Skip to main content
SpringerLink
Log in

Free Radical Profiles in an Encapsulated Pancreatic Cell Matrix Model

  • Published:
Annals of Biomedical Engineering Aims and scope Submit manuscript

Abstract

The survival of encapsulated pancreatic cells or islets is often limited because of nutrient deficiency, fibrotic overgrowth, and immune attack. Activated immune cells, such as macrophages, release nitric oxide (NO) and superoxide O -2 These species or their reactive intermediates, such as peroxynitrite, can be cytotoxic, mutagenic, and/or carcinogenic. The transport of these free radicals to encapsulated pancreatic cells cannot be impeded by the present immunoisolation technology. A model has been developed simulating free radical profiles within an encapsulation matrix due to macrophage immune cells attached to the surface of an encapsulation matrix. The model incorporates the transport and reactions of NO,O -2 O2 and total peroxynitrite (PER). The model predictions of NO, O -2 and PER concentrations to which pancreatic cells are potentially exposed are in the range of 8–42 μM, 0.5–8 nM, and 0.1–0.8 μM, respectively, for a 100–500 μm radius encapsulation matrix. The results demonstrate that the potential exists for free radical damage of encapsulated pancreatic cells and also demonstrates that additional exposure studies may be necessary for assessing free radical effects on pancreatic cell function. Also, care must be taken in assuming that encapsulated cell systems are completely protected from immunological action. © 2002 Biomedical Engineering Society.

PAC2002: 8716Ac, 8239Rt, 8716Uv

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. Brown, G. C. Regulation of mitochondrial respiration by nitric oxide inhibition of cytochrome c oxidase. Biochim. Biophys. Acta 1504:46–57, 2001.

  2. Chen, B., M. Keshive, and W. M. Deen. Diffusion and reaction of nitric oxide in suspension cell cultures. Biophys. J. 75:745–754, 1998.

    Google Scholar 

  3. Crank, J. The Mathematics of Diffusion, 2nd ed. Oxford: Clarendon, 1975.

    Google Scholar 

  4. Cunningham, J. M., J. G. Mabley, C. A. Delaney, and I. C. Green. The effects of nitric oxide donors on insulin secretion, cyclic GMP and cyclic AMP in rat islets of Langerhans and the insulin-secreting cell lines HIT-T15 and RINm5F. Mol. Cell. Endocrinol. 102:23–29, 1994.

    Google Scholar 

  5. Davenport, H. W. The ABC of Acid-Base Chemistry, 6th ed. Chicago: University of Chicago Press, 1974, p. 41.

    Google Scholar 

  6. De Vos, P., J. F. M. Van Straaten, A. G. Nieuwenhuizen, M. de Groot, R. J. Ploeg, B. J. De Haan, and R. V. Schilfgaarde. Why do microencapsulated islet grafts fail in the absence of fibrotic overgrowth? Diabetes 48:1381–1388, 1999.

    Google Scholar 

  7. Delaney, C. A., B. Tyrberg, L. Bouwens, H. Vaghef, B. Hellman, and D. L. Eizirik. Sensitivity of human pancreatic islets to peroxynitrite-induced cell dysfunction and death. FEBS Lett. 394:300–306, 1996.

    Google Scholar 

  8. Eizirik, D. L., C. A. Delaney, M. H. L. Green, J. M. Cunningham, J. R. Thorpe, D. G. Pipeleers, C. Hellerstorm, and I. C. Green. Nitric oxide donors decrease the function and survival of human pancreatic islets. Mol. Cell. Endocrinol. 118:71–83, 1996.

    Google Scholar 

  9. Fan, M. Y., Z. P. Lum, X. W. Fu, L. Levesque, I. T. Tai, and A. M. Sun. Reversal of diabetes in BB rats by transplantation of encapsulated pancreatic islets. Diabetes 39:519–522, 1990.

    Google Scholar 

  10. Fielden, E. M., P. B. Roberts, R. C. Bray, D. J. Lowe, G. N. Mautner, G. Rotilio, and L. Calabrese. The mechanism of action of superoxide dismutase from pulse radiolysis and electron paramagnetic resonance. Biochem. J. 139:49–60, 1974.

    Google Scholar 

  11. Fridovich, I. Oxygen toxicity: A radical explanation. J. Exp. Biol. 201:1203–1209, 1998.

    Google Scholar 

  12. Hadjivassiliou, V., M. H. Green, R. F. James, S. M. Swift, H. A. Clayton, and I. C. Green. Insulin secretion, DNA damage, and apoptosis in human and rat islets of Langerhans following exposure to nitric oxide, peroxynitrite, and cytokines. Nitric Oxide 2:429–441, 1998.

    Google Scholar 

  13. Huie, R. E., and S. Padmaja. The reaction of NO with superoxide. Free Rad. Res. Comm. 18:195–199, 1993.

    Google Scholar 

  14. Imlay, J. A., and I. Fridovich. Assay of metabolic superoxide production in Escherichia coli. J. Biol. Chem. 266:6957–6965, 1991.

