Brain Death–Induced Inflammatory Activity in Human Pancreatic Tissue

Rech, Tatiana Helena; Crispim, Daisy; Rheinheimer, Jakeline; Barkan, Sabrina Sigal; Osvaldt, Alessandro Bersch; Filho, Tomaz J. M. Grezzana; Kruel, Cléber Dario Pinto; Martini, Juliano; Gross, Jorge Luiz; Leitão, Cristiane Bauermann

doi:10.1097/tp.0b013e3182a949fa

Cited by 28 publications

(31 citation statements)

References 49 publications

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“…Indeed, combining the deleterious effects of BD and IRI, microcirculation assessed by IVFM was dramatically impaired when organs from BD donors were transplanted and reperfused for 2 h as compared to naïve or sham control animals (Figure 2B and C). Contrary to already published data 27, we detected an influence of donor BD itself as compared only with naïve animals (Group III vs. Group I, p < 0.05) but not sham controls (Figure 2B).…”

Section: Discussioncontrasting

confidence: 99%

“…While it has been well described that BD causes severe alterations in donor organs, data on the impact of donor BD on pancreatic allograft quality remain scarce 26, 27. Meanwhile, one decade ago, only two experimental studies demonstrated that BD results in pathophysiological alterations in the pancreas, reflected by microcirculatory deterioration, elevated inflammatory tissue response and histological pancreas damage reducing islet yields and functionality 28, 29.…”

Section: Discussionmentioning

confidence: 99%

“…Although a comprehensive analysis of cytokine expression in pancreatic tissues is still lacking, a recent study of human pancreatic tissues identified highly upregulated mRNA levels of TNFα in pancreatic tissue from BD donors, whereas IL‐1ß or IFNy mRNA did not appear to be increased 27. In contrast, a significant induction for inflammatory cytokines including IL‐1ß and IL‐6 and adhesion molecules such as VCAM‐1 and P‐selectin was observed after BD induction in our study, corroborating the finding that donor BD itself leads to an inflammatory response in organs 23, 44, 45 (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

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Treatment With Tetrahydrobiopterin Overcomes Brain Death–Associated Injury in a Murine Model of Pancreas Transplantation

Oberhuber

Ritschl

Fabritius

et al. 2015

American Journal of Transplantation

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Brain death (BD) has been associated with an immunological priming of donor organs and is thought to exacerbate ischemia reperfusion injury (IRI). Recently, we showed that the essential nitric oxide synthase co‐factor tetrahydrobiopterin (BH4) abrogates IRI following experimental pancreas transplantation. We therefore studied the effects of BD in a murine model of syngeneic pancreas transplantation and tested the therapeutic potential of BH4 treatment. Compared with sham‐operated controls, donor BD resulted in intragraft inflammation reflected by induced IL‐1ß, IL‐6, VCAM‐1, and P‐selectin mRNA expression levels and impaired microcirculation after reperfusion (p < 0.05), whereas pretreatment of the BD donor with BH4 significantly improved microcirculation after reperfusion (p < 0.05). Moreover, BD had a devastating impact on cell viability, whereas BH4‐treated grafts showed a significantly higher percentage of viable cells (p < 0.001). Early parenchymal damage in pancreatic grafts was significantly more pronounced in organs from BD donors than from sham or non‐BD donors (p < 0.05), but BH4 pretreatment significantly ameliorated necrotic lesions in BD organs (p < 0.05). Pretreatment of the BD donor with BH4 resulted in significant recipient survival (p < 0.05). Our data provide novel insights into the impact of BD on pancreatic isografts, further demonstrating the potential of donor pretreatment strategies including BH4 for preventing BD‐associated injury after transplantation.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Treatment With Tetrahydrobiopterin Overcomes Brain Death–Associated Injury in a Murine Model of Pancreas Transplantation

Oberhuber

Ritschl

Fabritius

et al. 2015

American Journal of Transplantation

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“…A study conducted by our research group found that, in the case of BD donors, the pancreas appears to be damaged long before isolation, as evidenced by an increase in TNF levels in the organ (57). Another recent study has also found that the organs of BD donors produce islets of lower quality when compared to those whose donors died of heart-related causes (51).…”

Section: Islet Transplantation and The Current Status Of This Procedumentioning

confidence: 92%

“…In light of these facts, a number of islet transplantation centers have focused on the development of different methods for islet isolation and, when possible, for the selection of organs that might be more adequate for transplantation and are more likely to produce positive results in terms of the quantity and quality of isolated islets and insulin independence in the long term (37,57,60).…”

Section: Islet Transplantation and The Current Status Of This Procedumentioning

confidence: 99%

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Rheinheimer

Bauer

Silveiro

et al. 2015

Arch. Endocrinol. Metab.

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Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with "brittle T1DM" , who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre -Rio Grande do Sul, Brazil. Arch Endocrinol Metab. 2015;59(2):161-70

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Exendin‐4 attenuates brain death–induced liver damage in the rat

et al. 2015

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The majority of liver grafts destined for transplantation originate from brain dead donors. However, significantly better posttransplantation outcomes are achieved when organs from living donors are used, suggesting that brain death (BD) causes irreversible damage to the liver tissue. Recently, glucagon-like peptide-1 (GLP1) analogues were shown to possess interesting hepatic protection effects in different liver disease models. We hypothesized that donor treatment with the GLP1 analogue exendin-4 (Ex-4) could alleviate BD-induced liver damage. A rat model of BD was employed in order to estimate BD-induced liver damage and Ex-4's potential protective effects. Liver damage was assessed by biochemical determination of circulating hepatic markers. Apoptosis in the hepatic tissue was assessed by immunoblot and immunohistochemistry using an antibody that only recognizes the active form of caspase-3. Gene expression changes in inflammation and stress response genes were monitored by quantitative real-time polymerase chain reaction. Here, we show that Ex-4 administration to the brain dead liver donors significantly reduces levels of circulating aspartate aminotransferase and lactate dehydrogenase. This was accompanied by a remarkable reduction in hepatocyte apoptosis. In this model, BD caused up-regulation of tumor necrosis factor and stress-related genes, confirming previous findings in clinical and animal studies. In conclusion, treatment of brain dead rats with Ex-4 reduced BD-induced liver damage. Further investigation is needed to determine the molecular basis of the observed liver protection. After testing in a randomized clinical trial, the inclusion of GLP1 analogues in organ donor management might help to improve organ quality, maximize organ donation, and possibly increase liver transplantation success rates.

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Brain Death–Induced Inflammatory Activity in Human Pancreatic Tissue

Abstract: Brain death induces inflammation evidenced by the up-regulation of TNF in serum and pancreatic tissue. Blocking the expression of key inflammatory mediators in brain-dead donors should be evaluated as a new approach to improve the outcomes of islet transplantation.

Cited by 28 publications

References 49 publications

Treatment With Tetrahydrobiopterin Overcomes Brain Death–Associated Injury in a Murine Model of Pancreas Transplantation

Treatment With Tetrahydrobiopterin Overcomes Brain Death–Associated Injury in a Murine Model of Pancreas Transplantation

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Exendin‐4 attenuates brain death–induced liver damage in the rat

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