Skip to main content
SpringerLink
Log in

Metal tissue kinetics in regenerating liver, thymus, spleen, and submandibular gland after partial hepatectomy in mice

  • Original Articles
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

Liver regeneration after partial hepatectomy (pHx) is a well-defined process, which involves the concerted action of extra- and intracellular factors resulting in induction of cell replication and its inhibition at the time when the entire liver mass is restored. Concomitantly, the breakdown of previously maintained tolerance and the exposure of self-antigens lead to the activation of preimmune and immune repertoires, which participate in surveillance against aberrant cells and the re-establishment of previous morphostasis. Because, in these events, important biological function might have tissue minerals that are affecting the structural integrity and enzyme activities, transduction signals, transcription and replication factors during cell proliferation and apoptosis, as well as the development and maintenance of immune functions and cytokine production, in this study we analyzed tissue dynamics of zinc, ioron magnesium, and calcium in the liver, thymus, spleen, and submandibular gland in intact and pHx mice on the 1st, 2nd, 7th, and 15th d after one-third pHx, using microwave digestion and inductivity coupled plasma spectrometry. The data showed that pHx induces significant and interconnected changes in all of the estimated metals not only in the regenerating liver but also in the lymphatic tissues and submandibular gland, indicating their importance for the control of growth processes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. N. Fausto, A. D. Laird, and E. M. Webber, Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration, FASEB J. 9, 1527–1536 (1995).

    PubMed  CAS  Google Scholar 

  2. G. K. Michalopoulos and M. C. DeFrances, Liver regeneration, Science 276, 60–66 (1997).

    Article  PubMed  CAS  Google Scholar 

  3. N. Fausto, Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells, Hepatology 39, 477–487 (2004).

    Article  Google Scholar 

  4. R. Traub, Liver regeneration: from myth to mechanism, Nature Rev. 5, 836–847 (2004).

    Article  CAS  Google Scholar 

  5. E. M. Webber, J. Bruix, R. H. Pierce, et al., Tumor necrosis factor primes hepatocytes for DNA replication in the rat, Hepatology 28, 1226–1234 (1998).

    Article  PubMed  CAS  Google Scholar 

  6. A. M. Diehl and R. M. Rai, Liver regeneration 3: Regulation of signal transduction during liver regeneration, FASEB J. 10, 215–227 (1996).

    PubMed  CAS  Google Scholar 

  7. B. A. Haber, K. L. Mohn, R. H. Diamond, et al., Induction patterns of 70 genes during nine days after hepatectomy define the temporal course of liver regeneration, J. Clin. Invest. 9, 1319–1326 (1993).

    Article  Google Scholar 

  8. J. H. Albrecht and L. K. Hansen, Cyclin D1 promotes mitogen-independent cell cycle progression in hepatocytes, Cell Growth Differ. 10, 397–404 (1999).

    PubMed  CAS  Google Scholar 

  9. D. B. Stolz, W. M. Mars, B. E. Petersen, et al., Growth factor signal transduction immediately after two-thirds partial hepatectomy in the rat, Cancer Res. 59, 4954–4960 (1999).

    Google Scholar 

  10. P. Skov Olsen, S. Boesby, P. Kirkegaard, et al., Influence of epidermal growth factor on liver regeneration after partial hepatectomy in rats, Hepatology 8, 992–996 (1988).

    Article  PubMed  CAS  Google Scholar 

  11. S. Noguchi, Y. Ohba, and T. Oka, Influence of epidermal growth factor on liver regeneration after partial hepatectomy in mice, J. Endocrinol. 128, 425–431 (1991).

    Article  PubMed  CAS  Google Scholar 

  12. M. Jo, D. B. Stolz, J. E. Esplen, et al., Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells, J. Biol. Chem. 275, 8806–8811 (2000).

    Article  PubMed  CAS  Google Scholar 

  13. J. L. Cruise, S. J. Knechtle, R. R. Bollinger, et al., Alpha 1-adrenergic effects and liver regeneration, Hepatology 7, 1189–1194 (1987).

    Article  PubMed  CAS  Google Scholar 

  14. P. Matzinger, The danger model: a renewed sense of self, Science 296, 301–305 (2002).

    Article  PubMed  CAS  Google Scholar 

  15. T. Abo, T. Kawamura, and H. Watanabe, Physiological responses of extrathymic T cells in the liver, Immunol. Rev. 174, 135–149 (2000).

    Article  PubMed  CAS  Google Scholar 

  16. T. Kato, Y. Sato, S. Takalashi, et al., Involvement of natural killer T cells and granulocytes in the inflammation induced by partial hepatectomy, J. Hepatol. 40, 285–290 (2004).

