组织病理切片及组织病理学评分结果的影响Note： A. The flow cytometry results of the inflammatory cell (eosinophils, lymphocytes, macrophages and neutrophils) counts in the BALF of mice in each group after exposure to PS-NPs. B. Pathological sections of mouse lung tissue, including H-E staining (×200), PAS staining (×400), Ly6G immunohistochemical staining (×400). C. Eosinophil and airway inflammation scores. ①P<0.001, ④P=0.035, ⑤P=0.002, compared with the control group; ②P<0.001, ③P=0.001, ⑥P=0.008, ⑦P=0.002, compared with the HDM/LPS/PBS group.

Fig 2 Effect of exposure to PS-NPs on BALF inflammatory cell counts, lung tissue pathological sections and histopathological scores in mice with severe asthma

图3 暴露于PS-NPs对重症哮喘小鼠肺泡结构的影响Note： A. Mouse lung alveolar pathological sections stained with H-E (×40, ×200). B. Analysis of alveolar density and alveolar cross-sectional area. ①P<0.001, compared with the HDM/LPS/PBS group.

Fig 3 Histopathological changes of mice lung alveolars among various groups after exposure to PS-NPs

图4 PS-NPs对AT2细胞增殖、凋亡及相关基因mRNA表达水平的影响Note： A. Confocal microscopy shows the distribution of PS-NPs in MLE-12 cells, namely AT2 cells (×1 000, ×4 000). AT2 cells were stained with PS-NP (green) and DAPI (blue). B. The effect of PS-NPs (5, 10, 20, 40 μg·mL-1) on the proliferation of AT2 cells after 0, 24 or 48 h. C/D. Analysis of the effect of PS-NPs on apoptosis of AT2 cells by Annexin-Ⅴ FITC/PI staining. E. The effect of PS-NPs exposure on the expression levels of proliferation and apoptosis-related genes Ki67, Bax, Bid, and Trp53 in AT2 cells. ①P<0.001, compared with the control group; ②P=0.025, compared with the PS-NPs 5 μg·mL-1 group; ③P<0.001, compared with the PS-NPs 10 μg·mL-1 group; ④P<0.001, compared with the PS-NPs 20 μg·mL-1 group.

Fig 4 Effects of PS-NPs on the proliferation, apoptosis and mRNA expression levels of related gene of AT2 cells

图5 PS-NPs暴露后重症哮喘小鼠肺组织的细胞凋亡水平Note： A. TUNEL staining of mouse alveolar pathological sections (×400). AT2 cells were stained with TUNEL (green) and DAPI (blue). B. The results of apoptosis rates in each group. ①P<0.001, compared with the HDM/LPS/PBS group.

Fig 5 Level of cellular apoptosis in lung tissue of severe asthma mice after PS-NPs exposure

图6 体外实验证实PS-NPs暴露引起AT2细胞DNA损伤并上调ATR/Chk1/p53信号通路Note： A. Immunofluorescence method to detect the effect of PS-NPs on DNA damage of AT2 cells (×1 000). AT2 cells were co-stained with γ-H2A.X (red) and PS-NPs (green) and DAPI (blue). B. qPCR analysis of the expression of ATR/Chk1/p53 signaling pathway and apoptosis-related genes in MLE-12 cells after exposure to PS-NPs. C. Western blotting analysis of the expression and phosphorylation of ATR, Chk1, and p53 proteins after exposure to PS-NPs. ①P=0.013, ②P=0.001, ③P=0.000, ④P=0.006, ⑤P=0.007, ⑥P=0.042, ⑦P=0.004, ⑧P=0.012, compared with the control group. GAPDH—glyceraldehyde-3-phosphate dehydrogenase.

Fig 6 In vitro experiments confirmed the DNA damage induction and the upregulation of the ATR/Chk1/p53 signaling pathway in AT2 cells after PS-NPs exposure

图7 体内实验证实PS-NPs暴露上调重症哮喘小鼠 Sftpc＋AT2中ATR、p53表达水平Note： A. AT2 cells from lung tissues were co-stained with ATR (red) and SFTPC (green) and DAPI (blue) (×400, ×800). B. AT2 cells from lung tissues were co-stained with p53 (red) and SFTPC (green) and DAPI (blue) (×400, ×800).

Fig 7 In vivo experiments confirmed that the upregulated expression levels of ATR and p53 in Sftpc＋ AT2 cells of severe asthma mice after PS-NPs exposure

图8 Ceralasertib对PS-NPs诱导的AT2细胞增殖、凋亡的恢复作用Note： A. Ceralasertib restores the proliferation of AT2 cells after 0, 24 or 48 h. B/C. Ceralasertib restores the apoptosis rate of AT2 cells induced by PS-NPs. ①P=0.010, compared with the PS-NPs (20 μg·mL-1) group; ②P=0.001, ③P<0.001, compared with the control group; ④P<0.001, compared with the PS-NPs (10 μg·mL-1) group.

Fig 8 Ceralasertib restores the effects induced by PS-NPs on proliferation and apoptosis of AT2 cells

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纳米塑料诱导肺泡Ⅱ型上皮细胞DNA损伤加重重症哮喘

Nanoplastics aggravate severe asthma by inducing DNA damage of alveolar type Ⅱ epithelial cells

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