    Google Scholar 

  15. Kaneto, H., J. Fujii, H. G. Seo, K. Suzuki, T. Matsuoka, M. Nakamura, H. Tatsumi, Y. Yamasaki, T. Kamada, and N. Taniguchi. Apoptotic cell death triggered by nitric oxide in pancreatic beta-cells. Diabetes 44:733–738, 1995.

    Google Scholar 

  16. Kaufman, D. B., P. L. Jeffrey, F. L. Rabe, D. L. Dunn, F. H. Bach, and D. E. R. Sutherland. Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts. J. Exp. Med. 172:291–302, 1990.

    Google Scholar 

  17. Kavdia, M., J. Stanfield, and R. S. Lewis. Nitric oxide, superoxide, and peroxynitrite effects on the insulin secretion and viability of bTC3 cells. Ann. Biomed. Eng. 28:102–109, 2000.

    Google Scholar 

  18. Keshive, M., S. Singh, J. S. Wishnok, S. R. Tannenbaum, and W. M. Deen. Kinetics of S-nitrosation of thiols in nitric oxide solutions. Chem. Res. Toxicol. 9:988–993, 1996.

  19. Koppenol, W. H., J. J. Moreno, W. A. Pryor, H. Ischiropoulos, and J. S. Beckman. Peroxynitrite: A cloaked oxidant from superoxide and nitric oxide. Chem. Res. Toxicol. 5:834–842, 1992.

    Google Scholar 

  20. Krestow, M., Z. P. Lum, I. T. Tai, and A. Sun. Xenotransplantation of microencapsulated fetal rat islets. Transplantation 51:651–655, 1991.

    Google Scholar 

  21. Kroncke, K. D., H. H. Brenner, M. L. Rodriguez, K. Etzkorn, E. A. Noack, H. Kolb, and V. Kolb-Bachofen. Pancreatic islet cells are highly susceptible towards the cytotoxic effects of chemically generated nitric oxide. Biochim. Biophys. Acta 1182:221–229, 1993.

    Google Scholar 

  22. Lancaster, J. R., Jr. Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc. Natl. Acad. Sci. U.S.A. 91:8137–8141, 1994.

    Google Scholar 

  23. Lewis, R. S., and W. M. Deen. Kinetics of the reaction of nitric oxide with oxygen in aqueous solutions. Chem. Res. Toxicol. 7:568–574, 1994.

    Google Scholar 

  24. Lewis, R. S., S. Tamir, S. R. Tannenbaum, and W. M. Deen. Kinetic analysis of the fate of nitric oxide synthesize by macrophage in vitro.J. Biol. Chem. 270:29350–29355, 1995.

    Google Scholar 

  25. Lewis, R. S., S. R. Tannenbaum, and W. M. Deen. Kinetics of N-nitrosation in oxygenated nitric oxide solutions at physiological pH: Role of nitrous anhydride and effects of phosphate and chloride. J. Am. Chem. Soc. 117:3933–3939, 1995.

    Google Scholar 

  26. Lum, Z. P., M. Krestow, I. T. Tai, I. Vacek, and A. M. Sun. Xenografts of rat islets into diabetic mice. Transplantation 53:1180–1183, 1992.

    Google Scholar 

  27. Mandrup-Poulsen, T., S. Helquist, L. D. Wogensen, J. Molvig, F. Pociot, J. Johannesen, and J. Nerup. Cytokines and free radicals as effector molecules in the destruction of pancreatic beta cells. Curr. Top. Microbiol. Immunol. 164:169–193, 1990.

    Google Scholar 

  28. Mauricio, D., and T. Mandrup-Poulsen. Apoptosis and the pathogenesis of IDDM: A question of life and death. Diabetes 47:1537–1543, 1998.

    Google Scholar 

  29. Miller, W. M.,C. R. Wilke, and H. W. Blanch. Effects of dissolved oxygen concentration on hybridoma growth and metabolism in continuous culture. J. Cell Physiol. 132:524–530, 1987.

    Google Scholar 

  30. Morvan, D., and M. Y. Jaffrin. Unsteady diffusion mass transfer in a microencapsulated islet of Langerhans for a bioartificial pancreas. Int. J. Heat Mass Transf. 32:995–999, 1989.

    Google Scholar 

  31. Oliveira, H. R., R. Curi, and A. R. Carpinelli. Glucose induces an acute increase of superoxide dismutase activity in incubated rat pancreatic islets. Am. J. Physiol. 276:C507-C510, 1999.

    Google Scholar 

  32. O'Shea, G. M., and A. M. Sun. Encapsulation of rat islets of Langerhans prolongs xenograft survival in diabetic mice. Diabetes 35:943–946, 1986.

    Google Scholar 

  33. Pfeiffer, S., A. C. F. Gorren, K. Schmidt, E. R. Werner, B. Hansert, D. S. Bohle, and B. Mayer. Metabolic fate of peroxynitrite in aqueous solution. J. Biol. Chem. 272:3465–3470, 1997.

