Abstract
Nickle (Ni) is a heavy metal found in particulate matter. We previously reported that Ni ions are strongly associated with high apoptosis rates and high expression of IL-1β in human bronchial epithelial cells following exposure to PM2.5; however, the effects of Ni ions on pulmonary fibrosis have not been fully elucidated. In the current study, we evaluated whether Ni ions can exacerbate bleomycin (BLM)-induced pulmonary fibrosis in a mouse model and illustrated the potential mechanism. Ni ions inhibited cell proliferation and induced apoptosis in A549 and MRC-5 cells. BLM-induced lung injury and fibrosis in mice were significantly enhanced by nickel treatment, and these findings were also supported by inflammatory cell accumulation in bronchoalveolar lavage fluid and elevated levels of pro-inflammatory cytokines in lung tissues. Ni ions also increased extracellular matrix protein levels, including those of type I collagen and MMP9 in mouse lung tissues and cell lines. Moreover, Ni ions promoted the phosphorylation of AKT in this mouse model. The effect of increased collagen levels and MMP9 expression was inhibited by blocking the AKT phosphorylation. Together, these findings suggest AKT activation as a critical contributor to this Ni-exacerbated pulmonary fibrotic process.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adegunsoye A, Balachandran J (2015) Inflammatory response mechanisms exacerbating hypoxemia in coexistent pulmonary fibrosis and sleep apnea. Mediat Inflamm 2015:510105. https://doi.org/10.1155/2015/510105
Andersson-Sjoland A, Karlsson JC, Rydell-Tormanen K (2016) ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling. Lab Investig 96(2):206–217. https://doi.org/10.1038/labinvest.2015.100
Behr J (2013) The diagnosis and treatment of idiopathic pulmonary fibrosis. Dtsch Arztebl Int 110(51–52):875–881. https://doi.org/10.3238/arztebl.2013.0875
Borchers AT, Chang C, Keen CL, Gershwin ME (2011) Idiopathic pulmonary fibrosis-an epidemiological and pathological review. Clin Rev Allergy Immunol 40(2):117–134. https://doi.org/10.1007/s12016-010-8211-5
Borg L, Christensen JM, Kristiansen J, Nielsen NH, Menne T, Poulsen LK (2000) Nickel-induced cytokine production from mononuclear cells in nickel-sensitive individuals and controls. Cytokine profiles in nickel-sensitive individuals with nickel allergy-related hand eczema before and after nickel challenge. Arch Dermatol Res 292(6):285–291
Bringardner BD, Baran CP, Eubank TD, Marsh CB (2008) The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis. Antioxid Redox Signal 10(2):287–301. https://doi.org/10.1089/ars.2007.1897
Caminati A, Madotto F, Cesana G, Conti S, Harari S (2015) Epidemiological studies in idiopathic pulmonary fibrosis: pitfalls in methodologies and data interpretation. Eur Respir Rev 24(137):436–444. https://doi.org/10.1183/16000617.0040-2015
Cicko S, Grimm M, Ayata K, Beckert J, Meyer A, Hossfeld M et al (2015) Uridine supplementation exerts anti-inflammatory and anti-fibrotic effects in an animal model of pulmonary fibrosis. Respir Res 16:105. https://doi.org/10.1186/s12931-015-0264-9
Craig VJ, Zhang L, Hagood JS, Owen CA (2015) Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 53(5):585–600. https://doi.org/10.1165/rcmb.2015-0020TR
Cui Y, Robertson J, Maharaj S, Waldhauser L, Niu J, Wang J et al (2011) Oxidative stress contributes to the induction and persistence of TGF-beta1 induced pulmonary fibrosis. Int J Biochem Cell Biol 43(8):1122–1133. https://doi.org/10.1016/j.biocel.2011.04.005
Dong Y, Geng Y, Li L, Li X, Yan X, Fang Y et al (2015) Blocking follistatin-like 1 attenuates bleomycin-induced pulmonary fibrosis in mice. J Exp Med 212(2):235–252. https://doi.org/10.1084/jem.20121878
