Effect of N-Acetylcysteine on Acute Allograft Rejection After Rat Lung Transplantation

Erne, Barbara; Jungraithmayr, Wolfgang; Buschmann, Johanna; Arni, Stephan; Weder, Walter; İnci, İlhan

doi:10.1016/j.athoracsur.2012.11.008

Cited by 11 publications

(5 citation statements)

References 36 publications

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“…Causes may be ischemia-reperfusion induced oxidative stress, inflammatory cytokines or monocyte/macrophage produced reactive oxygen species [3], [6], [40]. The critical role of oxidative stress in rejection is supported by the observations that N-acetylcysteine prevents early rejection in animal models [41]. In addition, numerous human data indicate N-acetylcysteine improves graft function in transplanted patients [42]–[44].…”

Section: Discussionmentioning

confidence: 96%

PARP Inhibition Attenuates Acute Kidney Allograft Rejection by Suppressing Cell Death Pathways and Activating PI-3K-Akt Cascade

et al. 2013

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BackgroundNovel immunosuppressive therapy facilitates long term allograft survival, but acute tubular necrosis and ischemia-reperfusion during transplantation can compromise allograft function. These processes are related to oxidative stress which activates poly- (ADP-ribose) polymerase (PARP) contributing to the activation of cell death pathways. Here we raised the possibility that PARP inhibition curbs cell death pathways and shifts kinase signaling to improved graft survival.Methods FindingsIn an acute rat kidney rejection model, we provided evidence that the PARP inhibitor 4-hydroxy-quinazoline (4OHQ) attenuates rejection processes initiated oxidative/nitrosative stress, nuclear poly-ADP-ribosylation and the disintegration of the tubulo-interstitial structures. The PARP inhibitor attenuated rejection processes induced pro-apoptotic pathways by increasing Bcl-2/Bax ratio and suppressing pro-apoptotic t-Bid levels. In transplanted kidneys, the cell death inducing JNK1/2 is normally activated, but PARP inhibition suppressed this activation with having only modest effects on ERK1/2 and p38 MAP kinases. In untreated transplanted kidneys, no significant alterations were detected in the cytoprotective PI-3K-Akt pathway, but the PARP inhibitor significantly activated Akt (by S473 phosphorylation) and suppressed GSK-3β, as well as activated acute NF-kappaB activation contributing to graft protection.ConclusionThese data show the protective role of PARP inhibition on graft survival by attenuating poly-ADP-ribosylation, oxidative stress, suppressing pro-apoptotic and increasing anti-apoptotic protein level, and by shifting MAP kinases and PI-3-K-Akt pathways to cytoprotective direction. Thus, addition of PARP inhibitors to standard immunosuppressive therapies during kidney transplantation may provide increased protection to prolong graft survival.

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Section: Discussionmentioning

confidence: 96%

PARP Inhibition Attenuates Acute Kidney Allograft Rejection by Suppressing Cell Death Pathways and Activating PI-3K-Akt Cascade

et al. 2013

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“…Orthotopic left lung transplantation was performed under aseptic conditions from Brown-Norway donor rats (231–271 g) to MHC–mismatched Lewis recipient rats (268–305 g). This established mismatch model of lung transplantation leads to irreversible acute total graft rejection within 6–7 d. 9 - 11 …”

Section: Methodsmentioning

confidence: 99%

“…Orthotopic left lung transplantation was performed under aseptic conditions from Brown-Norway donor rats (231-271 g) to MHC-mismatched Lewis recipient rats (268-305 g). This established mismatch model of lung transplantation leads to irreversible acute total graft rejection within 6-7 d. [9][10][11] Figure 1 illustrates the study design. Recipients were randomly assigned into a treatment (NAD + ) group and a control group (each group, n = 8).…”

Section: Experimental Designmentioning

confidence: 99%

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Effect of β-Nicotinamide Adenine Dinucleotide on Acute Allograft Rejection After Rat Lung Transplantation

