切换至 "中华医学电子期刊资源库"
高级检索
中华肺部疾病杂志(电子版)

中华肺部疾病杂志(电子版) ›› 2021, Vol. 14 ›› Issue (06) : 734 -740. doi: 10.3877/cma.j.issn.1674-6902.2021.06.006

论著

PM2.5通过上调颗粒酶B促进IL-18表达加重肺部炎症
王在强1, 李兰玉2, 傅恩清1, 韩璐瑶1, 林红卫1, 高彦军1, 张倩1, 刘雨柔1, 金发光1,†()   
  1. 1. 710038　西安，空军军医大学第二附属医院呼吸与危重症医学科
    2. 200127　上海，上海交通大学附属仁济医院急诊科
  • 收稿日期:2021-07-13 出版日期:2021-12-25
  • 通信作者: 金发光
  • 基金资助:
    陕西省重点研发计划(2017ZDL-SF-14-6)

PM2.5 aggravates lung inflammation by up-regulating granzyme B to promote IL-18 expression

Zaiqiang Wang1, Lanyu Li2, Enqing Fu1, Luyao Han1, Hongwei Lin1, Yanjun Gao1, Qian Zhang1, Yurou Liu1, Faguang Jin1,†()   

  1. 1. Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Air Force Medical University, Xi′an 710038, China
    2. Department of Emergency, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
  • Received:2021-07-13 Published:2021-12-25
  • Corresponding author: Faguang Jin
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

王在强, 李兰玉, 傅恩清, 韩璐瑶, 林红卫, 高彦军, 张倩, 刘雨柔, 金发光. PM2.5通过上调颗粒酶B促进IL-18表达加重肺部炎症[J]. 中华肺部疾病杂志(电子版), 2021, 14(06): 734-740.

Zaiqiang Wang, Lanyu Li, Enqing Fu, Luyao Han, Hongwei Lin, Yanjun Gao, Qian Zhang, Yurou Liu, Faguang Jin. PM2.5 aggravates lung inflammation by up-regulating granzyme B to promote IL-18 expression[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2021, 14(06): 734-740.

目的

颗粒酶B促进组织炎症的作用日益引起重视，但其在PM2.5导致的肺部炎症中是否发挥作用还不清楚，本文对在PM2.5导致的肺部炎症中颗粒酶B的作用进行了研究。

方法

第一步构建经气管滴注PM2.5混悬液诱导大鼠肺部炎症的动物模型，实验分组为PBS组、PM2.5(2 mg/kg)组、PM2.5(6 mg/kg)组、PM2.5(18 mg/kg)组。通过设置PM2.5滴注剂量梯度，检测不同PM2.5暴露剂量下大鼠肺组织颗粒酶B表达、病理和炎症评分，以探讨颗粒酶B表达水平与肺部炎症严重程度间有无相关性。第二步通过阻断颗粒酶B，探究在PM2.5导致的肺部炎症中颗粒酶B是否发挥促进作用。第三步通过阻断IL-18，探究在PM2.5导致的肺部炎症中颗粒酶B是否通过IL-18发挥作用。

结果

随着PM2.5滴注剂量升高，肺组织颗粒酶B表达增加，肺组织病理切片炎症细胞浸润和肺水肿程度加重，炎症评分增加，PM2.5促进了肺组织颗粒酶B表达和肺部炎症；阻断颗粒酶B抑制了IL-18表达和NF-κB磷酸化，改善了PM2.5导致的肺部炎症；阻断IL-18抑制了NF-κB磷酸化，改善了PM2.5导致的肺部炎症。

结论

PM2.5通过上调颗粒酶B促进IL-18表达加重肺部炎症，其机制可能与激活NF-κB信号通路有关。

关键词: 颗粒物, 颗粒酶类, 肺部炎症
Objective

The role of granzyme B in promoting tissue inflammation has attracted increasing attention, but whether it plays a role in pulmonary inflammation caused by PM2.5 is still unclear. This study investigated the role of granzyme B in pulmonary inflammation caused by PM2.5.

