Ischemia and reperfusion injury in uterus transplantation: A comprehensive review

Zitkute, Viktorija; Kvietkauskas, Mindaugas; Leber, Bettina; Strupas, Kęstutis; Stiegler, Philipp; Schemmer, Peter

doi:10.1016/j.trre.2020.100550

Cited by 11 publications

(12 citation statements)

References 54 publications

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“…Successful uterus transplantation (UTx) has been shown to be the best treatment option for patients with absolute uterus factor infertility (AUFI) [1]. AUFI specifies women who are unable to become pregnant or maintain pregnancy because of the absence of a uterus (due to Mayer-Rokitansky-Küster-Hauser syndrome, or hysterectomy due to uterine benign/malignant tumors or postpartum bleeding), or the presence of a uterus that is anatomically dysfunctional (Asherman syndrome, septate, bicornuate, arcuate, hypoplastic or myomic uterus) [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

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Melatonin and Glycine Reduce Uterus Ischemia/Reperfusion Injury in a Rat Model of Warm Ischemia

Zitkute

Kvietkauskas

Maskoliūnaitė

et al. 2021

IJMS

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Ischemia/reperfusion injury (IRI) remains a significant problem to be solved in uterus transplantation (UTx). Melatonin and glycine have been shown to possess direct cytoprotective activities, mainly due to their antioxidative and anti-inflammatory properties. The aim of this study was to investigate the protective effects of melatonin and glycine and their combination on IRI in a rat model of warm ischemia. In this study, Sprague-Dawley rats were assigned to eight groups, including sham and IRI (n = 80). Melatonin and glycine alone or their combination were administered prior to 1 h of uterus ischemia followed by 1 h of reperfusion. Melatonin (50 mg/kg) was administered via gavage 2 h before IRI and glycine in an enriched diet for 5 days prior to intervention. Uterus IRI was estimated by histology, including immunohistochemistry, and biochemical tissue analyses. Histology revealed that uterus IRI was significantly attenuated by pretreatment with melatonin (p = 0.019) and glycine (p = 0.044) alone as well as their combination (p = 0.003). Uterus IRI led to increased myeloperoxidase expression, which was significantly reduced by melatonin (p = 0.004), glycine (p < 0.001) or their combination (p < 0.001). The decline in superoxide dismutase activity was significantly reduced in the melatonin (p = 0.027), glycine (p = 0.038) and combined treatment groups (p = 0.015) when compared to the IRI control group. In conclusion, melatonin, glycine and their combination significantly reduced oxidative stress-induced cell damage after IRI in a small animal warm ischemia model, and, therefore, clinical studies are required to evaluate the protective effects of these well-characterized substances in uterus IRI.

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Section: Introductionmentioning

confidence: 99%

“…Transplant success is limited by ischemia/reperfusion injury (IRI), and researchers are still struggling to answer key questions about uterus tolerance to IRI [4]. During ischemia, severe imbalance of metabolic supply and demand occurs, subsequently causing tissue hypoxia [8,9].…”

Section: Introductionmentioning

confidence: 99%

Melatonin and Glycine Reduce Uterus Ischemia/Reperfusion Injury in a Rat Model of Warm Ischemia

Zitkute

Kvietkauskas

Maskoliūnaitė

et al. 2021

IJMS

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“…At reperfusion, these changes induce inflammation and oxidative stress that can lead to an organ's loss of function [30]. The detrimental effects of warm I/R are well known in solid organ transplantation, and it is crucial to limit ischemia exposure time [31,32]. Warm ischemia during transplantation usually lasts less than 1 h, but in complicated cases, could rise to 2-3 h.…”

