Evidence for Increased Nitric Oxide Production After Liver Transplantation in Humans

Ioannidis, I; Hellinger, A.; Dehmlow, C; Rauen, Ursula; Erhard, J; Fw, Eigler; H, de Groot

doi:10.1097/00007890-199505000-00012

Cited by 60 publications

(11 citation statements)

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“…27 Vos et al 7 reported that hepatocytes are an important source of iNOS and consequently of NO production during endotoxemia. Ioannadis et al 28 could not show that mononuclear cells produced NO at the time of elevated plasma nitrate levels after orthotopic liver transplantation. Moreover, Stevens et al 29 showed in rodents that transplanted pancreas islets expressed significant amounts of iNOS.…”

Section: Discussionmentioning

confidence: 92%

Intrahepatic expression of inducible nitric oxide synthase in acute liver allograft rejection: Evidence of modulation by corticosteroids

Romero¹,

García‐Monzón

Clemente³

et al. 2001

Liver Transplantation

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Nitric oxide (NO) has been proposed to have an important role in the immune response. Plasma nitrate levels increase during acute rejection and decrease after treatment with corticosteroids, but little is known about its potential cellular source. We studied inducible NO synthase (iNOS) expression in liver biopsy specimens of 12 patients with acute rejection compared with biopsy specimens from the same patients after treatment with high doses of intravenous corticosteroids. We also compared iNOS expression during acute rejection with a control group (9 patients without histological rejection). iNOS expression was assessed by immunohistochemistry. Intrahepatic iNOS expression was only observed in the cytoplasm of hepatocytes, which were diffusely distributed throughout hepatic lobules. iNOS expression could not be shown in portal tracts, inflammatory cells, or endothelial and sinusoidal lining cells. In patients with acute rejection, iNOS expression was significantly stronger than in the control group (2 ؎ 0.7 v 0.6 ؎ 0.7; P < .05). After treatment with corticosteroids, iNOS expression decreased significantly (2 ؎ 0.7 v 1.3 ؎ 0.9; P < .05). In conclusion, the findings of the present study show that during acute liver rejection, hepatocytes are the main cellular source for NO production and treatment with corticosteroids induces significant downregulation of intrahepatic iNOS expression. (Liver Transpl 2001;7:16-21.)

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Section: Discussionmentioning

confidence: 92%

Intrahepatic expression of inducible nitric oxide synthase in acute liver allograft rejection: Evidence of modulation by corticosteroids

Romero¹,

García‐Monzón

Clemente³

et al. 2001

Liver Transplantation

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“…Macrophages may exert cytotoxic effect on allogeneic cells by the production of NO [7, 171. It was shown that the quantities of NO produced by activated macrophages are sufficiently high to be toxic for a variety of cells [9,17,301. Significantly elevated levels of NO have been detected during organ and tissue transplant rejection in mice, rats and humans [17,21,35,36,431 and in skin allo-and xenografts in amphibians [23]. 6A, B.…”

Section: Discussionmentioning

confidence: 99%

Alloantigen-induced, T-cell-dependent production of nitric oxide by macrophages infiltrating skin allografts in mice

et al. 2002

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The immunological rejection reaction occurring after organ or tissue transplantation is characterized by a strong infiltration of the graft by T cells and macrophages. Since the rejection reaction is highly specific, we tested the role of T cells in the activation of macrophages and in the induction of nitric oxide (NO) production during graft rejection. The rejection of both MHC and non-MHC antigen-disparate skin allografts was associated with a significantly increased production of NO in the graft. The kinetics of NO production after transplantation correlated with the rejection reaction and with the fate of the allograft. A significant reduction in NO production was found in immunologically hyporeactive mice treated with cyclosporine, and no specific production of NO was found in tolerated skin allografts from neonatally tolerant mice.The production of NO was completely suppressed in graft explants from mice with depleted CD4+ cells, but remained at a normal level in skin allografts from mice treated with anti-CD8 monoclonal antibody. The treatment of recipients of fully allogeneic skin grafts with 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a specific inhibitor of the inducible NO synthase, resulted in a significant prolongation of graft survival. The results thus show CD4+ T-cell-dependent, alloantigen-induced production of NO by graft-infiltrating macrophages and the role of NO in the rejection reaction. We suggest that this pathway may represent one of the local effector mechanisms of graft rejection.