    Google Scholar 

  34. Press, W. H., S. A. Teukolsky, W. T. Vetterling, and B. P. Flannery. Numerical Recipes in Fortran. Cambridge: Cambridge University Press, 1972, pp. 745–777.

    Google Scholar 

  35. Radi, R. Peroxynitrite reactions and diffusion in biology. Chem. Res. Toxicol. 11:720–721, 1998.

    Google Scholar 

  36. Reach, G. Bioartificial pancreas. Diabetic Med. 10:105–109, 1993.

  37. Sambanis, A., K. K. Papas, P. C. Flanders, R. C. Long, H. Kang, and I. Constantinidis. Toward the development of a bioartificial pancreas: Immunoisolation and NMR monitoring of mouse insulinomas. Cytotechnology. 15:351–363, 1994.

    Google Scholar 

  38. Soon-Shiong, P., E. Feldman, R. Nelson, J. Komtebedde, O. Smidsrod, G. Skjak-Braek, T. Espevik, R. Heintz, and M. Lee. Successful reversal of spontaneous diabetes in dogs by intraperitoneal microencapsulated islets. Transplantation 54:769–774, 1992.

    Google Scholar 

  39. Stamler, J. S., O. Jaraki, J. Osborne, D. I. Simon, J. Keaney, J. Vita, D. Singel, C. R. Valeri, and J. Loscalzo. Nitric oxide circulates in mammalian plasma primarily as an S-nitroso adduct of serum albumin. Proc. Natl. Acad. Sci. U.S.A. 89:7674–7677, 1992.

    Google Scholar 

  40. Stuehr, D. J., and M. A. Marletta. Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lymphokines, or interferons-g. J. Immunol. 139:518–525, 1987.

    Google Scholar 

  41. Sun, Y., X. Ma, D. Zhou, I. Vacek, and A. M. Sun. Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. J. Clin. Invest. 98:1417–1422, 1996.

    Google Scholar 

  42. Suzuki, Y. J., H. J. Forman, and A. Sevanian. Oxidants as stimulators of signal transduction. Free Radic. Biol. Med. 22:269–285, 1997.

    Google Scholar 

  43. Tamir, S., T. deRojas-Walker, J. S. Wishnok, and S. R. Tannenbaum. DNA damage and genotoxicity by nitric oxide. Methods Enzymol. 269:230–243, 1996.

    Google Scholar 

  44. Tziampazis, E., and A. Sambanis. Tissue engineering of a bioartificial pancreas: Modeling the cell environment and device function. Biotechnol. Prog. 11:115–126, 1995.

    Google Scholar 

  45. Uppu, R. M., G. L. Squadrito, and W. A. Pryor. Acceleration of peroxynitrite oxidations by carbon dioxide. Arch. Biochem. Biophys. 327:335–343, 1996.

    Google Scholar 

  46. Vaughn, M. W., L. Kuo, and J. C. Liao. Estimation of nitric oxide production and reaction rates in tissue by use of a mathematical model. Am. J. Physiol. 274:H2163-H2176, 1998.

    Google Scholar 

  47. Wallgren, A. C., A. Karlsson-Parra, and O. Korsgren. The main infiltrating cell in xenograft rejection is a CD41 macrophage and not a T lymphocyte. Transplantation 60:594–601, 1995.

    Google Scholar 

  48. Welsh, N., B. Margulis, L. A. Borg, H. J. Wiklund, J. Saldeen, M. Flodstrom, M. A. Mello, A. Andersson, D. G. Pipeleers, C. Hellerstrom, and D. L. Eizirik. Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: Implications for the pathogenesis of insulin-dependent diabetes mellitus. Mol. Med. 1:806–820, 1995.

    Google Scholar 

  49. Westrin, B. A., and A. Axelsson. Diffusion in gels containing immobilized cells: A critical review. Biotechnol. Bioeng. 38:439–454, 1991.

    Google Scholar 

  50. Wiegand, F., K. D. Kroncke, and V. Kolb-Bachofen. Macrophage-generated nitric oxide as cytotoxic factor in destruction of alginate-encapsulated islets. Transplantation 56:1206–1212, 1993.

    Google Scholar 

  51. Winterbourn, C. C., and D. Metodiewa. Generation of superoxide and tyrosine peroxide as a result of tyrosyl radical scavenging by glutathione. Arch. Biochem. Biophys. 314:284–290, 1994.

    Google Scholar 

  52. Wohlpart, D., D. Kirwan, and J. Gainer. Effects of cell density and glucose and glutamine levels on the respiration rates of hybridoma cells. Biotechnol. Bioeng. 36:630–635, 1990.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Chemical Engineering, Oklahoma State University, 423 EN, Stillwater, OK

    Mahendra Kavdia & Randy S. Lewis

Authors
  1. Mahendra Kavdia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Randy S. Lewis
    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

Kavdia, M., Lewis, R.S. Free Radical Profiles in an Encapsulated Pancreatic Cell Matrix Model. Annals of Biomedical Engineering 30, 721–730 (2002). https://doi.org/10.1114/1.1481054

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1114/1.1481054

Search

Navigation