Methods

In the first step, the animal model of rat lung inflammation induced by intratracheal instillation of PM2.5 suspension was established. The experiment was divided into PBS group, PM2.5 (2 mg/kg) group, PM2.5 (6 mg/kg) group and PM2.5 (18 mg/kg) group. By setting the PM2.5 instillation dose gradient, we detected the expression of granzyme B, pathology and inflammation scores in rat lung tissues under different PM2.5 exposure doses to explore whether there is a correlation between the expression level of granzyme B and the severity of lung inflammation. In the second step, whether granzyme B plays a role in promoting pulmonary inflammation caused by PM2.5 was investigated by blocking granzyme B. In the third step, whether granzyme B acts through IL-18 in PM2.5-induced pulmonary inflammation was investigated by blocking IL-18.

Results

As the PM2.5 instillation dose increased, the expression of granzyme B in lung tissue increased, the degree of inflammatory cell infiltration and pulmonary edema, and the inflammation score in lung tissue pathological sections increased. PM2.5 increased granzyme B expression and inflammation in the lungs. Blocking granzyme B inhibited IL-18 expression and NF-κB phosphorylation, and reduced lung inflammation caused by PM2.5. Blocking IL-18 inhibited Phosphorylation of NF-κB and reduced lung inflammation caused by PM2.5.

Conclusion

PM2.5 aggravates lung inflammation by up-regulating granzyme B to promote IL-18 expression, and the mechanism may be related to the activation of NF-κB signaling pathway.

