Abstract
Graft vasculopathy is the main feature of chronic rejection in organ transplantation, with oxidative stress being a major trigger. Inflammation-associated prooxidant processes may be controlled by antioxidants; however, interference with redox-regulated mechanisms is a complex endeavor. An essential feature of the cellular immune response is the acceleration of tryptophan (Trp) breakdown, leading to the formation of several bioactive catabolites. Long-term activation of this immunobiochemical pathway contributes to the establishment of a tolerogenic environment, thereby supporting allograft survival. Herein, the impact of the antioxidant sodium sulfite on the development of graft vasculopathy was assessed in murine aortic transplantation. Allogeneic (BALB/c to C57BL/6) heterotopic murine aortic transplantations were performed. Animals were left untreated or were treated with 10 μl of 0.1 M, of 0.01 M sodium sulfite, or of 0.1 M sodium sulfate, intraperitoneally once/day, until postoperative day (POD) 100. Grafts were assessed by histology, immunohistochemistry, and adhesion molecule gene expression. Serum concentrations of tryptophan and its catabolite kynurenine (Kyn) were measured. On day 100, graft vasculopathy was significantly increased upon treatment with 0.1 M sodium sulfite, compared to allogeneic untreated controls (p = 0.004), which correlated with a significant increase of α-smooth-muscle-actin, Vcam-1, and P-selectin. Serum Kyn concentrations increased in the allogeneic control group over time (p < 0.05, POD ≥ 50), while low-dose sodium sulfite treatment (0.01 M) treatment resulted in a decrease in Kyn levels over time (p < 0.05, POD ≥ 10), compared to the respective baselines (p < 0.05). Longitudinal analysis of serum metabolite concentrations in the different treatment groups further identified an overall effect of sodium sulfite on Kyn concentrations. Antioxidative treatment may result in ambivalent consequences. Our data reveal that an excess of antioxidants like sodium sulfite can aggravate allograft vasculopathy, which further highlights the challenges associated with interventions that interfere with the complex interplay of redox-regulated inflammatory processes.
Highlights
The incidence of acute allograft rejection has been reduced effectively by the introduction of modern immunosuppressive regimes, yet the development of chronic rejection remains a vital and unresolved issue in solid organ transplantation
To quantify the extent of graft vascular hyperplasia, intima and media thickness of grafts were assessed in H&Eand Elastic van Gieson-stained sections on postoperative day (POD) 100
A significant increase in the intima/media ratio was found for the 0.1 M sodium sulfite treatment group (3 44 ± 0 17), compared to the allogeneic (2 29 ± 0 26) as well as sodium sulfate-treated (2 45 ± 0 19) recipients (Table 1)
Summary
The incidence of acute allograft rejection has been reduced effectively by the introduction of modern immunosuppressive regimes, yet the development of chronic rejection remains a vital and unresolved issue in solid organ transplantation. Oxidative as well as antioxidative pathways are involved in various immune and inflammatory reactions and may play a role in the development of transplant vasculopathy [3]. As for heart transplant recipients, an increase in oxidative stress and antioxidant enzyme activity was shown to be associated with development of cardiac allograft vasculopathy [4]. The deprivation of Trp and the presence of some of its downstream catabolites contribute to immunoregulation by suppressing adaptive T cell-mediated responses [9]. This contributes to tolerance induction in pregnancy, autoimmunity, tumor surveillance, and transplantation [10,11,12]. The hepatic enzyme tryptophan 2,3-dioxygenase (TDO) can degrade Trp, though this enzyme is mainly involved in the regulation of physiological Trp concentrations [13]
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