Differential localization of allograft nitric oxide synthesis: comparison of liver and heart transplantation in the rat model

Nitric oxide (NO) is a free radical with a diversity of cellular origins and potential functions. Within the realm of solid organ transplantation, NO has been the focus of much attention. Discordant reports have documented both suppression and potentiation of the alloimmune response. In addition to questions regarding its functional role, little is known of the cellular origins of NO in acute rejection of vascularized allografts. To address this question, acute rejection models of rat heterotopic heart and orthotopic liver transplantation were chosen. When compared with naive controls and isografted animals, acute rejection in both heart and liver transplantation was associated with elevated systemic levels of the NO metabolite, nitrite. This was accompanied by increased graft content of iNOS protein as determined by immunoblot analysis of protein extracts. Expression of iNOS mRNA was localized with in situ hybridization. In both heart and liver transplantation, iNOS mRNA was found in the inflammatory infiltrate accompanying acute rejection. In addition, hepatocytes also expressed iNOS mRNA in the rejecting liver allograft. In contrast, cardiac myocytes in the rejecting heart allograft did not stain for iNOS mRNA. These results indicate that organ‐specific, differential cellular expression of iNOS occurs in the acutely rejecting allograft. Transcriptional regulation of iNOS may vary among various organs according to the local cellular milieu. In addition, there may be a variable allograft specific response to acute rejection which may modify the associated immunologic biology.

[1]  K. Abe,et al.  Cellular localization and effect of nitric oxide synthesis in a rat model of orthotopic liver transplantation. , 1996, Transplantation.

[2]  B. Holm,et al.  A comparison of spontaneous versus induced tolerance in an experimental model of rat hepatic allograft transplantation. , 1995, The Journal of surgical research.

[3]  T. P. Misko,et al.  Modulation of in vivo alloreactivity by inhibition of inducible nitric oxide synthase , 1995, The Journal of experimental medicine.

[4]  V. Cattell,et al.  Localization of inducible nitric oxide synthase in acute renal allograft rejection in the rat. , 1994, Transplantation.

[5]  M. W. Flye,et al.  Outcome of Kupffer cell antigen presentation to a cloned murine Th1 lymphocyte depends on the inducibility of nitric oxide synthase by IFN-gamma. , 1994, Journal of immunology.

[6]  S. Barnes,et al.  Nitric oxide regulation of superoxide and peroxynitrite-dependent lipid peroxidation. Formation of novel nitrogen-containing oxidized lipid derivatives. , 1994, The Journal of biological chemistry.

[7]  C. Marboe,et al.  Induction of myocardial nitric oxide synthase by cardiac allograft rejection. , 1994, The Journal of clinical investigation.

[8]  T. Billiar,et al.  New insights into the regulation of inducible nitric oxide synthesis. , 1994, The American journal of physiology.

[9]  P. Kuo,et al.  Nitric oxide decreases oxidant-mediated hepatocyte injury. , 1994, The Journal of surgical research.

[10]  N. Bastian,et al.  N omega -monomethyl-L-arginine inhibits nitric oxide production in murine cardiac allografts but does not affect graft rejection. , 1994, Biochimica et biophysica acta.

[11]  E. Wing,et al.  Arginine analogues suppress antigen-specific and -nonspecific T lymphocyte proliferation. , 1994, Cellular immunology.

[12]  P. Kubes,et al.  Nitric oxide prevents leukocyte adherence: role of superoxide. , 1993, The American journal of physiology.

[13]  Joseph Loscalzo,et al.  A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds , 1993, Nature.

[14]  P. Huie,et al.  Rapamycin inhibits arterial intimal thickening caused by both alloimmune and mechanical injury. Its effect on cellular, growth factor, and cytokine response in injured vessels. , 1993, Transplantation.

[15]  J. R. Lancaster,et al.  Nitric oxide--a new endogenous immunomodulator. , 1993, Transplantation.

[16]  John D. Roberts,et al.  Nitric oxide modulates lymphocyte proliferation but not secretion of IL-2. , 1993, Immunological investigations.

[17]  P. Neuhaus,et al.  Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat. , 1992, The Journal of clinical investigation.

[18]  J. Lancaster,et al.  EPR detection of heme and nonheme iron-containing protein nitrosylation by nitric oxide during rejection of rat heart allograft. , 1992, The Journal of biological chemistry.

[19]  J. Cunningham,et al.  Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. , 1992, The Journal of biological chemistry.

[20]  P. Kubes,et al.  Nitric oxide: an endogenous modulator of leukocyte adhesion. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[21]  K Ono,et al.  Improved technique of heart transplantation in rats. , 1969, The Journal of thoracic and cardiovascular surgery.

[22]  F. D. Snell,et al.  Colorimetric Methods Of Analysis , 1950 .

[23]  P. Kubes,et al.  Nitric oxide syni hesis inhibition induces leukocyte adhesion via superoxid and mast cells , 2004 .

[24]  R. Calne,et al.  A surgical experience with five hundred thirty liver transplants in the rat. , 1983, Surgery.