Section: Discussionmentioning

confidence: 99%

Targeting connexins with Gap27 during cold storage of the human donor uterus protects against cell death

et al. 2020

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Uterus transplantation is an experimental infertility treatment for women with uterine factor infertility. During donor uterus retrieval and subsequent storage, ischemia and other stressors are likely to occur, resulting in the delayed restoration of organ function and increased graft rejection. The uterus expresses connexin-based hemichannels, the opening of which can promote ischemic cell death, as well as gap junctions that may expand cell death by bystander signaling. We investigated if connexin channel inhibition with connexin channel inhibitor Gap27 could protect the uterus against cell death during the storage period. The study involved 9 female patients undergoing gender-change surgery. Before uterus removal, it was exposed to in situ warm ischemia with or without reperfusion. Uterus biopsies were taken before, during, and after ischemia, with or without reperfusion, and were subsequently stored under cold (4ᵒC) or warm (37ᵒC) conditions. TUNEL cell death assay was done at various time points along the combined in vivo/ex vivo experimental timeline. We found that Gap27 protected against storage-related cell death under cold but not warm conditions when the uterus had experienced in situ ischemia/reperfusion. For in situ brief ischemia without reperfusion, Gap27 reduction of cell death was delayed and significantly less, suggesting that protection critically depends on processes initiated when the organ was still in the donor. Thus, the inclusion of the connexin channel inhibitor Gap27 during cold storage protects the uterus against cell death, and the degree of protection depends on the history of exposure to warm ischemia. Gap27 protection may be indicated for uteri from deceased donors, in which ischemia is likely because life-saving organs have retrieval priority.

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“…Uterus transplantation (UTx) is the first and only available treatment for absolute uterine factor infertility (AUFI). Up to 7% of women suffer from AUFI [1,2], which is linked to either congenital uterine agenesis (Mayer-Rokitansky-Küster-Hauser syndrome), major congenital uterine malformation (hypoplastic uterus, fraction of bicornuate/unicornuate uterus), a surgically absent uterus, or an acquired condition (intrauterine adhesions, leiomyoma) related to uterine malfunction that causes implantation failure or defect placentation [3].…”

Section: Introductionmentioning

confidence: 99%

“…Since then, several births have occurred in multiple centers worldwide utilizing uterus grafts from both living and deceased donors [6]. However, wider clinical application is inherently limited by an organ shortage, ischemia/reperfusion injury (IRI), since all of these factors limit success rates of UTx [2]. To date, the living donor is preferred in UTx, [7] due to the possibility of better donor evaluation and elective planning of the operation.…”

Section: Introductionmentioning

confidence: 99%

Custodiol-N Is Superior to Custodiol® Solution in Experimental Rat Uterus Preservation

Zitkute

Kvietkauskas

Maskoliūnaitė

et al. 2020

IJMS

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Uterus transplantation (UTx) is the first and only available treatment for women with absolute uterine factor infertility. However, clinical application is limited by the lack of organs, ischemia/reperfusion injury, as well as immunosuppression after UTx. Several different preservation solutions are used in experimental and clinical UTx, including Custodiol® solution. Recently, the novel Custodiol-N solution was developed with superior results in organ preservation. However, the solution was not tested yet in UTx. Therefore, the aims of this study were to evaluate the effect of Custodiol-N in uterus prolonged cold preservation time (8 and 24 h), compared to Custodiol® solution. Uterus tissue samples were obtained from adult Sprague Dawley rats (n = 10/group). Cold ischemic injury was estimated by histology, including immunohistochemistry, and biochemical tissue analyses. After 8 h of cold ischemia, higher percentage of tissue edema, necrosis signs and myeloperoxidase expression, as well as lower superoxide dismutase activity were found in Custodiol® compared to Custodiol-N (p < 0.05). These differences were more pronounced after 24 h of cold preservation time (p < 0.05). This study demonstrated that Custodiol-N protects uterus grafts from cold ischemic injury better than standard Custodiol® most likely via inhibition of oxidative stress and tissue edema. It seems that iron chelators in the composition of Custodiol-N play an important protective role against cold ischemia.

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Ischemia and reperfusion injury in uterus transplantation: A comprehensive review

Cited by 11 publications

References 54 publications

Melatonin and Glycine Reduce Uterus Ischemia/Reperfusion Injury in a Rat Model of Warm Ischemia

Melatonin and Glycine Reduce Uterus Ischemia/Reperfusion Injury in a Rat Model of Warm Ischemia

Targeting connexins with Gap27 during cold storage of the human donor uterus protects against cell death

Custodiol-N Is Superior to Custodiol® Solution in Experimental Rat Uterus Preservation

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