Molecular Mechanisms Regulating Nitric Oxide Biosynthesis

Role of Xenobiotics in Epithelial Inflammation
  • Diane E. Heck
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 387)


The squamous epithelium, which comprises the outermost barrier to the environment, functions as the primary initial site of xenobiotic insult. Following xenobiotic insult, the epithelium responds by producing a complex inflammatory micro-environment. During inflammation, hyperplasia, edema as well as leukocyte infiltration are typically observed (Adams, 1993). Stromal cells, keratinocytes in the case of the skin, resident immune-type dendritic cells, and infiltrating leukocytes release an array of cytokines and inflammatory mediators that regulate the inflammatory process. Initially, these mediators induce increased vascular permeability, which in turn facilitates an influx of serum-derived factors including complement, hormones, leukotrienes and cytokines (Camp, 1990, Gallo, 1989). These mediators then enhance recruitment of additional leukocytes to the site of xenobiotic insult as well as stimulating the proliferation of resident epithelial cells and fibroblasts. This later effect is required for the resolution of inflammation and successful wound repair (Friedman, 1993, Knighton, 1991, Kupper, 1990).


Epidermal Growth Factor Nitric Oxide Cutaneous Wound Healing Epidermal Growth Factor Treatment Intrinsic Tyrosine Kinase Activity 
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  1. Adams, R.A., Disorders due to Drugs and Chemical Agents, in: Fitzpatrick, T.B., Eisen, A.Z., Wolff, K., Freedberg, I.M., Austen, K.F., eds. Dermatology in General Medicine, pp. 1767–1783. New York, McGraw-Hill Inc., 1993.Google Scholar
  2. Asano, K., Chee. C. B. E., Gaston, B., Lilly, C. M., Gerard, C, Drazen, J., M., Stamler, J. S., Constitutive and Inducible Nitric Oxide Synthase Gene Expression, Regulation, and Activity in Human Lung Epithelial Cells., Proc. Natl. Acad. Sci. USA, 91, 10089–10093, 1994.PubMedCrossRefGoogle Scholar
  3. Barken J.N.W.N., Mitra, R.S., Griffiths, C.E.M., Dixit, V.M., Nickoloff, B.J. Keratinocytes as initiators of inflammation. The Lancet. 337: 211–214, 1991.CrossRefGoogle Scholar
  4. Clark, R.A., The commonality of cutneous wound repair and lung injury, Chest 99: 575–605, 1991.CrossRefGoogle Scholar
  5. Camp, R.D.R., Fincham, N.J., Ross, J.S., Bacon, K.B., Gearing, A.J.H., Leukocyte chemoattractant cytokines of the epidermis. J. Invest. Dermatol., 95: 108S–110S, 1990.PubMedCrossRefGoogle Scholar
  6. Darnell, J. E., Kerr, I. M., Stark, G. R., Jak-STAT Pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science, 264, 1415–1421, 1994.PubMedCrossRefGoogle Scholar
  7. Feng, Q., Hedner, T., Endothelium derived relaxing factor (EDRF) and nitric oxide (NO). I. physiology, pharmacology and pathophysiological implications. Clin. Physiol., 10: 407–426, 1990.PubMedCrossRefGoogle Scholar
  8. Flohe, L., Beckman, R., Giertz, H., Loschen, G., Oxygen centered free radicals as mediators of inflammation. in: Sies, H. ed., Oxidative Stress, pp.403–428, Orlando F1., Academic Press, 1985.Google Scholar
  9. Fu, X-Y., Zhang, J-J., Transcription factor p91 interacts with the epidermal growth factor receptor and mediates activation of the c-FOS gene promoter. Cell, 74, 1135–1145, 1993.PubMedCrossRefGoogle Scholar
  10. Friedmann, P.S., Strickland, I., Memomoa, A.A., Johnson, P.M., Early time course of recruitment of immune surveillance in human skin after chemical provocation. Clin.Exp. Immunol. 91: 351–356, 1993.PubMedCrossRefGoogle Scholar
  11. Gallo, R.L., Staszewski, R., Granstein, R.D., Physiology and pathology of skin photoimmunology, in: Bos, J.D. ed., Skin and the Immune System, pp. 381–402. Boca Raton, Fl., CRC Press, 1989.Google Scholar
  12. Gewert, D., Finter, N. B., Antiviral Effects of the interferons: Studies in animals and at the cellular level, in: Interferon, Principles and Medical Applications, pp. 129–138, Galveston TX, The University of Galveston Medical Branch at Galveston Department of Microbiology, 1992.Google Scholar
  13. Heck, DE and JD Laskin, Pertussis toxin inhibits induction of p-91 STAT by γ-interferon in A549 pulmonary epithelial cells. Proceedings of the American Association for Cancer Research, 1995 (in Press).Google Scholar
  14. Heck, DE, DL Laskin and JD Laskin, γ-Interferon and inhaled irritants induce production of vasoregulatory mediators by rat alveolar Type II epithelial cells. Am. J. Respir. Crit. Care Med., 149 (2) A551, 1994.Google Scholar
  15. Heck DE, JD Laskin, Interferon dependent regulation of cytoplasmic transcription factors in keratinocytes during wound healing. J. Invest. Dermatol., 102, 528, 1994.Google Scholar
