Abstract
Benzo[a]pyrene (BaP), a representative polycyclic aromatic hydrocarbon, exists widely in automobile emissions and polluted atmosphere. The current study aimed to describe pulmonary inflammation during BaP-induced acute lung injury (ALI). All mice except controls were intratracheally instilled with a single dose of BaP (90 μg per mouse). The alveolar structure was damaged, accompanied by numerous inflammatory cell infiltration around pulmonary interstitium and small airway. Airway wall area and mean linear intercept were reduced in BaP-exposed mouse lungs. By contrast, airway wall thickness and destructive index were elevated in BaP-exposed mouse lungs. Several inflammatory genes, such as Tnf-α, Il-1β, Il-6, Mip-2, Kc, and Mcp-1, were upregulated in mouse lungs. Phosphorylated IκBα was elevated in BaP-exposed mouse lungs. Nuclear translocation of NF-κB p65 and p50 was accordingly observed in BaP-exposed mouse lungs. Several molecules of the MAPK pathway, including JNK, ERK1/2, and p38, were activated in mouse lungs. Of interest, pretreatment with N-acetylcysteine (NAC), an antioxidant, alleviated BaP-induced ALI. Moreover, NAC attenuated BaP-induced inflammatory cell infiltration in mouse lungs and inflammatory gene upregulation in A549 cells. In addition, NAC attenuated BaP-induced NF-κB activation in A549 cells and mouse lungs. These results suggest that NAC alleviates pulmonary inflammatory response during BaP-evoked ALI.
Similar content being viewed by others
Data availability
Not applicable.
Abbreviations
- ALI:
-
acute lung injury
- BaP:
-
benzo[a]pyrene
- BALF:
-
bronchoalveolar lavage fluid
- COPD:
-
chronic obstructive pulmonary disease
- HPF:
-
high-power field
- IHC:
-
immunohistochemistry
- IL-6:
-
interleukin-6
- IL-1β:
-
interleukin-1β
- KC:
-
keratinocyte chemoattractant
- MAPK:
-
mitogen-activated protein kinase
- MLI:
-
mean linear intercept
- MIP-2:
-
macrophage inflammatory protein-2
- MCP-1:
-
macrophage chemoattractant protein-1
- NAC:
-
N-acetylcysteine
- PVDF:
-
polyvinylidene difluoride
- TNF-α:
-
tumor necrosis factor-α
- WBC:
-
white blood cell
References
Abbas I, Badran G, Verdin A, Ledoux F, Roumie M, Courcot D, Garcon G (2018) Polycyclic aromatic hydrocarbon derivatives in airborne particulate matter: sources, analysis and toxicity. Environ Chem Lett 16:439–475. https://doi.org/10.1007/s10311-017-0697-0
Ali MU, Siyi LY, Yousaf B, Abbas Q, Hameed R, Zheng CM, Kuang XX, Wong MH (2020) Emission sources and full spectrum of health impacts of black carbon associated polycyclic aromatic hydrocarbons (PAHs) in urban environment: a review. Crit Rev Environ Sci Technol 51:857–896. https://doi.org/10.1080/10643389.2020.1738854
Arafa MH, Mohamed DA, Atteia HH (2015) Ameliorative effect of N-acetyl cysteine on alpha-cypermethrin-induced pulmonary toxicity in male rats. Environ Toxicol 30(1):26–43. https://doi.org/10.1002/tox.21891
Balansky R, D'Agostini F, Ganchev G, Izzotti A, Di MB, Lubet RA, Zanesi N, Croce CM, De Flora S (2006) Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: chemoprevention by budesonide and N-acetylcysteine. Proc Natl Acad Sci U S A 103(20):7823–7828. https://doi.org/10.1073/pnas.0601412103
Barnwal P, Vafa A, Afzal SM, Shahid A, Hasan SK, Alpashree Sultana S (2018) Benzo(a)pyrene induces lung toxicity and inflammation in mice: prevention by carvacrol. Hum Exp Toxicol 37:752–761. https://doi.org/10.1177/0960327117735572
Boente C, Baragano D, Gallego JR (2020) Benzo[a]pyrene sourcing and abundance in a coal region in transition reveals historical pollution, rendering soil screening levels impractical. Environ Pollut 266:115341. https://doi.org/10.1016/j.envpol.2020.115341
