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Zikute, V.
Reduction of ischemia and reperfusion injury in experimental uterus transplantation
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 83 [OPEN ACCESS]


Authors Med Uni Graz:
Leber Bettina
Schemmer Peter
Stiegler Philipp

Background: Uterus transplantation (UTx) is a promising fertility-restoring treatment modality for women with absolute uterine factor infertility. However, clinical use of UTx is limited by the lack of organ donors, ethical issues, ischemia/reperfusion injury (IRI), and immunosuppressive therapy-related risks. IRI still remains the main problem to be solved in UTx. IRI includes warm and cold periods during organ retrieval and organ preservation. Custodiol® has been demonstrated to be a viable preservation solution for solid organs, including the uterus. More recently, an improved solution, Custodiol-N, was introduced with superior results in experimental models. However, this new solution was not studied in UTx. Knowing the fact that melatonin has antioxidant and anti-inflammatory effects, glycine prevents IRI by direct cytoprotection and inhibition of the inflammatory response in other organs, we chose to investigate the protective effects of both supplements, in experimental IRI exposed rat uteri warm ischemia. In addition, the protective effects of Custodiol-N solution in uterus prolonged static cold storage (SCS) were analysed and compared with Custodiol® solution. Materials and Methods: For uterus IRI in a rat warm ischemia model, Sprague Dawley rats (12-weeks-old) were randomly assigned into eight groups (n = 10/group). Half of the animals received a glycine-enriched diet, while the others – control diet (without glycine). After five days of diet, animals were split into two subgroups, receiving either 50 mg/kg of melatonin or microcrystalline cellulose via gavage 2 h prior to IRI. The experimental procedure involved 1 h of ischemia followed by 1 h period of reperfusion, obtained by clamping the abdominal aorta above the bifurcation and ovarian arteries. After the ischemic and reperfusion periods, the uterus samples were collected for biochemical and histopathologic analysis. For the uterus preservation model, uterus tissue samples from rats (after 8 and 24 h of SCS; n = 10/group) were used. For both experiment parts expression levels of myeloperoxidase were assessed by immunohistochemical staining. Histological tissue damage was evaluated using the modified scoring system. Superoxide dismutase activities were measured in tissue samples. Results: Melatonin alone and together with glycine significantly increased the concentration of superoxide dismutase activity (p = 0.015) in IRI affected uterus tissues. We found significantly lower myeloperoxidase levels in immunohistochemically stained uterus tissue while pretreatment with melatonin (p = 0.004), glycine (p < 0.001) or their combination (p < 0.001). Histopathological evaluation showed that melatonin and glycine treatment in IRI resulted in significantly less endometrial stroma neutrophil infiltration, oedema, and vasocongestion compared to the IRI + control treatment. Moreover, after 8 h of SCS, a lower percentage of tissue oedema (p = 0.004), myeloperoxidase expression (p = 0.002), as well as higher superoxide dismutase activity (p = 0.002) were found in Custodiol-N compared to Custodiol®. These differences were even more prominent after 24 h of SCS (p < 0.05). Conclusion: The present results showed that application of melatonin and glycine has promising anti-inflammatory and antioxidant effects on the uterus IRI and can be safely used in UTx. Additionally, the novel Custodiol-N solution provides better protection of uterus grafts against cold ischemic injury than standard Custodiol®, most likely due to iron chelators in the composition of Custodiol-N.

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