    Article  PubMed  Google Scholar 

  17. T. Naito, T. Kawamura, M. Bannai, et al., Simultaneous activation of natural killer T cells and autoantibody production in mice injected with denatured syngeneic liver tissue, Clin. Exp. Immunol. 129, 397–404 (2002).

    Article  PubMed  CAS  Google Scholar 

  18. A. Bendelac, Mouse NK1+T cells, Curr. Opln. Immunol. 7, 367–374 (1995).

    Article  CAS  Google Scholar 

  19. D. I. Godfrey, H. R. MacDonald, M. Kronenberg, et al., NKT cells: what's in a name? Nat. Rev. Immunol. 4, 231–237 (2004).

    Article  PubMed  CAS  Google Scholar 

  20. B. Radosevic-Stasic, Z. Trobonjaca, J. Ravlic-Gulan, et al., On the role of natural killer cells in liver regeneration, Period. Biol. 100, 429–434 (1998).

    Google Scholar 

  21. I. Mrakovcic-Sutic, M. Simin, D. Radic, et al., Syngeneic pregnancy induces overex-pression of natural killer T cells in matermal liver, Scand. J. Immunol. 58, 358–366 (2003).

    Article  PubMed  CAS  Google Scholar 

  22. I. Mrakovcic-Sutic, B. Radosevic-Stasic, M. Simin, et al., Augmentation of NKT and NK cell-mediated cytotoxicity by peptidoglycan monomer linked with zinc, Mediators Inflamm. 11, 129–135 (2002).

    Article  PubMed  CAS  Google Scholar 

  23. J. F. Bach Autoimmume diseases as the loss of active “self-control”, Ann. NY Acad. Sci. 998, 161–177 (2003).

    Article  PubMed  CAS  Google Scholar 

  24. H. Tapiero and K. D. Tew, Trace elements in human physiology and pathology: zinc and metallothioneins, Biomed. Pharmacother. 57, 399–411 (2003).

    Article  PubMed  CAS  Google Scholar 

  25. A. S. Prasad, Zinc deficiency: its characterization and treatment, Metal Ions Biol. Syst. 41, 103–137 (2004).

    CAS  Google Scholar 

  26. P. J. Fraker and L. E. King, Reprogramming of the immune system during zinc deficiency, Annu. Rev. Nutr. 24, 277–298 (2004).

    Article  PubMed  CAS  Google Scholar 

  27. L. Rink and P. Gabriel, Zinc and the immune system, Proc. Nutr. Soc. 59, 541–552 (2000).

    Article  PubMed  CAS  Google Scholar 

  28. E. Mocchegiani, R. Giacconi, E. Muti, et al., Zinc, immune plasticity, aging, and successful aging: role of metallothionein, Ann. NY Acad. Sci. 1019, 127–134 (2004).

    Article  PubMed  CAS  Google Scholar 

  29. M. D. Lastra, R. Pastelin, A. Camacho, et al., Zinc intervention on macrophages and lymphocytes response, J. Trace Elements Med. Biol. 15, 5–10 (2001).

    Article  CAS  Google Scholar 

  30. T. Dudev and C. Lim, Principles governing Mg, Ca, and Zn binding and selectivity in proteins, Chem. Rev. 103, 773–788 (2003).

    Article  PubMed  CAS  Google Scholar 

  31. M. P. Vaquero, Magnesium and trace elements in the elderly: intake, status and recommendations, J. Nutr. Health Aging 6, 147–153 (2002).

    PubMed  CAS  Google Scholar 

  32. P. Evans and B. Halliwell, Micronutrients: oxidant/antioxidant status, Br. J. Nutr. 85(Suppl. 2), S67-S74 (2001).

    Article  PubMed  CAS  Google Scholar 

  33. D. Verbanac, C. Milin, R. Domitrovic, et al., Determination of standard zinc values in the intact tissues of mice by ICP spectrometry, Biol. Trace Element Res. 57, 91–96 (1997).

    CAS  Google Scholar 

  34. C. Milin, B. Radosevic-Stasic, D. Verbanac, et al., Changes of hepatic and thymic zinc during the liver regeneration in hepatectomized mice, Croatica Chem. Acta 68, 559–567 (1995).

    CAS  Google Scholar 

  35. E. Mocchegiani, D. Verbanac, L. Santarelli, et al., Zinc and metallothioneins on cellular immune effectiveness during liver regeneration in young and old mice, Life Sci. 61, 1125–1145 (1997).

    Article  PubMed  CAS  Google Scholar 

  36. C. Cipriano, R. Giacconi, M. Muzzioli, et al., Metallothionein (I+II) confers, via c-myc, immune plasticity in oldest mice: model of partial hepatectomy/liver regeneration, Mech. Ageing. Dev. 124, 877–886 (2003).