Calzetta L, Matera MG, Rogliani P, Cazzola M (2018) Multifaceted activity of N-acetyl-l-cysteine in chronic obstructive pulmonary disease. Expert Rev Respir Med 12:693–708. https://doi.org/10.1080/17476348.2018.1495562
Chang JR, Tao J, Xu CY, Li YP, Li N, Tang ZG, Yang YB, Liu Z, Wang Q, Xu DQ (2019) Pollution characteristics of ambient PM2.5-bound benzo[a]pyrene and its cancer risks in Beijing. Sci Total Environ 654:735–741. https://doi.org/10.1016/j.scitotenv.2018.11.085
Cortijo J, Cerda-Nicolas M, Serrano A, Bioque G, Estrela JM, Santangelo F, Esteras A, Llombart-Bosch A, Morcillo EJ (2001) Attenuation by oral N-acetylcysteine of bleomycin-induced lung injury in rats. Eur Respir J 17:1228–1235. https://doi.org/10.1183/09031936.01.00049701
David RM, Gooderham NJ (2018) Dose-dependent synergistic and antagonistic mutation responses of binary mixtures of the environmental carcinogen benzo[a]pyrene with food-derived carcinogens. Arch Toxicol 92:3459–3469. https://doi.org/10.1007/s00204-018-2319-4
Ellickson KM, Herbrandson C, Krause MJ, Pratt GC, Kellock KA (2020) Comparative risk estimates of an expanded list of PAHs from community and source-influenced air sampling. Chemosphere 253:126680. https://doi.org/10.1016/j.chemosphere.2020.126680
Faghfouri AH, Zarezadeh M, Tavakoli-Rouzbehani OM, Radkhah N, Faghfuri E, Kord-Varkaneh H, Tan SC, Ostadrahimi A (2020) The effects of N-acetylcysteine on inflammatory and oxidative stress biomarkers: a systematic review and meta-analysis of controlled clinical trials. Eur J Pharmacol 884:173368. https://doi.org/10.1016/j.ejphar.2020.173368
Fei J, Fu L, Hu B, Chen YH, Zhao H, Xu DX, Li JB (2019) Obeticholic acid alleviate lipopolysaccharide-induced acute lung injury via its anti-inflammatory effects in mice. Int Immunopharmacol 66:177–184. https://doi.org/10.1016/j.intimp.2018.11.005
Feng SJ, Shen XB, Hao XW, Cao XY, Li X, Yao XL, Shi Y, Lv TT, Yao ZL (2021) Polycyclic and nitro-polycyclic aromatic hydrocarbon pollution characteristics and carcinogenic risk assessment of indoor kitchen air during cooking periods in rural households in North China. Environ Sci Pollut Res 28(9):11498–11508. https://doi.org/10.1007/s11356-020-11316-8
Fu L, Chen YH, Bo QL, Song YP, Ma L, Wang B, Xu S, Zhang C, Wang H, Xu DX (2019) Lipopolysaccharide downregulates 11β-hydroxysteroid dehydrogenase 2 expression through inhibiting peroxisome proliferator-activated receptor-γ in placental trophoblasts. J Immunol 203(5):1198–1207. https://doi.org/10.4049/jimmunol.1900132
Fu L, Fei J, Tan ZX, Chen YH, Hu B, Xiang HX, Zhao H, Xu DX (2021a) Low vitamin D status is associated with inflammation in patients with chronic obstructive pulmonary disease. J Immunol 206(3):515–523. https://doi.org/10.4049/jimmunol.2000964
Fu L, Zhao H, Xiang Y, Xiang HX, Hu B, Tan ZX, Lu X, Gao L, Wang B, Wang H, Zhang C, Xu DX (2021b) Reactive oxygen species-evoked endoplasmic reticulum stress mediates 1-nitropyrene-induced epithelial-mesenchymal transition and pulmonary fibrosis. Environ Pollut 283:117134. https://doi.org/10.1016/j.envpol.2021.117134
Gao M, Li H, Dang F, Chen L, Liu X, Gao J (2020) Induction of proliferative and mutagenic activity by benzo(a)pyrene in PC-3 cells via JAK2/STAT3 pathway. Mutat Res 821:111720. https://doi.org/10.1016/j.mrfmmm.2020.111720
Han J, Liang YS, Zhao B, Wang Y, Xing FT, Qin LB (2019) Polycyclic aromatic hydrocarbon (PAHs) geographical distribution in China and their source, risk assessment analysis. Environ Pollut 251:312–327. https://doi.org/10.1016/j.envpol.2019.05.022
