Cold Storage Injury to Rat Small-bowel Transplants—Beneficial Effect of a Modified HTK Solution

Lautenschläger, Ingmar; Pless-Petig, Gesine; Middel, Peter; Groot, Herbert de; Rauen, Ursula; Stojanović, Tomislav

doi:10.1097/tp.0000000000002318

Cited by 16 publications

(9 citation statements)

References 45 publications

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“…Cold stress-induced tissue damage during organ preservation is an example of clinical environment. Recently, some organ preservation methods have been developed, including a machine perfusion system (Jing et al, 2018) and preservation solution supplemented with iron chelators (Lautenschl€ ager et al, 2018). However, there are few drugs targeting the molecules or mechanisms of cold stress-induced tissue damage.…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial Ca ²⁺ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis

et al. 2021

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Ferroptosis has recently attracted much interest because of its relevance to human diseases such as cancer and ischemiareperfusion injury. We have reported that prolonged severe cold stress induces lipid peroxidation-dependent ferroptosis, but the upstream mechanism remains unknown. Here, using genome-wide CRISPR screening, we found that a mitochondrial Ca 2+ uptake regulator, mitochondrial calcium uptake 1 (MICU1), is required for generating lipid peroxide and subsequent ferroptosis under cold stress. Furthermore, the gatekeeping activity of MICU1 through mitochondrial calcium uniporter (MCU) is suggested to be indispensable for cold stress-induced ferroptosis. MICU1 is required for mitochondrial Ca 2+ increase, hyperpolarization of the mitochondrial membrane potential (MMP), and subsequent lipid peroxidation under cold stress. Collectively, these findings suggest that the MICU1-dependent mitochondrial Ca 2+ homeostasis-MMP hyperpolarization axis is involved in cold stress-induced lipid peroxidation and ferroptosis.

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Section: Introductionmentioning

confidence: 99%

The mitochondrial Ca ²⁺ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis

et al. 2021

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“…With partial substitution of histidine with N-α-acetyl-L-histidine and the complement of iron chelators and AAs, HTK-N was expected to be a promising alternative to the currently used standard preservation solutions UW and HTK. Previous studies documented nontoxic property of HTK-N in a variety of organs and grafts including liver, kidney, lung, pancreas, intestine and heart [51][52][53][54][55][56][57]. In addition, animal models showed protective effects of HTK-N on different organs including liver [18,51,52,58], lung [53] and heart [54,59,60].…”

Section: Discussionmentioning

confidence: 94%

“…With the special focus on the small bowel, HTK-N was recently used in a rat small bowel transplantation model [57]. It was shown that HTK-N elicited a significant improvement in intestinal microcirculation during the early post-transplant stage following 24h CS, an effect that was attributed to the addition of iron chelators.…”

Section: Discussionmentioning

confidence: 99%

A novel histidine–tryptophan–ketoglutarate formulation ameliorates intestinal injury in a cold storage and ex vivo warm oxygenated reperfusion model in rats

et al. 2020

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Correspondence: Linus Kebschull (Kebschull@googlemail.com)Aim: The present study aims to evaluate protective effects of a novel histidine-tryptophan-k etoglutarate solution (HTK-N) and to investigate positive impacts of an additional luminal preservation route in cold storage-induced injury on rat small bowels. Methods: Male Lewis rats were utilized as donors of small bowel grafts. Vascular or vascular plus luminal preservation were conducted with HTK or HTK-N and grafts were stored at 4 • C for 8 h followed by ex vivo warm oxygenated reperfusion with Krebs-Henseleit buffer for 30 min. Afterwards, intestinal tissue and portal vein effluent samples were collected for evaluation of morphological alterations, mucosal permeability and graft vitality. Results: The novel HTK-N decreased ultrastructural alterations but otherwise presented limited effect on protecting small bowel from ischemia-reperfusion injury in vascular route. However, the additional luminal preservation led to positive impacts on the integrity of intestinal mucosa and vitality of goblet cells. In addition, vascular plus luminal preservation route with HTK significantly protected the intestinal tissue from edema. Conclusion: HTK-N protected the intestinal mucosal structure and graft vitality as a luminal preservation solution. Additional luminal preservation route in cold storage was shown to be promising.

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“…But, the possible risks of the method should be considered [ Wei 2016]. Another known effect of tissue-preserving solutions is that they are protective against hypothermic damage as well [Lautenschläger 2018]. For this reason, tissue-preserving solutions may be a good combination in hypothermic brain protection.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of Brain Protection With Histidine-Tryptophan-Ketoglutarate Solutions

Oğuz

Aşgün

Bűyűk

2020

HSF

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Background: Tissue-protective solutions increase resistance of cells to ischemic conditions. Especially in carotid and aortic arch surgeries where the brain perfusion is at risk, these solutions may be beneficial to prevent ischemic brain damage. This study was designed to demonstrate the effectiveness of histidine-tryptophan-ketoglutarate (HTK) solution in increasing resistance of brain tissue to ischemic conditions. Methods: Three separate randomized groups were created, each consisting of eight rabbits. The groups were called the ischemia, HTK and sham groups, respectively. In the ischemia group, temporary brain ischemia was created for 15 minutes by placing clamps on the bilateral subclavian and common carotid arteries. Then the clamps were removed, and the brain was reperfused for 30 minutes. In the HTK group, HTK solution was sent to the brain through the internal carotid artery before the same ischemia-reperfusion protocol was applied. Histopathological analyses using a visual scoring system to assess the degree of ischemic changes and the apoptotic cell index by TUNEL test were performed in all brain tissue samples. Results: Apoptotic cell indices of the HTK (20.6%) and sham (17.8%) groups were lower than the ischemia group (56.8%) (P < .05). Statistically significant differences were detected between all groups in categorical scores (P < .05). Conclusions: It was shown that less ischemic damage occurs in the brain tissue with the use of HTK solution, and it may be a candidate approach to prevent the brain from ischemic insults during cerebrovascular surgery. Further studies are required to demonstrate its exact effectiveness, in terms of dose, duration, and temperature.

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Cold Storage Injury to Rat Small-bowel Transplants—Beneficial Effect of a Modified HTK Solution

Abstract: The modified preservation solution improved the microcirculation of the transplants and needs detailed evaluation in further models of small-bowel transplantation.

Cited by 16 publications

References 45 publications

The mitochondrial Ca ²⁺ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis

The mitochondrial Ca ²⁺ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis

A novel histidine–tryptophan–ketoglutarate formulation ameliorates intestinal injury in a cold storage and ex vivo warm oxygenated reperfusion model in rats

Effectiveness of Brain Protection With Histidine-Tryptophan-Ketoglutarate Solutions

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Cold Storage Injury to Rat Small-bowel Transplants—Beneficial Effect of a Modified HTK Solution

Abstract: The modified preservation solution improved the microcirculation of the transplants and needs detailed evaluation in further models of small-bowel transplantation.

Cited by 16 publications

References 45 publications

The mitochondrial Ca 2+ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis

The mitochondrial Ca 2+ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis

A novel histidine–tryptophan–ketoglutarate formulation ameliorates intestinal injury in a cold storage and ex vivo warm oxygenated reperfusion model in rats

Effectiveness of Brain Protection With Histidine-Tryptophan-Ketoglutarate Solutions

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The mitochondrial Ca ²⁺ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis

The mitochondrial Ca ²⁺ uptake regulator, MICU1, is involved in cold stress‐induced ferroptosis