Protective effects of hydrogen inhalation during the warm ischemia phase against lung ischemia-reperfusion injury in rat donors after cardiac death

Uncontrolled donation after cardiac death (uDCD) contributes little to ameliorating donor lung shortage due to rapidly progressive warm ischemia after circulatory arrest. Here, we demonstrated non-hypoxia improves donor lung viability in a novel uDCD lung transplant model undergoing rapid ventilation after cardiac death and compared the evolution of ischemia-reperfusion injury in mice that underwent pulmonary artery ligation (PAL). The tolerable warm ischemia time at 37ºC was initially determined in mice using a modified PAL model. The donor lung following PAL was also transplanted into syngeneic mice and compared to those that underwent rapid ventilation or no ventilation at 37ºC prior to transplantation. Twenty-four hours following reperfusion, lung histology, PaO2/FIO2 ratio, and inflammatory mediators were measured. Four hours of PAL had little impact on PaO2/FIO2 ratio and acute lung injury score in contrast to significant injury induced by 5 hours of PAL. Four-hour PAL lungs showed an early myeloid-dominant inflammatory signature when compared to naïve lungs and substantially injured five-hour PAL lungs. In the context of transplantation, unventilated donor lungs showed severe injury after reperfusion, whereas ventilated donor lungs showed minimal changes in PaO2/FIO2 ratio, histologic score, and expression of inflammatory markers. Taken together, the tolerable warm ischemia time of murine lungs at 37oC can be extended by maintaining alveolar ventilation for up to 4 hours. Non-hypoxic lung warm ischemia-reperfusion injury shows an early transcriptional signature of myeloid cell recruitment and extracellular matrix proteolysis prior to blood-gas barrier dysfunction and significant tissue damage.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22168373 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8373

Author(s):

Viktorija Zitkute ◽

Mindaugas Kvietkauskas ◽

Vygante Maskoliunaite ◽

Bettina Leber ◽

Diana Ramasauskaite ◽

...

Keyword(s):

Reperfusion Injury ◽

Rat Model ◽

Ischemia Reperfusion Injury ◽

Cell Damage ◽

Ischemia Reperfusion ◽

Combined Treatment ◽

Warm Ischemia ◽

Control Group ◽

Protective Effects ◽

Sprague Dawley

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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The Protective Effects of Carbon Monoxide Against Hepatic Warm Ischemia–Reperfusion Injury in MHC-Inbred Miniature Swine

Journal of Gastrointestinal Surgery ◽

10.1007/s11605-019-04283-0 ◽

2019 ◽

Vol 24 (5) ◽

pp. 974-982 ◽

Cited By ~ 1

Author(s):

Takahiro Murokawa ◽

Hisashi Sahara ◽

Mitsuhiro Sekijima ◽

Thomas Pomposelli ◽

Takehiro Iwanaga ◽

...

Keyword(s):

Carbon Monoxide ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Warm Ischemia ◽

Protective Effects ◽

Miniature Swine

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Selective cyclooxygenase-2 inhibitor ameliorates warm ischemia-reperfusion injury of the canine liver

Transplantation Proceedings ◽

10.1016/s0041-1345(00)02351-4 ◽

2001 ◽

Vol 33 (1-2) ◽

pp. 862 ◽

Cited By ~ 1

Author(s):

Y Sunose ◽

I Takeyoshi ◽

S Ohwada ◽

H Tsutsumi ◽

S Iwazaki ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Warm Ischemia ◽

Cyclooxygenase 2

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Acteoside Presents Protective Effects on Cerebral Ischemia/reperfusion Injury Through Targeting CCL2, CXCL10, and ICAM1

Cell Biochemistry and Biophysics ◽

10.1007/s12013-020-00965-8 ◽

2021 ◽

Author(s):

Weijiang Wu ◽

Gang Wu ◽

Deyan Cao

Keyword(s):

Cerebral Ischemia ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Protective Effects ◽

Cerebral Ischemia Reperfusion ◽

Cerebral Ischemia Reperfusion Injury

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Dual and Opposite Costimulatory Targeting with a Novel Human Fusion Recombinant Protein Effectively Prevents Renal Warm Ischemia Reperfusion Injury and Allograft Rejection in Murine Models

International Journal of Molecular Sciences ◽

10.3390/ijms22031216 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1216

Author(s):

Jordi Guiteras ◽

Laura De Ramon ◽

Elena Crespo ◽

Nuria Bolaños ◽

Silvia Barcelo-Batllori ◽

...

Keyword(s):

Surface Plasmon Resonance ◽

Recombinant Protein ◽

Reperfusion Injury ◽

Surface Plasmon ◽

Plasmon Resonance ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Warm Ischemia ◽

Solid Organ ◽

Inflammatory Models

Many studies have shown both the CD28—D80/86 costimulatory pathway and the PD-1—PD-L1/L2 coinhibitory pathway to be important signals in modulating or decreasing the inflammatory profile in ischemia-reperfusion injury (IRI) or in a solid organ transplant setting. The importance of these two opposing pathways and their potential synergistic effect led our group to design a human fusion recombinant protein with CTLA4 and PD-L2 domains named HYBRI. The objective of our study was to determine the HYBRI binding to the postulated ligands of CTLA4 (CD80) and PD-L2 (PD-1) using the Surface Plasmon Resonance technique and to evaluate the in vivo HYBRI effects on two representative kidney inflammatory models—rat renal IRI and allogeneic kidney transplant. The Surface Plasmon Resonance assay demonstrated the avidity and binding of HYBRI to its targets. HYBRI treatment in the models exerted a high functional and morphological improvement. HYBRI produced a significant amelioration of renal function on day one and two after bilateral warm ischemia and on days seven and nine after transplant, clearly prolonging the animal survival in a life-sustaining renal allograft model. In both models, a significant reduction in histological damage and CD3 and CD68 infiltrating cells was observed. HYBRI decreased the circulating inflammatory cytokines and enriched the FoxP3 peripheral circulating, apart from reducing renal inflammation. In conclusion, the dual and opposite costimulatory targeting with that novel protein offers a good microenvironment profile to protect the ischemic process in the kidney and to prevent the kidney rejection, increasing the animal’s chances of survival. HYBRI largely prevents the progression of inflammation in these rat models.

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