Han C, Oh J, Lim YH, Kim S, Hong YC (2020) Long-term exposure to fine particulate matter and development of chronic obstructive pulmonary disease in the elderly. Environ Int 143:105895. https://doi.org/10.1016/j.envint.2020.105895
Hao X, Zhang X, Cao X, Shen X, Shi J, Yao Z (2018) Characterization and carcinogenic risk assessment of polycyclic aromatic and nitro-polycyclic aromatic hydrocarbons in exhaust emission from gasoline passenger cars using on-road measurements in Beijing, China. Sci Total Environ 645:347–355. https://doi.org/10.1016/j.scitotenv.2018.07.113
Islam J, Shree A, Afzal SM, Vafa A, Sultana S (2020) Protective effect of diosmin against benzo(a)pyrene-induced lung injury in Swiss albino mice. Environ Toxicol 35:747–757. https://doi.org/10.1002/tox.22909
Jorge BC, Reis ACC, Sterde ET, Balin PD, Scarano WR, Hisano H, Arena AC (2021) Exposure to benzo(a)pyrene from juvenile period to peripubertal impairs male reproductive parameters in adult rats. Chemosphere 263:128016. https://doi.org/10.1016/j.chemosphere
Ju M, Liu B, He H, Gu Z, Liu Y, Su Y, Zhu D, Cang J, Luo Z (2018) MicroRNA-27a alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis through modulating TLR4/MyD88/NF-κB pathway. Cell Cycle 17(16):2001–2018. https://doi.org/10.1080/15384101.2018.1509635
Kim KH, Jahan SA, Kabir E, Brown RJ (2013) A review of airborne polycyclic aromatic hydrocarbons (PAHs) and their human health effects. Environ Int 60:71–80. https://doi.org/10.1016/j.envint.2013.07.019
Lei J, Wei Y, Song P, Li Y, Zhang T, Feng Q, Xu G (2018) Cordycepin inhibits LPS-induced acute lung injury by inhibiting inflammation and oxidative stress. Eur J Pharmacol 818:110–114. https://doi.org/10.1016/j.ejphar.2017.10.029
Ling X, Yang W, Zou P, Zhang GW, Wang Z, Zhang X, Chen HQ, Peng KG, Han F, Liu JY, Cao J, Ao L (2018) TERT regulates telomere-related senescence and apoptosis through DNA damage response in male germ cells exposed to BPDE in vitro and to B[a]P in vivo. Environ Pollut 235:836–849. https://doi.org/10.1016/j.envpol.2017.12.099
Liu R, He R, Cui X, Ma LQ (2018a) Impact of particle size on distribution, bioaccessibility, and cytotoxicity of polycyclic aromatic hydrocarbons in indoor dust. J Hazard Mater 357:341–347. https://doi.org/10.1016/j.jhazmat.2018.05.058
Liu Y, Li A, Feng X, Sun X, Zhu X, Zhao Z (2018b) Pharmacological Investigation of the anti-inflammation and anti-oxidation activities of diallyl disulfide in a rat emphysema model induced by cigarette smoke extract. Nutrients 10(1):79. https://doi.org/10.3390/nu10010079
Liu S, Jørgensen JT, Ljungman P, Pershagen G, Bellander T, Leander K, Magnusson PKE, Rizzuto D, Hvidtfeldt UA, Raaschou-Nielsen O, Wolf K, Hoffmann B, Brunekreef B, Strak M, Chen J, Mehta A, Atkinson RW, Bauwelinck M, Varraso R et al (2021) Long-term exposure to low-level air pollution and incidence of chronic obstructive pulmonary disease: the ELAPSE project. Environ Int 146:106267. https://doi.org/10.1016/j.envint.2020.106267
Luo F, Liu J, Yan T, Miao M (2017) Salidroside alleviates cigarette smoke-induced COPD in mice. Biomed Pharmacother 86:155–161. https://doi.org/10.1016/j.biopha.2016.12.032
Ma WL, Zhu FJ, Liu LY, Jia HL, Yang M, Li YF (2020) PAHs in Chinese atmosphere part II: health risk assessment. Ecotoxicol Environ Saf 200:110774. https://doi.org/10.1016/j.ecoenv.2020.110774
Mata M, Ruiz A, Cerda M, Martinez-Losa M, Cortijo J, Santangelo F, Serrano-Mollar A, Llombart-Bosch A, Morcillo EJ (2003) Oral N-acetylcysteine reduces bleomycin-induced lung damage and mucin Muc5ac expression in rats. Eur Respir J 22:900–905. https://doi.org/10.1183/09031936.03.00018003