Edelman DA, Roggli VL (1989) The accumulation of nickel in human lungs. Environ Health Perspect 81:221–224
Fiorentino DF, Zlotnik A, Vieira P, Mosmann TR, Howard M, Moore KW, O'Garra A (1991) IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol 146(10):3444–3451
Forti E, Salovaara S, Cetin Y, Bulgheroni A, Tessadri R, Jennings P et al (2011) In vitro evaluation of the toxicity induced by nickel soluble and particulate forms in human airway epithelial cells. Toxicol In Vitro 25(2):454–461. https://doi.org/10.1016/j.tiv
Jin HL, Dong JC (2011) Pathogenesis of idiopathic pulmonary fibrosis: from initial apoptosis of epithelial cells to lung remodeling? Chin Med J 124(24):4330–4338
Johannson KA, Vittinghoff E, Lee K, Balmes JR, Ji W, Kaplan GG et al (2014) Acute exacerbation of idiopathic pulmonary fibrosis associated with air pollution exposure. Eur Respir J 43(4):1124–1131. https://doi.org/10.1183/09031936.0012221309031936.00122213
Kasprzak KS, Bal W, Karaczyn AA (2003) The role of chromatin damage in nickel-induced carcinogenesis. A review of recent developments. J Environ Monit 5(2):183–187
Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN et al (2006) Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 103(35):13180–13185. https://doi.org/10.1073/pnas.0605669103
Kuwano K, Hagimoto N, Tanaka T, Kawasaki M, Kunitake R, Miyazaki H et al (2000) Expression of apoptosis-regulatory genes in epithelial cells in pulmonary fibrosis in mice. J Pathol 190(2):221–229. https://doi.org/10.1002/(SICI)1096-9896(200002)190:2<221::AID-PATH495>3.0.CO;2-J
Lee SK, Tan KW, Ng SW (2016) Topoisomerase I inhibition and DNA cleavage by zinc, copper, and nickel derivatives of 2-[2-bromoethyliminomethyl]-4-[ethoxymethyl]phenol complexes exhibiting anti-proliferation and anti-metastasis activity. J Inorg Biochem 159:14–21. https://doi.org/10.1016/j.jinorgbio.2016.02.010
Liu Q, Chu H, Ma Y, Wu T, Qian F, Ren X et al (2016) Salvianolic acid B attenuates experimental pulmonary fibrosis through inhibition of the TGF-beta signaling pathway. Sci Rep 6:27610. https://doi.org/10.1038/srep27610
Lu H, Shi X, Costa M, Huang C (2005) Carcinogenic effect of nickel compounds. Mol Cell Biochem 279(1–2):45–67. https://doi.org/10.1007/s11010-005-8215-2
Lu Y, Azad N, Wang L, Iyer AK, Castranova V, Jiang BH, Rojanasakul Y (2010) Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am J Respir Cell Mol Biol 42(4):432–441. https://doi.org/10.1165/rcmb.2009-0002OC
Mao X, Kashii T, Wang Q, Tong J, Liu S (2000) Studies on cell transformation and cell cycle in human embryo lungs induced by nickel compounds. Zhonghua Yu Fang Yi Xue Za Zhi 34(6):339–341
Mercer PF, Woodcock HV, Eley JD, Plate M, Sulikowski MG, Durrenberger PF et al (2016) Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF. Thorax. https://doi.org/10.1136/thoraxjnl-2015-207429
Ogami A, Morimoto Y, Myojo T, Oyabu T, Murakami M, Todoroki M, Tanaka I (2009) Pathological features of different sizes of nickel oxide following intratracheal instillation in rats. Inhal Toxicol 21(10):812–818. https://doi.org/10.1080/08958370802499022
Rassler B (2013) Role of alpha- and beta-adrenergic mechanisms in the pathogenesis of pulmonary injuries characterized by edema, inflammation and fibrosis. Cardiovasc Hematol Disord Drug Targets 13(3):197–207
Roberts AB, Sporn MB (1988) Transforming growth factor beta. Adv Cancer Res 51:107–145
Rockey DC, Bell PD, Hill JA (2015) Fibrosis—a common pathway to organ injury and failure. N Engl J Med 372(12):1138–1149. https://doi.org/10.1056/NEJMra1300575
