Original article
General thoracic
Effect of N-Acetylcysteine on Acute Allograft Rejection After Rat Lung Transplantation

https://doi.org/10.1016/j.athoracsur.2012.11.008Get rights and content

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.

Section snippets

Animals

Specific pathogen-free, male Brown-Norway and Lewis rats (Harlan, Venray, the Netherlands), weighing 250 to 320 g, received adequate care in accordance with the Guide for the Use of Laboratory Animals (National Institutes of Health Publication 85-23, revised 1996; Bethesda, MD). The study protocol was approved by the local animal committee (License No. 214/2008).

Experimental Design

Orthotopic left lung Tx was performed from Brown-Norway donor rats to major histocompatibility complex–mismatched Lewis recipient

Oxygenation

On day 1, arterial blood oxygenation was not significantly different between transplant recipients (CON1, 21.6 ± 3.3 kPa; NAC1, 17.9 ± 4.0 kPa) and nontransplanted healthy rats (28.5 ± 1.1 kPa; p = 0.145 for CON1, p = 0.267 for NAC1). Arterial oxygenation in NAC5 (8.7 ± 2.7 kPa) was significantly lower than in nontransplanted animals (p = 0.024). In contrast, only 3 animals in CON5 tolerated clamping of the nontransplanted lung. The measured value (5.2 ± 0.6 kPa) is therefore not representative

Comment

We designed the present study to investigate a potential effect of the antioxidant NAC on acute rejection of lung allografts. We found that (1) NAC treatment has a significant influence on the GSH pool in the lung, such that GSH is significantly decreased on day 1 after Tx but can be increased to near physiologic levels by NAC administration; (2) NAC treatment significantly reduces NF-κB activation; and (3) this is reflected by significantly less macrophage and T-cell infiltration in the NAC

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