Barbara V Erne's research while affiliated with University of Zurich and other places

BACKGROUND: N-Acetylcysteine (NAC) attenuates ischemia-reperfusion injury after lung transplantation in animal models. The purpose of this study is to evaluate a protective effect of NAC against acute lung rejection. METHODS: Rat single-lung transplantation was performed in four groups (n = 7 per group). In NAC groups, donors and recipients received NAC 150 mg/kg per day intraperitoneally before transplantation and recipients thereafter until euthanasia. Control groups (CON) received 0.5 mL of 0.9% saline solution intraperitoneally instead of NAC. Animals were euthanized on day 1 (CON1, NAC1) or day 5 (CON5, NAC5) after transplantation. Lung tissue was assessed by histology, immunohistochemistry for CD68+/CD163+ macrophages and CD3+ T cells, immunofluorescence for interleukin 4 and interleukin 12, concentration of reduced glutathione, and activated nuclear factor-kappa B. RESULTS: CD68+ macrophages in CON5 accumulated significantly compared with NAC5 grafts (p < 0.001). No significant difference was observed for CD163+ macrophages on day 5. T cells were significantly more frequent in NAC1 (p < 0.001), but significantly less in NAC5 (p < 0.001) compared with control groups, respectively. Interleukin 4 and interleukin 12 expression did not differ between groups. Treatment with NAC significantly influenced glutathione levels (p = 0.019) and reduced nuclear factor-kappa B activation (p = 0.034) in transplanted lungs. CONCLUSIONS: N-Acetylcysteine has the potential to attenuate acute pulmonary rejection by reduction of macrophage and T-cell infiltration, which is intimately linked to a reduced action of the nuclear factor-kappa B proinflammatory signaling pathway. In view of these observations, NAC should be considered a promising substance that could play a role in strategies for the prevention of acute rejection.

Our objective was to evaluate whether platinum concentrations in chest wall tissue and in serum are optimized by intracavitary application of cisplatin loaded to a fibrin carrier compared with cisplatin solution in a randomized setting of a pig model. After left-sided pneumonectomy including parietal pleurectomy, pigs were randomly assigned to receive either 90 mg/m(2) cisplatin intracavitary solution (n = 6) or to receive 5 mg cisplatin-fibrin (n = 5) applied on a predefined area of the chest wall. Platinum concentration in serum as well as in chest wall tissue was determined at several early time points until day 5 after treatment. Platinum levels were measured by inductively coupled plasma sector field mass spectrometric detection with a matrix-matched calibration procedure. The dose- and surface-corrected (geometric) mean concentration of cisplatin in chest wall tissue 2 hours but also at day 5 after the application was doubled in animals treated with cisplatin-fibrin compared with the animals treated with cisplatin-solution. In serum, the dose- and surface-corrected exposure toward cisplatin (area under the curve(0-5d)) was significantly lower with cisplatin-fibrin than with cisplatin-solution (P < .0005). This is also reflected by significantly reduced serum creatinine and urea values in the cisplatin-fibrin group (P < .0001). Animals treated with cisplatin-fibrin additionally had a significantly better postoperative course as assessed by a well-being score (P < .001). After cisplatin-fibrin treatment, cisplatin tissue concentration was increased whereas systemic cisplatin concentrations were significantly reduced in comparison with cisplatin-solution treatment. This finding offers a clear advantage inasmuch as rate and severity of systemic adverse events can be reduced while local cytotoxic concentrations are at least maintained.

N-Acetylcysteine (NAC), a thiol-containing compound that has been used as an anti-oxidant, may also lead to an increased glutathione synthesis. This study assessed the protective effect of NAC on primary graft dysfunction after lung transplantation. Porcine single left-lung transplantation was performed in 2 experimental groups after 24 hours of cold storage. Donor and recipient animals were treated with intravenous injection of 150 mg/kg NAC 60 minutes before harvest and reperfusion, followed by 12.5 mg/kg/hour continuous perfusion during the 8-hour observation period (NAC). Control animals did not receive any treatment. Hemodynamic and respiratory parameters were recorded throughout the observation period. Bronchoalveolar lavage (BAL) nitrite, neutrophil elastase (NE), protein accumulation, interleukin (IL)-8, nuclear factor-κB (p50 sub-unit), and reduced glutathione (GSH) in lung tissue and red blood were measured. During the observation period, the mean pulmonary artery pressure, oxygenation, airway pressure, and static lung compliance were significantly better in NAC animals compared with controls (p < 0.05). Extravascular lung water index was higher at points during the reperfusion in the control group. BAL protein, nitrite, NE, and IL-8 cytokine levels at the end of the experiment were significantly higher in the controls than in the NAC group (p < 0.05). Lung tissue reduced GSH levels were significantly higher in the NAC group than in the control group. Red blood cell GSH levels were always higher in the NAC group during the reperfusion period. Reverse transcription polymerase chain reaction for IL-8 messenger RNA was significantly higher in controls during the reperfusion period than in the NAC group (p = 0.001). The amount of lung tissue nuclear NF-κB (p50 sub-unit) was significantly higher in controls than in NAC pigs (p = 0.03). In this model, donor and recipient treatment with NAC effectively protected the lung from primary graft dysfunction after prolonged cold ischemia.