Key words: Particulate Matter, Granzymes, Pulmonary inflammation
图1 不同处理组肺组织颗粒酶B表达情况；注：***P<0.001，n.s.表示无统计学差异
图2 不同处理组肺组织病理切片和炎症评分；注：A：PBS组；B：PM2.5(2 mg/kg)组；C：PM2.5(6 mg/kg)组；D：PM2.5(18 mg/kg)组；E：肺组织炎症评分；注：***P<0.001，n.s.表示无统计学差异
图3 不同处理组肺组织颗粒酶B、IL-18表达和NF-κB磷酸化情况；注：p-NF-κb: phosphorylated NF-κB，*P<0.05，**P<0.01，***P<0.001，n.s.表示无统计学差异
图4 不同处理组肺组织病理切片和炎症评分；注：A:生理盐水+PM2.5组；B: Serpina3n+PBS组；C:生理盐水+PM2.5组；D: Serpina3n+PM2.5组；E:肺组织炎症评分；注：***P<0.001，n.s.表示无统计学差异
图5 不同处理组肺组织颗粒酶B、IL-18表达和NF-κB磷酸化情况；注：p-NF-κb: phosphorylated NF-κB，**P<0.01，***P<0.001，n.s.表示无统计学差异
图6 不同处理组肺组织病理切片和炎症评分；注：A：生理盐水+PM2.5组；B：IL-18BP+PBS组；C：生理盐水+PM2.5组；D：IL-18BP+PM2.5组；E：肺组织炎症评分；注：*P<0.05，**P<0.01，***P<0.001，n.s.表示无统计学差异
1
Cohen AJ, Brauer M, Burnett R, et al. Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015[J]. Lancet, 2017, 389(10082): 1907-1918.
2
曹丽敏，周　芸，张　庄，等. 环境空气颗粒物及其组分对呼吸系统健康的影响[J]. 中华预防医学杂志，2016, 50(12): 1114-1118.
3
Dominici F, Peng RD, Bell ML, et al. Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases[J]. JAMA, 2006, 295(10): 1127-1134.
4
Zanobetti A, Franklin M, Koutrakis P, et al. Fine particulate air pollution and its components in association with cause-specific emergency admissions[J]. Environ Health, 2009, 8: 58.
5
Xing YF, Xu YH, Shi MH, et al. The impact of PM2.5 on the human respiratory system[J]. J Thorac Dis, 2016, 8(1): E69-E74.
6
Yang B, Guo J, Xiao C. Effect of PM2.5 environmental pollution on rat lung[J]. Environ Sci Pollut Res Int, 2018, 25(36): 36136-36146.
7
Wang H, Song L, Ju W, et al. The acute airway inflammation induced by PM2.5 exposure and the treatment of essential oils in Balb/c mice[J]. Sci Rep, 2017, 7: 44256.
8
He M, Ichinose T, Yoshida S, et al. PM2.5-induced lung inflammation in mice: Differences of inflammatory response in macrophages and type Ⅱ alveolar cells[J]. J Appl Toxicol, 2017, 37(10): 1203-1218.
9
Boivin WA, Cooper DM, Hiebert PR, et al. Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma[J]. Lab Invest, 2009, 89(11): 1195-1220.
10
Ewen CL, Kane KP, Bleackley RC. A quarter century of granzymes[J]. Cell Death Differ, 2012, 19(1): 28-35.
11
Zeglinski MR, Granville DJ. Granzymes in cardiovascular injury and disease[J]. Cell Signal, 2020, 76: 109804.
12
Kurschus FC, Kleinschmidt M, Fellows E, et al. Killing of target cells by redirected granzyme B in the absence of perforin[J]. FEBS Lett, 2004, 562(1-3): 87-92.
13
Sanad EF, Hamdy NM, El-Etriby AK, et al. Peripheral leucocytes and tissue gene expression of granzyme B/perforin system and serpinB9: Impact on inflammation and insulin resistance in coronary atherosclerosis[J]. Diabetes Res Clin Pract, 2017, 131: 132-141.
14
Hodge S, Hodge G, Nairn J, et al. Increased airway granzyme b and perforin in current and ex-smoking COPD subjects[J]. COPD, 2006, 3(4): 179-187.
15
Bratke K, Bottcher B, Leeder K, et al. Increase in granzyme B+ lymphocytes and soluble granzyme B in bronchoalveolar lavage of allergen challenged patients with atopic asthma[J]. Clin Exp Immunol, 2004, 136(3): 542-548.
16
Tremblay GM, Wolbink AM, Cormier Y, et al. Granzyme activity in the inflamed lung is not controlled by endogenous serine proteinase inhibitors[J]. J Immunol, 2000, 165(7): 3966-3969.
17
Ma QY, Huang DY, Zhang HJ, et al. Exposure to particulate matter 2.5 (PM2.5) induced macrophage-dependent inflammation, characterized by increased Th1/Th17 cytokine secretion and cytotoxicity[J]. Int Immunopharmacol, 2017, 50: 139-145.
18
Bao CX, Chen HX, Mou XJ, et al. GZMB gene silencing confers protection against synovial tissue hyperplasia and articular cartilage tissue injury in rheumatoid arthritis through the MAPK signaling pathway[J]. Biomed Pharmacother, 2018, 103: 346-354.
19
Hendel A, Hsu I, Granville DJ. Granzyme B releases vascular endothelial growth factor from extracellular matrix and induces vascular permeability[J]. Lab Invest, 2014, 94(7): 716-725.
20
张天宇，Shen S, 杨　琳. 颗粒酶B在慢性鼓膜穿孔炎症损伤修复中的应用[J]. 中国眼耳鼻喉科杂志，2016, 16(1): 7-9, 15.
21
