Pulmonary persistence of graphene nanoplatelets may disturb physiological and immunological homeostasis

Accumulated evidence suggests that chronic pulmonary accumulation of harmful particles cause adverse pulmonary and systemic health effects. In our previous study, most of the graphene nanoplatelet (GNP) remained in the lung until 28 days after a single instillation. In this study, we sought to evaluate the local and systemic health effect after a long pulmonary persistence of GNP. As expected, GNP remained in the lung on day 90 after a single intratracheal instillation (1.25, 2.5 and 5 mg kg−1). In the lung exposed at the highest dose, the total number of cells and the percentage of lymphocytes significantly increased in the BAL fluid with an increase in both the number of GNP‐engulfed macrophages and the percentage of apoptotic cells. A Th1‐shifted immune response, the elevated chemokine secretion and the enhanced expression of cytoskeletal‐related genes were observed. Additionally, the expression of natriuretic‐related genes was noteworthy altered in the lungs. Moreover, the number of white blood cells (WBC) and the percentage of macrophages and neutrophils clearly increased in the blood of mice exposed to a 5‐mg kg−1 dose, whereas total protein, BUN and potassium levels significantly decreased. In conclusion, we suggest that the long persistence of GNP in the lung may cause adverse health effects by disturbing immunological‐ and physiological‐homeostasis of our body. Copyright © 2016 John Wiley & Sons, Ltd.

[1]  Ying K. Tam,et al.  Cytokines in the generation and maturation of dendritic cells: recent advances. , 2002, European cytokine network.

[2]  D. Stivers,et al.  H2-Ea Deficiency Is a Risk Factor for Bleomycin-Induced Lung Fibrosis in Mice , 2004, Cancer Research.

[3]  I. Svane,et al.  Cellular based cancer vaccines: type 1 polarization of dendritic cells. , 2012, Current medicinal chemistry.

[4]  J. Cyster,et al.  Chemokines as regulators of T cell differentiation , 2001, Nature Immunology.

[5]  Vinayak Sant,et al.  Graphene-based nanomaterials for drug delivery and tissue engineering. , 2014, Journal of controlled release : official journal of the Controlled Release Society.

[6]  Hedwig M Braakhuis,et al.  Physicochemical characteristics of nanomaterials that affect pulmonary inflammation , 2014, Particle and Fibre Toxicology.

[7]  Kostas Kostarelos,et al.  Safety considerations for graphene: lessons learnt from carbon nanotubes. , 2013, Accounts of chemical research.

[8]  Eun-Jung Park,et al.  Toxic response of graphene nanoplatelets in vivo and in vitro , 2014, Archives of Toxicology.

[9]  K. Novoselov Graphene: materials in the Flatland (Nobel lecture). , 2011, Angewandte Chemie.

[10]  Oscar N. Ruiz,et al.  Graphene oxide: a nonspecific enhancer of cellular growth. , 2011, ACS nano.

[11]  Kai Yang,et al.  Nano-graphene in biomedicine: theranostic applications. , 2013, Chemical Society reviews.

[12]  L. Leinwand,et al.  Myofibroblasts: molecular crossdressers. , 2001, Current topics in developmental biology.

[13]  Shufeng Zhou,et al.  Increased susceptibility of db/db mice to rosiglitazone-induced plasma volume expansion: role of dysregulation of renal water transporters. , 2013, American journal of physiology. Renal physiology.

[14]  Yuan Zhang,et al.  TH1/TH2 cell differentiation and molecular signals. , 2014, Advances in experimental medicine and biology.

[15]  K. HayGlass,et al.  T cell chemokine receptor expression in human Th1- and Th2-associated diseases. , 2000, Archivum immunologiae et therapiae experimentalis.

[16]  D. Deryabin,et al.  Toxicity of Graphene Shells, Graphene Oxide, and Graphene Oxide Paper Evaluated with Escherichia coli Biotests , 2015, BioMed research international.