Matera MG, Calzetta L, Cazzola M (2016) Oxidation pathway and exacerbations in COPD: the role of NAC. Expert Rev Respir Med 10:89–97. https://doi.org/10.1586/17476348.2016.1121105
Meier MJ, O'Brien JM, Beal MA, Allan B, Yauk CL, Marchetti F (2017) In utero exposure to benzo[a]pyrene increases mutation burden in the soma and sperm of adult mice. Environ Health Perspect 125(1):82–88. https://doi.org/10.1289/EHP211
Moon J, Cho ES, Lee MY, Son HY, Lee K (2021) Magnesium augments immunosuppressive effects of a corticosteroid in obese mice with airway inflammation. Asian Pac J Allergy Immunol 39(1):15–24. https://doi.org/10.12932/AP-091018-0412
Qamar W, Khan R, Khan AQ, Rehman MU, Lateef A, Tahir M, Ali F, Sultana S (2012) Alleviation of lung injury by glycyrrhizic acid in benzo(a)pyrene exposed rats: probable role of soluble epoxide hydrolase and thioredoxin reductase. Toxicology 291(1-3):25–31. https://doi.org/10.1016/j.tox.2011.10.012
Rezazadeh Azari M, Mohammadian Y, Pourahmad J, Khodagholi F, Peirovi H, Mehrabi Y, Omidi M, Rafieepour A (2019) Individual and combined toxicity of carboxylic acid functionalized multi-walled carbon nanotubes and benzo a pyrene in lung adenocarcinoma cells. Environ Sci Pollut Res Int 26(13):12709–12719. https://doi.org/10.1007/s11356-019-04795-x
Rhoden CR, Lawrence J, Godleski JJ, Gonzalez-Flecha B (2004) N-acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambient particles. Toxicol Sci 79:296–303. https://doi.org/10.1093/toxsci/kfh122
Rushworth GF, Megson IL (2014) Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Therapeut 141:150–159. https://doi.org/10.1016/j.pharmthera.2013.09.006
Sharma D, Jain S (2020) Carcinogenic risk from exposure to PM2.5 bound polycyclic aromatic hydrocarbons in rural settings. Ecotoxicol Environ Saf 190:110135. https://doi.org/10.1016/j.ecoenv.2019.110135
Shen R, Wang Y, Gao W, Cong X, Cheng L, Li X (2019) Size-segregated particulate matter bound polycyclic aromatic hydrocarbons (PAHs) over China: size distribution, characteristics and health risk assessment. Sci Total Environ 685:116–123. https://doi.org/10.1016/j.scitotenv.2019.05.436
Sun X, Feng X, Zheng D, Li A, Li C, Li S, Zhao Z (2019) Ergosterol attenuates cigarette smoke extract-induced COPD by modulating inflammation, oxidative stress and apoptosis in vitro and in vivo. Clin Sci (Lond) 133(13):1523–1536. https://doi.org/10.1042/CS20190331
Tan ZX, Chen YH, Xu S, Qin HY, Wang H, Zhang C, Xu DX, Zhao H (2016) Calcitriol inhibits tumor necrosis factor alpha and macrophage inflammatory protein-2 during lipopolysaccharide-induced acute lung injury in mice. Steroids 112:81–87. https://doi.org/10.1016/j.steroids.2016.05.005
Tanaka KI, Kubota M, Shimoda M, Hayase T, Miyaguchi M, Kobayashi N, Ikeda M, Ishima Y, Kawahara M (2021) Thioredoxin-albumin fusion protein prevents urban aerosol-induced lung injury via suppressing oxidative stress-related neutrophil extracellular trap formation. Environ Pollut 268(Pt A):115787. https://doi.org/10.1016/j.envpol.2020.115787
Tian L, Yan J, Li K, Zhang W, Lin B, Lai W, Bian L, Liu H, Xi Z, Liu X (2021) Ozone exposure promotes pyroptosis in rat lungs via the TLR2/4-NF-κB-NLRP3 signaling pathway. Toxicology 450:152668. https://doi.org/10.1016/j.tox.2020.152668
Tsushima K, King LS, Aggarwal NR, De Gorordo A, D'Alessio FR, Kubo K (2009) Acute lung injury review. Intern Med 48(9):621–630. https://doi.org/10.2169/internalmedicine.48.1741
Wang C, Meng X, Meng M, Shi M, Sun W, Li X, Zhang X, Liu R, Fu Y, Song L (2020) Oxidative stress activates the TRPM2-Ca2+-NLRP3 axis to promote PM2.5-induced lung injury of mice. Biomed Pharmacother 130:110481. https://doi.org/10.1016/j.biopha.2020.110481