Salnikow K, Su W, Blagosklonny MV, Costa M (2000) Carcinogenic metals induce hypoxia-inducible factor-stimulated transcription by reactive oxygen species-independent mechanism. Cancer Res 60(13):3375–3378
Serrano-Mollar A, Closa D, Prats N, Blesa S, Martinez-Losa M, Cortijo J et al (2003) In vivo antioxidant treatment protects against bleomycin-induced lung damage in rats. Br J Pharmacol 138(6):1037–1048. https://doi.org/10.1038/sj.bjp.0705138
Teixeira KC, Soares FS, Rocha LG, Silveira PC, Silva LA, Valenca SS et al (2008) Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine. Pulm Pharmacol Ther 21(2):309–316. https://doi.org/10.1016/j.pupt.2007.07.006
Wang YR, Ma XT, Wang SQ, Kong LF, Yang ZG (2007) Cell apoptosis and the associated signal expression in epithelial cells from patients with idiopathic pulmonary fibrosis. Zhonghua Jie He He Hu Xi Za Zhi 30(10):767–770
Winters CJ, Koval O, Murthy S, Allamargot C, Sebag SC, Paschke JD et al (2016) CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis. Am J Physiol Lung Cell Mol Physiol 310(1):L86–L94. https://doi.org/10.1152/ajplung.00132.2015
Xaubet A, Ancochea J, Bollo E, Fernandez-Fabrellas E, Franquet T, Molina-Molina M et al (2013) Guidelines for the diagnosis and treatment of idiopathic pulmonary fibrosis. Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) Research Group on Diffuse Pulmonary Diseases. Arch Bronconeumol 49(8):343–353. https://doi.org/10.1016/j.arbres.2013.03.011S0300-2896(13)00099-9
Xie H, Wang R, Tang X, Xiong Y, Xu R, Wu X (2012) Paraquat-induced pulmonary fibrosis starts at an early stage of inflammation in rats. Immunotherapy 4(12):1809–1815. https://doi.org/10.2217/imt.12.122
Yang L, Liu G, Lin Z, Wang Y, He H, Liu T, Kamp DW (2014) Pro-inflammatory response and oxidative stress induced by specific components in ambient particulate matter in human bronchial epithelial cells. Environ Toxicol. https://doi.org/10.1002/tox.22102
Yang L, Wang Y, Lin Z, Zhou X, Chen T, He H et al (2015) Mitochondrial OGG1 protects against PM2.5-induced oxidative DNA damage in BEAS-2B cells. Exp Mol Pathol 99(2):365–373. https://doi.org/10.1016/j.yexmp.2015.08.005S0014-4800(15)00167-7
Yu SH, Liu LJ, Lv B, Che CL, Fan DP, Wang LF, Zhang YM (2015) Inhibition of bleomycin-induced pulmonary fibrosis by bone marrow-derived mesenchymal stem cells might be mediated by decreasing MMP9, TIMP-1, INF-gamma and TGF-beta. Cell Biochem Funct 33(6):356–366. https://doi.org/10.1002/cbf.3118
Zhao J, Shi X, Castranova V, Ding M (2009) Occupational toxicology of nickel and nickel compounds. J Environ Pathol Toxicol Oncol 28(3):177–208
Funding
This work was supported by the Natural Science Foundation of China (grant no. NSFC81172615, NSFC81570062, NSFC81600049); Guangdong Natural Science Foundation (2016A030313681); and Guangdong Medical University Scientific Research fund (grant no. M2014046, M2014031, M2015009).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
All procedures and animal handling were carried out according to the guidelines for the care and use of laboratory animals in China and approved by the Animal Care and Use Committee of Guangdong Medical University.
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Responsible editor: Philippe Garrigues
Rights and permissions
About this article
Cite this article
Yang, L., Lin, Z., Wang, Y. et al. Nickle(II) ions exacerbate bleomycin-induced pulmonary inflammation and fibrosis by activating the ROS/Akt signaling pathway. Environ Sci Pollut Res 25, 4406–4418 (2018). https://doi.org/10.1007/s11356-017-0525-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-017-0525-x