  16. Heck DE. DL Laskin, JD Laskin, J Finkelstein, T Liberati and G Oberdorster, Effects of silicon dioxide on the production of vasoregulatory mediators by rat alveolar type II epithelial cells. The Toxicologist, 14, 200. 1994.Google Scholar
  17. Heck DE, DL Laskin, CR Gardner and JD Laskin, Role of nitric oxide in chemical induced skin injury. The Toxicologist, 13, 183. 1993.Google Scholar
  18. Heck, D.E., and J.D. Laskin, Nitric oxide production by mouse and human keratinocytes is regulated by insulin-like growth factor-1. J. Invest. Dermatol., 100, 511, 1993.Google Scholar
  19. Heck, D. E., Laskin, D.L., Gardner, C.R., Laskin, J.D., Epidermal growth factor supresses nitric oxide and hydrogen peroxide production by keratinocytes. J. Biol. Chem., 267: 21277–21280, 1992.PubMedGoogle Scholar
  20. Hill, C.S., Treisman, C.S., Transcriptional regulation by extracellular signals: Mechanisms and specificity. Cell, 80, 199–212, 1995.PubMedCrossRefGoogle Scholar
  21. Holbrook, K. A., Wolff, K., The structure and development of skin. in: Fitzpatrick, T.B., Eisen, A.Z., Wolff, K., Freedberg, I.M., Austen, K.F., eds. Dermatology in General Medicine, pp. 1767–1783. New York, McGraw-Hill Inc., 1993.Google Scholar
  22. Hunter, T., Protein kinases and phosphatases: The yin and yang of protein phosphorylation and signaling. Cell, 80, 225–236, 1995.PubMedCrossRefGoogle Scholar
  23. Hunter, T., Cytokine connections. Nature, 366, 114–116, 1993.PubMedCrossRefGoogle Scholar
  24. Katz, A.M., Rosenthal, D., Sauder, D.N., Cell adhesion molecules. Structure, function and implication in a variety of cutaneous and other pathologic conditions. Int. J. Dermatol., 30, 153–160, 1991.PubMedCrossRefGoogle Scholar
  25. Kingsworth, A.N., Slavin, J., Peptide growth factors and wound healing. Br. J. Surg., 78: 1286–1290, 1991.CrossRefGoogle Scholar
  26. Knighton, D.R. and Fiegel, V.D., Regulation of cutaneous wound healing by growth factors and the microenvironment, Invest. Radiol. 26: 604–611, 1991.PubMedCrossRefGoogle Scholar
  27. Kupper, T.S., Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations, J. Clin. Invest 86: 1783–1789, 1990.PubMedCrossRefGoogle Scholar
  28. Luger, T.A. and Schwarz, T., Evidence for an epidermal cytokine network, J. Invest. Dermatol., 95: 100s–104s.Google Scholar
  29. Mariano, T. M., Donnely, R. J., Soh, J., Pestka, S. Structure and function of the Type I interferon receptor, in: Interferon, Principles and Medical Applications, pp. 129–138, Galveston TX, The University of Galveston Medical Branch at Galveston Department of Microbiology, 1992.Google Scholar
  30. Marietta, M.A., Mammalian synthesis of nitrite, nitrite, nitric oxide and N-nitrosylating agents. Chem. Res. Toxicol., 1: 249–257, 1993.CrossRefGoogle Scholar
  31. McKay, I.A. and Leigh, I.M., Epidermal cytokines and their roles in cutaneous wound healing, Brit. J. Dermatol., 124: 513–518, 1991.CrossRefGoogle Scholar
  32. McKenzie, R.C. and Sauder, D.N., The role of keratinocyte cytokines in inflammation and immunity, J. Invest. Dermatol., 95: 105s–107s, 1990.PubMedCrossRefGoogle Scholar
  33. Nathan, C, Nitric oxide as a secretory product of mammalian cells. FASEB J., 6: 3051–3064, 1992.PubMedGoogle Scholar
  34. Ruff-Jamison, S., Zhong, Z., Wen, Z., Chen, K., Darnell, J. E., Cohen, S. Epidermal Growth Factor and Lipopolysaccharide Activate STAT 3 Transcription Factor in Mouse Liver, J. Biol. Chem., 269, 21933–21935, 1994.PubMedGoogle Scholar
  35. Ruff-Jamison, S., Chen, K., Cohen, S., Induction by EGF and interferon-γ of tyrosine phosphorylated DNA binding proteins in mouse liver nuclei. Science, 261, 1733–1736, 1993.PubMedCrossRefGoogle Scholar
  36. Sadowski, H. B., Shuai, K., Darnell, J. E., Gilman, M. Z., A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science, 261, 1739–1744, 1993.PubMedCrossRefGoogle Scholar
  37. Shuai, K., Stark, G. R., Kerr, I. M., Darnell, J. E. A single phosphotyrosine residue of STAT91 required for gene activation by interferon-γ. Science, 261, 1744–1746, 1993.PubMedCrossRefGoogle Scholar
  38. Stamler, J. S., Redox signaling: Nitrosylation and related target interactions of nitric oxide. Cell, 78, 931–936, 1994.PubMedCrossRefGoogle Scholar
  39. Stuber, D., Fountoulakis, M., Garotta, G., IFN-g Receptor: Protein structure and function in: Interferon, Principles and Medical Applications, pp. 129–138, Galveston TX, The University of Galveston Medical Branch at Galveston Department of Microbiology, 1992.Google Scholar
  40. Zhong, Z., Wen, Z., Darnell, J. E., STAT 3 and STAT 4: Members of the family of signal transducers and activators of transcription, Proc. Natl. Acad. Sci. USA, 91, 4806–4810, 1994.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Diane E. Heck
    • 1
  1. 1.Department of Pharmacology and ToxicologyRutgers UniversityPiscatawayUSA

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