[17]  C. Godson,et al.  Phagocytosis of apoptotic cells and the resolution of inflammation. , 2003, Biochimica et biophysica acta.

[18]  N. Chatterjee,et al.  A systems toxicology approach to the surface functionality control of graphene-cell interactions. , 2014, Biomaterials.

[19]  Nelson Durán,et al.  Nanotoxicity of graphene and graphene oxide. , 2014, Chemical research in toxicology.

[20]  L. Marks,et al.  Lung , 2013, ALERT • Adverse Late Effects of Cancer Treatment.

[21]  Huajian Gao,et al.  Graphene microsheets enter cells through spontaneous membrane penetration at edge asperities and corner sites , 2013, Proceedings of the National Academy of Sciences.

[22]  Ken Donaldson,et al.  Graphene-based nanoplatelets: a new risk to the respiratory system as a consequence of their unusual aerodynamic properties. , 2012, ACS nano.

[23]  Haiping Fang,et al.  Destructive extraction of phospholipids from Escherichia coli membranes by graphene nanosheets. , 2013, Nature nanotechnology.

[24]  Xu-xiang Zhang,et al.  Low levels of graphene and graphene oxide inhibit cellular xenobiotic defense system mediated by efflux transporters , 2016, Nanotoxicology.

[25]  Kostas Kostarelos,et al.  Purified Graphene Oxide Dispersions Lack In Vitro Cytotoxicity and In Vivo Pathogenicity , 2013, Advanced healthcare materials.

[26]  M. Kamal,et al.  Role of Graphene Nano-Composites in Cancer Therapy: Theranostic Applications, Metabolic Fate and Toxicity Issues. , 2014, Current drug metabolism.

[27]  S. Kim,et al.  Regulation of cytokine production during phagocytosis of apoptotic cells , 2006, Cell Research.

[28]  J. M. Navas,et al.  Internalization and cytotoxicity of graphene oxide and carboxyl graphene nanoplatelets in the human hepatocellular carcinoma cell line Hep G2 , 2013, Particle and Fibre Toxicology.

[29]  T. Tötterman,et al.  Dendritic cells engineered to express CD40L continuously produce IL12 and resist negative signals from Tr1/Th3 dominated tumors , 2006, Cancer Immunology, Immunotherapy.

[30]  B. Kaleta Role of Osteopontin in Systemic Lupus Erythematosus , 2014, Archivum Immunologiae et Therapiae Experimentalis.

[31]  D. Lamarre,et al.  Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection , 2010, The Journal of Immunology.

[32]  E. Fish,et al.  Chemokines: attractive mediators of the immune response. , 2003, Seminars in immunology.

[33]  和田 八三久 Materials science. , 1973, Science.

[34]  A. Rao,et al.  Intravenously delivered graphene nanosheets and multiwalled carbon nanotubes induce site-specific Th2 inflammatory responses via the IL-33/ST2 axis , 2013, International journal of nanomedicine.

[35]  Hsing-Yu Tuan,et al.  Graphene Oxide Triggers Toll‐Like Receptors/Autophagy Responses In Vitro and Inhibits Tumor Growth In Vivo , 2014, Advanced healthcare materials.

[36]  N. Mei,et al.  Assessment of the toxic potential of graphene family nanomaterials , 2014, Journal of food and drug analysis.

[37]  Vasileios Koutsos,et al.  Minimal oxidation and inflammogenicity of pristine graphene with residence in the lung , 2014, Nanotoxicology.

[38]  Alexander M. Seifalian,et al.  Toxicology of chemically modified graphene-based materials for medical application , 2014, Archives of Toxicology.

[39]  F. Sinigaglia,et al.  Modulation of chemokine receptor expression and chemotactic responsiveness during differentiation of human naive T cells into Th1 or Th2 cells , 2002, European journal of immunology.

[40]  Mark C Hersam,et al.  Minimizing oxidation and stable nanoscale dispersion improves the biocompatibility of graphene in the lung. , 2011, Nano letters.