    Article  PubMed  CAS  Google Scholar 

  37. K. Tsujikawa, N. Suzuki, K. Sagawa, et al., Induction and subcellular localization of metallothionein in regenerating rat liver, Eur. J. Cell. Biol. 63, 240–246 (1994).

    PubMed  CAS  Google Scholar 

  38. M. G. Cherian, Nuclear and cytoplasmic localization of metallothionein in human liver during development and in tumor cells, in Metallothionein III (K. T. Suzuki, N. Imura, and M. Kimura, eds.), Birkhaüser-Verlag, Basel, pp. 175–187 (1993).

    Google Scholar 

  39. M. Sato, M. Sasaki, and H. Hojo, Induction of metallothionein synthesis by oxidative stress and possible role in acute phase response, in Metallothionein III (K. T. Suzuki, N. Imura, and M. Kimura, eds.), Birkhaüser-Verlag, Basel, pp. 125–140 (1993).

    Google Scholar 

  40. W. Maret and B. L. Vallee, Thiolate ligands in metallothionein confer redox activity on zinc clusters, Proc. Natl. Acad. sci. USA 95, 3478–3482 (1998).

    Article  PubMed  CAS  Google Scholar 

  41. C. M. St Croix, K. J. Wasserloos, K. E. Dineley, et al., Nitric oxide-induced changes in intracellular zinc homeostasis are mediated by metallothionein/thionein, Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L185-L192 (2002).

    PubMed  CAS  Google Scholar 

  42. W. Maret, C. Jacob, B. L. Vallee, et al., Inhibitory sites in enzymes: zinc removal and reactivation by thionein, Proc. Natl. Acad. Sci. USA 96, 1936–1940 (1999).

    Article  PubMed  CAS  Google Scholar 

  43. J. Zeng, R. Heuchel, W. Schaffner, et al., Thionein (apometallothionein) can modulate DNA binding and transcription activation by zinc finger containing factor Sp1, FEBS Lett. 279, 310–312 (1991).

    Article  PubMed  CAS  Google Scholar 

  44. C. Kerkhoff, T. Vogl, W. Nacken, et al., Zinc binding reverses the calcium-induced arachidonic acid-binding capacity of the S100A8/A9 protein complex, FEBS Lett. 46, 134–138 (1999).

    Article  Google Scholar 

  45. W. Nacken, J. Roth, C. Sorg, et al., S100A9/S100A8: myeloid representatives of the S100 protein family as prominent players in innate immunity, Microsc. Res. Tech. 60, 569–580 (2003).

    Article  PubMed  CAS  Google Scholar 

  46. R. Shimoda, W. E. Achanzar, W. Qu, et al., Metallothionein is a potential negative regulator of apoptosis, Toxicol. Sci. 73, 294–300 (2003).

    Article  PubMed  CAS  Google Scholar 

  47. Y. Fukamachi, Y. Karasaki, T. Sugiura, et al., Zinc suppresses apoptosis of U937 cells induced by hydrogen peroxide through an increase of the Bcl-2/Bax ratio, Biochem. Biophys. Res. Commun. 246, 364–369 (1998).

    Article  PubMed  CAS  Google Scholar 

  48. C. Giannakis, I. J. Forbes, and P. D. Zalewski, Ca2+/Mg(2+)-dependent nuclease: tissue distribution, relationship to inter-nucleosomal DNA fragmentation and inhibition by Zn2+, Biochem. Biophys. Res. Commun. 181, 915–920 (1991).

    Article  PubMed  CAS  Google Scholar 

  49. P. Schneider, N. Holler, J. L. Bodmer, et al., Conversion of membrane-bound Fas (CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity, J. Exp. Med. 187, 1205–1213 (1998).

    Article  PubMed  CAS  Google Scholar 

  50. E. Mocchegiani, M. Muzzioli, and R. Giacconi, Zinc, metallothioneins, immune responses, survival and ageing, Biogerontology 1, 133–143 (2000).

    Article  PubMed  CAS  Google Scholar 

  51. E. Mocchegiani, R. Giacconi, C. Cipriano, et al., MtmRNA gene expression, via IL-6 and glucocorticoids, as potential genetic marker of immunosenescence: lessons from very old mice and humans, Exp. Gerontol. 37, 349–357 (2002).

    Article  PubMed  CAS  Google Scholar 

  52. A. Molotkov, N. Nishimura, M. Satoh, et al., Role of IL-6 in the induction of hepatic metallothionein in mice after partial hepatectomy, Life Sci. 66, 963–970 (2000).

    Article  PubMed  CAS  Google Scholar 

  53. H. Bruunsgaard, M. Pedersen, and B. K. Pedersen, Aging and proinflammatory cytokines, Curr. Opin. Hematol. 8, 131–136 (2001).