Shen Y, Cheng F, Sharma M, et al. Granzyme B deficiency protects against angiotensin Ⅱ-induced cardiac fibrosis[J]. Am J Pathol, 2016, 186(1): 87-100.
22
Li F, Wiegman C, Seiffert JM, et al. Effects of N-acetylcysteine in ozone-induced chronic obstructive pulmonary disease model[J]. PLoS One, 2013, 8(11): e80782.
23
Turner CT, Zeglinski MR, Richardson KC, et al. Granzyme B contributes to barrier dysfunction in oxazolone-induced skin inflammation through E-cadherin and FLG cleavage[J]. J Invest Dermatol, 2021, 141(1): 36-47.
24
Shen Y, Zeglinski MR, Turner CT, et al. Topical small molecule granzyme B inhibitor improves remodeling in a murine model of impaired burn wound healing[J]. Exp Mol Med, 2018, 50(5): 1-11.
25
Bao CX, Chen HX, Mou XJ, et al. GZMB gene silencing confers protection against synovial tissue hyperplasia and articular cartilage tissue injury in rheumatoid arthritis through the MAPK signaling pathway[J]. Biomed Pharmacother, 2018, 103: 346-354.
26
Cho CC, Hsieh WY, Tsai CH, et al. In vitro and in vivo experimental studies of PM2.5 on disease progression[J]. Int J Environ Res Public Health, 2018, 15(7): 1380.
27
Waugh SM, Harris JL, Fletterick R, et al. The structure of the pro-apoptotic protease granzyme B reveals the molecular determinants of its specificity[J]. Nat Struct Biol, 2000, 7(9): 762-765.
28
Omoto Y, Yamanaka K, Tokime K, et al. Granzyme B is a novel interleukin-18 converting enzyme[J]. J Dermatol Sci, 2010, 59(2): 129-135.
29
Akeda T, Yamanaka K, Tsuda K, et al. CD8+ T cell granzyme B activates keratinocyte endogenous IL-18[J]. Arch Dermatol Res, 2014, 306(2): 125-130.
30
Dinarello CA. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process[J]. Am J Clin Nutr, 2006, 83(2): 447S-455S.
31
Wang L, Jiang S, Xiao L, et al. Inhibition of granzyme B activity blocks inflammation induced by lipopolysaccharide through regulation of endoplasmic reticulum stress signaling in NK92 cells[J]. Mol Med Rep, 2018, 18(1): 580-586.
32
Nakanishi K, Yoshimoto T, Tsutsui H, et al. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu[J]. Cytokine Growth Factor Rev, 2001, 12(1): 53-72.
33
Reznikov LL, Kim SH, Zhou L, et al. The combination of soluble IL-18Ralpha and IL-18Rbeta chains inhibits IL-18-induced IFN-gamma[J]. J Interferon Cytokine Res, 2002, 22(5): 593-601.
34
刘　华，赵守琴，宋　扬，等. IL-18对大鼠分泌性中耳炎中耳NF-κB及Th2/Th1平衡的影响[J]. 中华耳科学杂志，2013, 11(4): 607-612.
35
郭蓓蓓，黄　晶，朱　悫，等. 探讨白介素18结合蛋白对球囊损伤后内膜增殖的影响及其机制[J]. 重庆医科大学学报，2011, 36(12): 1427-1431.
36
Jordan JA, Guo RF, Yun EC, et al. Role of IL-18 in acute lung inflammation[J]. J Immunol, 2001, 167(12): 7060-7068.
37
Zhang LM, Zhang J, Zhang Y, et al. Interleukin-18 binding protein attenuates lipopolysaccharide-induced acute lung injury in mice via suppression NF-kappaB and activation Nrf2 pathway[J]. Biochem Biophys Res Commun, 2018, 505(3): 837-842.
38
李光第，赵学凌，周如丹. IL-18激活NF-κB细胞信号通路对人脐静脉内皮细胞损伤作用的体外研究[J]. 重庆医学，2017, 46(24): 3313-3317.
39
Henderson RF, Driscoll KE, Harkema JR, et al. A comparison of the inflammatory response of the lung to inhaled versus instilled particles in F344 rats[J]. Fundam Appl Toxicol, 1995, 24(2): 183-197.
40
Driscoll KE, Costa DL, Hatch G, et al. Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations[J]. Toxicol Sci, 2000, 55(1): 24-35.
41
邓元荣，李泳宁，黄晓敏，等. 大气细颗粒物吸入动物模型建立及适用性评价[J]. 中国比较医学杂志，2016, 26(9): 42-49.
[1] 贺晓楠, 张城, 曹璇, 陈宇. 空气细颗粒物（PM2.5）对心血管疾病住院患者炎症因子的影响[J]. 中华危重症医学杂志(电子版), 2017, 10(04): 242-245.
[2] 王在强, 金发光, 傅恩清. 颗粒酶B在组织损伤修复中的研究进展[J]. 中华损伤与修复杂志(电子版), 2021, 16(04): 349-352.
[3] 任朋洁, 陆晓娜, 王欢, 尤建军, 张波, 徐奕昊, 范飞. 自体软骨颗粒移植在鼻整形术中的应用[J]. 中华损伤与修复杂志(电子版), 2017, 12(06): 463-466.
[4] 林红卫, 李王平, 金发光. PM2.5激活HIF-1α-NF-κB/VEGF通路对肺损伤的影响[J]. 中华肺部疾病杂志(电子版), 2022, 15(03): 316-322.
[5] 顾艳利, 宋勇, 张方. 姜黄素在肺部炎症性疾病中的免疫调节作用[J]. 中华肺部疾病杂志(电子版), 2021, 14(04): 539-542.
[6] 刘甚红, 艾合提热木·塔力甫, 牛灵. 大气细颗粒物对慢性阻塞性肺疾病状态影响的随访[J]. 中华肺部疾病杂志(电子版), 2020, 13(05): 628-632.
[7] 韩璐瑶, 金发光. 西安市大气污染物影响人群健康的现状[J]. 中华肺部疾病杂志(电子版), 2019, 12(06): 783-785.
[8] 李冰洁, 吴升华, 陈筱青. 促炎症消退介质与肺部炎性疾病的研究进展[J]. 中华肺部疾病杂志(电子版), 2017, 10(03): 361-364.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号