Inhibition of inducible nitric oxide synthase improves graft function and reduces tubulointerstitial injury in renal allograft rejection

Vos, I.H.C.; Joles, Jaap A.; Schurink, Merel; Weckbecker, Gisbert; Stojanović, Tomislav; Rabelink, Ton J.; Gröne, Hermann Josef

doi:10.1016/s0014-2999(00)00021-2

Cited by 45 publications

(29 citation statements)

References 27 publications

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“…Although some investigators have reported suppression of NK cell activity by CyA (47), others have noted no effect or enhancement (48,49), as observed in the present study (Table II). Suppression of NO production has been reported following in vitro CyA exposure (50), but a recent study strongly suggests that nephrotoxicity produced by CyA may be mediated by enhanced production of inducible NO in vivo (51). Thus, the increased nitrite production noted in this study was not surprising.…”

Section: Discussionsupporting

confidence: 45%

“…administration of 10 7 P815 allogeneic tumor cells (freshly passaged in syngeneic DBA/2 mice), as described (15). Tc activity in splenocyte preparations was determined using a standard 4-h 51 Cr release assay using labeled P815 target cells and E:T ratios of 100:1, 30:1, 10:1, and 3:1. LU per 10 7 splenocytes were calculated as described (16).…”

Section: Immunological and Host Resistance Assessmentsmentioning

confidence: 99%

“…NK cell lytic function. Splenic NK cell activity was measured using a standard 4-h 51 Cr release assay with labeled YAC-1 tumor cells as targets (18). Results are expressed as LU per spleen, which were calculated as described (16).…”

Section: Immunological and Host Resistance Assessmentsmentioning

confidence: 99%

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Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Keil¹,

Luebke

Pruett

2001

The Journal of Immunology

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Although reductionist experimental designs are excellent for identifying cells, molecules, or functions involved in resistance to particular microbes or cancer cells, they do not provide an integrated, quantitative view of immune function. In the present study, mice were treated with either dexamethasone (DEX) or cyclosporin A (CyA), and immune function and host resistance were evaluated. Multivariate statistical methods were used to describe the relative importance of a broad range of immunological parameters for host resistance in mice treated with various dosages of DEX. Multiple regression and logistic regression analysis indicated that changes in 24 immunological parameters explained a substantial portion of the changes in resistance to B16F10 tumor cells or streptococcus group B. However, at least 40% of the change in host resistance remained unexplained. DEX at all dosages substantially suppressed numerous relevant immunological parameters, but significantly decreased resistance to Listeria monocytogenes only at the highest dosage. In contrast, CyA substantially decreased resistance to L. monocytogenes at dosages that caused relatively minor suppression of just a few immunological parameters (unfortunately, CyA data and host resistance data for L. monocytogenes were not suitable for multivariate analysis). These results illustrate that mathematical models can be used to explain changes in host resistance on the basis of changes in immune parameters, and that moderate changes in relevant immunological parameters may not produce the types of changes in host resistance expected on the basis of results from reductionist experimental designs.

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Section: Discussionsupporting

confidence: 45%

Section: Immunological and Host Resistance Assessmentsmentioning

confidence: 99%

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Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Keil¹,

Luebke

Pruett

2001

The Journal of Immunology

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“…Experimental manipulation of iNOS has resulted in contradictory findings. Studies with selective iNOS blockers in an experimental model for CRTF attenuated functional and structural damage of the allograft (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

Expression of Inducible and Endothelial Nitric Oxide Synthases, Formation of Peroxynitrite and Reactive Oxygen Species in Human Chronic Renal Transplant Failure

Albrecht

Stegeman²,

Tiebosch

et al. 2002

American Journal of Transplantation

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Nitric oxide (NO¡) is produced by NO synthases (NOS)and can interact with reactive oxygen species (ROS) to form peroxynitrite, which induces protein damage by formation of nitrotyrosine. NO¡ has a promotional effect on acute rejection. To investigate the role of NO¡ during chronic renal transplant failure (CRTF), we studied the expression of eNOS and iNOS in conjunction with H 2 O 2 production and the formation of nitrotyrosines. Nephrectomy material from 10 patients and 10 control kidneys was used in this study. Expression of iNOS, eNOS, nitrotyrosine and the presence of ROS-producing cells and macrophages were determined using immunohistochemistry. INOS expression in nonsclerosed glomeruli and interstitium was significantly increased in patients with CRTF (p ∞0.05). Glomerular eNOS expression was decreased in patients with CRTF compared with glomeruli of control kidneys (p ∞0.01). Nitrotyrosine and ROS positive cells were significantly increased in CRTF in the interstitium (p ∞0.05), but not in glomeruli. In summary, we found a marked interstitial increase in iNOS protein expression together with a decrease in glomerular eNOS expression in CRTF patients, associated with a significant increment in ROS and nitrotyrosine-positive cells in the interstitium. Our results suggest that loss of NO¡ production by glomerular eNOS in conjunction with an increased NO¡ production by interstitial iNOS, together with the formation of ROS and nitrotyrosine, is involved in the pathogenesis of CRTF.

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“…NO arising from iNOS, is believed to play a significant detrimental role in a variety of allotransplanted cells or tissues including lung [9,10], kidney [11], pancreatic islets [12,13], cornea [14], and aorta [15]. There are disparate findings regarding the role of iNOS in solid organ transplant rejection, in general [see below].…”

Section: Introductionmentioning

confidence: 99%

The complex role of iNOS in acutely rejecting cardiac transplants

Pieper

Roza

2008

Free Radical Biology and Medicine

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This review summarizes the evidence for a detrimental role of nitric oxide (NO) derived from inducible NO synthase (iNOS) and/or reactive nitrogen species such as peroxynitrite in acutelyrejecting cardiac transplants. In chronic cardiac transplant rejection, iNOS may have an opposing beneficial component. The purpose of this review is primarily to address issues related to acute rejection which is a recognized risk factor for chronic rejection. The evidence for a detrimental role is based upon strategies involving non-selective NOS inhibitors, NO neutralizers, selective iNOS inhibitors and iNOS gene deletion in rodent models of cardiac rejection. The review is discussed in the context of the impact on various components including graft survival, histological rejection and cardiac function which may contribute in toto to the process of graft rejection. Possible limitations of each strategy are discussed in order to understand better the variance in published findings including issues related to the potential importance of cell localization of iNOS expression. Finally, the concept of a dual role of NO and its down-stream product, peroxynitrite, in rejection vs. immune regulation is discussed.

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Inhibition of inducible nitric oxide synthase improves graft function and reduces tubulointerstitial injury in renal allograft rejection

Cited by 45 publications

References 27 publications

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Quantifying the Relationship Between Multiple Immunological Parameters and Host Resistance: Probing the Limits of Reductionism

Expression of Inducible and Endothelial Nitric Oxide Synthases, Formation of Peroxynitrite and Reactive Oxygen Species in Human Chronic Renal Transplant Failure

The complex role of iNOS in acutely rejecting cardiac transplants

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