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“…Analysis of the causes of these problems, especially those emerging in the early post-operative period, has focused on the identification of the alterations leading to ischemic episodes (1)(2)(3). In a systematic study of OLT patients with different indications for transplantation, and keeping in mind previous results by several groups showing altered NO synthesis after OLT (3,(9)(10)(11), we centered our attention on the effect of the graft in the regulation of vascular NO synthesis. First and in view of a possible induction of iNOS in the graft in the course of organ preservation, we confirmed in agreement with previous data (28) a complete absence of iNOS expression in samples of the donated liver obtained immediately prior to transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Three isoenzymes of NOS have been identified; two which are constitutively expressed are referred to as neuronal (nNOS) and endothelial (eNOS) and which require Ca 2 + -calmodulin to be active, and the third an enzyme induced by endotoxin and pro-inflammatory cytokines (iNOS), the activity of which is mainly controlled at the transcription level and which is independent of Ca 2 + -calmodulin (4,5). Controversy exists regarding the origin and role of enhanced NO synthesis after organ transplantation (7,9,10). However, results from several groups using distinct human and experimental animal models of solid organ transplant suggest the involvement of NO overproduction in graft rejection (9)(10)(11).…”

mentioning

confidence: 99%

“…Controversy exists regarding the origin and role of enhanced NO synthesis after organ transplantation (7,9,10). However, results from several groups using distinct human and experimental animal models of solid organ transplant suggest the involvement of NO overproduction in graft rejection (9)(10)(11). For example, during OLT it has been found that there are higher nitrate plus nitrite plasma levels -end products of NO -in patients with primary ischemic graft injury than in those without ischemic injury, as well as a significant correlation between plasma nitrate plus nitrite levels and cardiac index 15 min after reperfusion (9).…”

mentioning

confidence: 99%

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Presence of a nitric oxide synthase inhibitor in the graft efflux during reperfusion in human liver transplantation

Martı́n-Sanz¹,

Olmedilla

Pérez-Peña

et al. 1999

Clinical Transplantation

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Involvement of the nitric oxide (NO) system in complications following human orthotopic liver transplants (OLT) has been reported, but the contribution of the graft to the modulation of the NO system during reperfusion in normal OLT has not been characterized. We have studied the contribution of the graft efflux to the modulation of the NO system in 20 consecutive OLT. We evaluated its effects on isolated vascular reactivity of the rabbit and on rat cultured macrophages stimulated with lipopolysaccharide (LPS). In none of the donor liver biopsies was expression of inducible NO synthase (iNOS) activity by Northern or Western blot analysis found. Graft efflux after the onset of liver reperfusion, but not pre-transplant patient plasma, reversibly inhibited the acetylcholine-induced relaxation of norepinephrine-contracted rabbit aortic rings. Moreover, graft efflux reversibly inhibited NO production in rat macrophages treated with LPS, as evidenced by both a decrease in nitrite plus nitrate formation and a decrease in the production of [14C]citrulline from [14C]arginine. Addition of a 10% dilution of graft efflux to cultured rat macrophages incubated with LPS increased iNOS mRNA levels, suggesting direct inhibition of the enzyme but not of its expression. These results cannot be ascribed to the depletion of arginine the iNOS substrate since they can be reproduced even in the presence of an excess (10 mM) of exogenously added arginine. No correlation was found between the iNOS inhibitory activity in each sample and the corresponding clinical parameters related to either the graft function after the OLT or the existence of post-reperfusion syndrome. Our results indicate the existence of a soluble factor in the graft efflux from human OLT that reversibly and unspecifically inhibits NOS activity. Its involvement in the physiology and/or pathology of human liver diseases deserves further study.

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Evidence for Increased Nitric Oxide Production After Liver Transplantation in Humans

Cited by 60 publications

References 0 publications

Intrahepatic expression of inducible nitric oxide synthase in acute liver allograft rejection: Evidence of modulation by corticosteroids

Intrahepatic expression of inducible nitric oxide synthase in acute liver allograft rejection: Evidence of modulation by corticosteroids

Alloantigen-induced, T-cell-dependent production of nitric oxide by macrophages infiltrating skin allografts in mice

Presence of a nitric oxide synthase inhibitor in the graft efflux during reperfusion in human liver transplantation

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