Ehrsam,

Chen,

Haberecker

et al. 2023

Transplantation Direct

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Background. Acute rejection is still a major limitation for a successful outcome in lung transplantation. Since β-nicotinamide adenine dinucleotide (NAD+) has been shown to have various immunomodulatory properties on the innate and adaptive immune system, we evaluate here a potential protective effect of NAD+ against acute lung rejection. Methods. Rat single-lung transplantation was performed in 2 groups (n = 8 per group), using Brown-Norway donors and major histocompatibility complex–mismatched Lewis recipients. Recipients of the NAD+ group received 1000 mg/kg NAD+ intraperitoneally before transplantation and daily thereafter until euthanasia, whereas the control group received saline solution. At autopsy on day 5, blood samples were analyzed and the lung allograft was assessed by bronchioalveolar lavage, histology, and immunochemistry. Results. The NAD+ group maintained an intact compliant lung tissue, a strong trend of lower acute cellular rejection (A3 versus A3-A4) and significantly less lymphocytic bronchiolitis (B0-B2R versus B1R-Bx). In addition, a trend of fewer alveolar CD68+ macrophages and significantly fewer interstitial CD163+ macrophages was observed. Bronchoalveolar lavage in the NAD+ group showed significantly fewer proinflammatory cytokines interleukin (IL)-6, IL-13, TNFα, and a protective IL-6/IL-10-ratio. In blood samples, we observed significantly fewer neutrophils, and proinflammatory GRO/KC in the NAD+ group. Conclusions. NAD+ might be a promising substance in prevention of acute allograft rejection in lung transplantation.

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“…Several methods and substances have been used as an attempt to protect the lungs during the early phase of posttransplantation and to improve short- and long-term graft performance; however, these efforts have generated limited results [ 6 , 7 ]. The techniques include lung protective ventilation [ 8 , 9 ], appropriate fluid management, the optimization of organ preservation in lung transplantation, and the minimization of ventilation and anoxic ischemic time [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

RC-3095, a Selective Gastrin-Releasing Peptide Receptor Antagonist, Does Not Protect the Lungs in an Experimental Model of Lung Ischemia-Reperfusion Injury

Oliveira-Freitas

Thomaz

Simoneti

et al. 2015

BioMed Research International

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RC-3095, a selective GRPR antagonist, has been shown to have anti-inflammatory properties in different models of inflammation. However, its protective effect on lungs submitted to lung ischemia-reperfusion injury has not been addressed before. Then, we administrated RC-3095 intravenously before and after lung reperfusion using an animal model of lung ischemia-reperfusion injury (LIRI) by clamping the pulmonary hilum. Twenty Wistar rats were subjected to an experimental model in four groups: SHAM, ischemia-reperfusion (IR), RC-Pre, and RC-Post. The final mean arterial pressure significantly decreased in IR and RC-Pre compared to their values before reperfusion (P < 0.001). The RC-Post group showed significant decrease of partial pressure of arterial oxygen at the end of the observation when compared to baseline (P = 0.005). Caspase-9 activity was significantly higher in the RC-Post as compared to the other groups (P < 0.013). No significant differences were observed in eNOS activity among the groups. The groups RC-Pre and RC-Post did not show any significant decrease in IL-1β (P = 0.159) and TNF-α (P = 0.260), as compared to IR. The histological score showed no significant differences among the groups. In conclusion, RC-3095 does not demonstrate a protective effect in our LIRI model. Additionally, its use after reperfusion seems to potentiate cell damage, stimulating apoptosis.

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Effect of N-Acetylcysteine on Acute Allograft Rejection After Rat Lung Transplantation

Cited by 11 publications

References 36 publications

PARP Inhibition Attenuates Acute Kidney Allograft Rejection by Suppressing Cell Death Pathways and Activating PI-3K-Akt Cascade

PARP Inhibition Attenuates Acute Kidney Allograft Rejection by Suppressing Cell Death Pathways and Activating PI-3K-Akt Cascade

Effect of β-Nicotinamide Adenine Dinucleotide on Acute Allograft Rejection After Rat Lung Transplantation

RC-3095, a Selective Gastrin-Releasing Peptide Receptor Antagonist, Does Not Protect the Lungs in an Experimental Model of Lung Ischemia-Reperfusion Injury

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