Wu D, Li Q, Ding X, Sun JF, Li D, Fu HB, Teich M, Ye XN, Chen JM (2018) Primary particulate matter emitted from heavy fuel and diesel oil combustion in a typical container ship: characteristics and toxicity. Environ Sci Technol 52:12943–12951. https://doi.org/10.1021/acs.est.8b04471
Wu YF, Zhang N, Wang YQ, Ren YB, Yuan ZY, Li N (2020) Concentrations of polycyclic aromatic hydrocarbons in street dust from bus stops in Qingyang city: estimates of lifetime cancer risk and sources of exposure for daily commuters in Northwest China. Environ Pollut 266:115222. https://doi.org/10.1016/j.envpol.2020.115222
Xu AR, Wang JY, Wang HY, Sun YQ, Hao TY (2019) Protective effect of lycopene on testicular toxicity induced by benzo[a] pyrene intake in rats. Toxicology 427:152301. https://doi.org/10.1016/j.tox.2019.152301
Yang LY, Wang WC, Lung SCC, Sun ZL, Chen CJ, Chen JK, Zou Q, Lin YH, Lin CH (2017) Polycyclic aromatic hydrocarbons are associated with increased risk of chronic obstructive pulmonary disease during haze events in China. Sci Total Environ 574:1649–1658. https://doi.org/10.1016/j.scitotenv.2016.08.211
Yao Y, Chen X, Chen W, Wang Q, Fan Y, Han Y, Wang T, Wang J, Qiu X, Zheng M, Que C, Zhu T (2021) Susceptibility of individuals with chronic obstructive pulmonary disease to respiratory inflammation associated with short-term exposure to ambient air pollution: a panel study in Beijing. Sci Total Environ 766:142639. https://doi.org/10.1016/j.scitotenv.2020.142639
Yuan X, Nie W, He Z, Yang J, Shao B, Ma X, Zhang X, Bi Z, Sun L, Liang X, Tie Y, Liu Y, Mo F, Xie D, Wei Y, Wei X (2020) Carbon black nanoparticles induce cell necrosis through lysosomal membrane permeabilization and cause subsequent inflammatory response. Theranostics 10:4589–4605. https://doi.org/10.7150/thno.34065
Zhang L, Xu H, Fang B, Wang H, Yang Z, Yang W, Hao Y, Wang X, Wang Q, Wang M (2020) Source identification and health risk assessment of polycyclic aromatic hydrocarbon-enriched PM2.5 in Tangshan, China. Environ Toxicol Chem 39(2):458–467. https://doi.org/10.1002/etc.4618
Funding
This study was supported by the National Natural Science Foundation of China (81670060 and 91743105), the National Natural Science Foundation Incubation Program of the Second Affiliated Hospital of Anhui Medical University (2020GQFY05), and the Scientific Research of Health Commission in Anhui Province (AHWJ2021b091).
Author information
Authors and Affiliations
Contributions
Hui Zhao: conceptualization, methodology, investigation, writing — original draft, and visualization. Lin Fu: conceptualization, methodology, resources, and writing — original draft. Hui-Xian Xiang: conceptualization, methodology, and resources. Ying Xiang, Meng-Die Li, Bian-Bian Lv, and Zhu-Xia Tan: methodology and software. Lan Gao: methodology, software, data curation, resources, and project administration. Cheng Zhang: conceptualization, validation, and resources. De-Xiang Xu: conceptualization and writing — review and editing. All authors contributed to the development of the manuscript and read and approved the final manuscript.
Corresponding author
Ethics declarations
Ethics approval
The current research was permitted by the Ethics Committee of Anhui Medical University (20200441).
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Responsible Editor: Philippe Garrigues
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Zhao, ., Fu, L., Xiang, HX. et al. N-acetylcysteine alleviates pulmonary inflammatory response during benzo[a]pyrene-evoked acute lung injury. Environ Sci Pollut Res 29, 3474–3486 (2022). https://doi.org/10.1007/s11356-021-15914-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-021-15914-y