[41]  K. Novoselov,et al.  Exploring the Interface of Graphene and Biology , 2014, Science.

[42]  Jing Sun,et al.  Specific nanotoxicity of graphene oxide during zebrafish embryogenesis , 2015, Nanotoxicology.

[43]  L. Ottaviano,et al.  Graphene oxide: from fundamentals to applications , 2015, Journal of physics. Condensed matter : an Institute of Physics journal.

[44]  Jeffrey S. Reynolds,et al.  Graphene Oxide Attenuates Th2-Type Immune Responses, but Augments Airway Remodeling and Hyperresponsiveness in a Murine Model of Asthma , 2014, ACS nano.

[45]  Sang Jin Lee,et al.  Chronic pulmonary accumulation of iron oxide nanoparticles induced Th1-type immune response stimulating the function of antigen-presenting cells. , 2015, Environmental research.

[46]  E. Kunkel,et al.  Rules of chemokine receptor association with T cell polarization in vivo. , 2001, The Journal of clinical investigation.

[47]  Kelly L McNear,et al.  Use of graphene as protection film in biological environments , 2014, Scientific Reports.

[48]  G. MacGregor,et al.  Beneficial effects of potassium on human health. , 2008, Physiologia plantarum.

[49]  Yang Xu,et al.  Toxicity and efficacy of carbon nanotubes and graphene: the utility of carbon-based nanoparticles in nanomedicine , 2014, Drug metabolism reviews.

[50]  D. Denhardt,et al.  Soluble osteopontin inhibits apoptosis of adherent endothelial cells deprived of growth factors * , 2002, Journal of cellular biochemistry.

[51]  Abhilash Sasidharan,et al.  Confocal Raman Imaging Study Showing Macrophage Mediated Biodegradation of Graphene In Vivo , 2013, Advanced healthcare materials.

[52]  Agnes B Kane,et al.  Biological interactions of graphene-family nanomaterials: an interdisciplinary review. , 2012, Chemical research in toxicology.

[53]  D. Allen,et al.  Intracellular Calcium and Myosin Isoform Transitions , 2002, The Journal of Biological Chemistry.

[54]  M. Almukainzi,et al.  Simulated Biological Fluids with Possible Application in Dissolution Testing , 2011 .

[55]  R. Noelle,et al.  The role of CD40/CD154 interactions in the priming, differentiation, and effector function of helper and cytotoxic T cells , 1998, Journal of leukocyte biology.

[56]  R. Hernández-Pando,et al.  Granulocyte–macrophage colony-stimulating factor: not just another haematopoietic growth factor , 2013, Medical Oncology.

[57]  D. Denhardt,et al.  Osteopontin: role in immune regulation and stress responses. , 2011, Cytokine & growth factor reviews.

[58]  Lei Wang,et al.  Graphene oxide induces toll-like receptor 4 (TLR4)-dependent necrosis in macrophages. , 2013, ACS nano.

[59]  Younghun Kim,et al.  Single-walled carbon nanotubes disturbed the immune and metabolic regulation function 13-weeks after a single intratracheal instillation. , 2016, Environmental research.

[60]  J. Klein-Seetharaman,et al.  The enzymatic oxidation of graphene oxide. , 2011, ACS nano.

[61]  R. Mariani-Costantini,et al.  Immunotoxicity of nanoparticles. , 2011, International journal of immunopathology and pharmacology.

[62]  J. Van Damme,et al.  Macrophage inflammatory protein-1. , 2002, Cytokine & growth factor reviews.

[63]  W. Paul,et al.  CD4 T cells: fates, functions, and faults. , 2008, Blood.

[64]  Tapas Kuila,et al.  Recent advances in the efficient reduction of graphene oxide and its application as energy storage electrode materials. , 2013, Nanoscale.

[65]  M. Glimcher,et al.  Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. , 2000, Science.

[66]  SUPARNA DUTTASINHA,et al.  Graphene: Status and Prospects , 2009, Science.