    Article  PubMed  CAS  Google Scholar 

  54. E. Mocchegiani, M. Muzzioli, R. Giacconi, et al., Metallothioneins/PARP-1/II-6 interplay on natural killer cell activity in elderly: parallelism with nonagenarians and old infected humans. Effect of zinc supply, Mech. Ageing Dev. 124, 459–468 (2003).

    Article  PubMed  CAS  Google Scholar 

  55. C. O. Simpkins, Metallothionein in human disease, Cell. Mol. Biol. (Noisy-le-Grand) 46, 465–488 (2000).

    CAS  Google Scholar 

  56. P. J. Fraker, L. E. King, T. Laakko, et al., The dynamic link between the integrity of the immune system and zinc status, J. Nutr. 130, 1399S-1406S (2000).

    PubMed  CAS  Google Scholar 

  57. L. E. King, F. Osati-Ashtiani, and P. J. Fraker, Apoptosis plays a distinct role in the loss of precursor lymphocytes during zinc deficiency in mice, J. Nutr. 132, 974–979 (2002).

    PubMed  CAS  Google Scholar 

  58. J. F. Bach and M. Dardenne, Thymulin, a zinc-dependent hormone, Med. Oncol. Tumor Pharmacother 6, 25–29 (1989).

    PubMed  CAS  Google Scholar 

  59. F. Di Virgilio, P. Chiozzi, D. Ferrari, et al., Nucleotide receptors: an emerging family of regulatory molecules in blood cells, Blood 97, 587–600 (2001).

    Article  PubMed  Google Scholar 

  60. R. S. Lewis, Calcium oscillations in T-cells: mechanisms and consequences for gene expression, Biochem. Soc. Trans. 31, 925–929 (2003).

    PubMed  CAS  Google Scholar 

  61. G. Panyi, Z. Varga, and R. Gaspar, Ion channels and lymphocyte activation, Immunol. Lett. 92, 55–66 (2004).

    Article  PubMed  CAS  Google Scholar 

  62. L. L. Chen, A. Whitty, D. Scott, et al., Evidence that ligand and metal ion binding to integrin alpha 4beta 1 are regulated through a coupled equilbrium, J. Biol. Chem. 276, 36,520–36,529 (2001).

    CAS  Google Scholar 

  63. R. Mathison, J. S. Davison, and A. D. Betus, Neuroendocrine regulation of intlammation and tissue repair by submandibular gland factors, Immunol. Today. 15, 527–532 (1994).

    Article  PubMed  CAS  Google Scholar 

  64. E. Sabbadini and I. Berczi, The submandibular gland: a key organ in the neuroimmuno-regulatory network?, Neuroimmunomodulation 2, 184–202 (1995).

    Article  PubMed  CAS  Google Scholar 

  65. C. Rougeot, I. Rosinski-Chupin, R. Mathison, et al., Rodent submandibular gland peptide hormones and other biologically active peptides, Peptides 21, 443–455 (2000).

    Article  PubMed  CAS  Google Scholar 

  66. T. J. Bartness, C. K. Song, and G. E. Demas, SCN efferents to peripheral tissues: implications for biological rhythms, J. Biol. Rhythms 16, 196–204 (2001).

    Article  PubMed  CAS  Google Scholar 

  67. S. Ruff-Jamison, Z. Zhong, Z. Wen, et al., Epidermal growth factor and lipopolysaccharide activate Stat3 transcription factor in mouse liver, J. Biol. Chem. 269, 21,933–21,935 (1994).

    CAS  Google Scholar 

  68. R. Giacconi, C. Cipriano, M. Muzzioli, et al., Interrelationships among brain, endocrine and immune response in ageing and successful ageing: role of metallothionein III isoform, Mech. Ageing Dev. 124, 371–378 (2003).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Medical Faculty of Rijeka, B. Branchetta 22, 51 000, Rijeka, Croatia

    Čedomila Milin, Marin Tota, Robert Domitrović, Jasminka Giacometti & Radojka Pantovic

  2. Department of Physiology and Immunology, Medical Faculty of Rijeka, B. Branchetta 22, 51 000, Rijeka, Croatia

    Mira Ćuk, Ines Mrakovčić-Šutić, Hrvoje Jakovac & Biserka Radošević-Stašić

Authors
  1. Čedomila Milin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marin Tota
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert Domitrović
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jasminka Giacometti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Radojka Pantovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mira Ćuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ines Mrakovčić-Šutić
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hrvoje Jakovac
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Biserka Radošević-Stašić
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Milin, Č., Tota, M., Domitrović, R. et al. Metal tissue kinetics in regenerating liver, thymus, spleen, and submandibular gland after partial hepatectomy in mice. Biol Trace Elem Res 108, 225–243 (2005). https://doi.org/10.1385/BTER:108:1-3:225

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/BTER:108:1-3:225

Index Entries

Search

Navigation