Elsevier

Resuscitation

Volume 84, Issue 1, January 2013, Pages 121-127
Resuscitation

Experimental paper
Effect of N-acetylcysteine (NAC) on acute lung injury and acute kidney injury in hemorrhagic shock,☆☆

https://doi.org/10.1016/j.resuscitation.2012.05.017Get rights and content

Abstract

Aim of the study

N-acetylcysteine (NAC) has been investigated to attenuate organ injury in various experimental and clinical studies. However, results in hemorrhagic shock (HS) were controversial. We determined the effects of continuous administration of NAC on acute lung injury (ALI) and acute kidney injury (AKI) in HS model.

Methods

Twenty male Sprague-Dawley rats were used. Pressure controlled HS model defined by mean arterial pressure (MAP) 40 ± 2 mmHg for 90 min followed by resuscitation and observation was used. Rats (n = 10 per group) were randomized into 2 groups with NAC or dextrose. Intravenous NAC was given continuously from 15 min after induction of HS to the end of observation period (2 h). We measured serum IL-6, nitrite/nitrate concentration. NF-κB p65 DNA binding activity, expressions of cytoplasmic phosphorylated IκB-α (p-IκB-α) and IκB-α, malondialdehyde (MDA) and histopathological injury scores in lung and kidney were also evaluated.

Results

MAP did not show any difference during the study period. NAC decreased histopathologic scores in both lung and kidney. Lung and kidney MDA levels were significantly lower in the NAC group compared to control group. Serum nitrite/nitrate and IL-6 were also significantly lower in the NAC group. The levels of lung cytoplasmic p-IκB-α expression was mitigated by NAC, and NF-κB p65 DNA binding activity was also significantly decreased in the NAC group.

Conclusions

Continuous infusion of NAC attenuated inflammatory response and acute lung and kidney injury after hemorrhagic shock in rats.

Introduction

Ischemic and reperfusion injury that results from hemorrhagic shock (HS) induce the development of systemic inflammatory response syndrome and subsequent multiple organ failure including acute lung injury (ALI) and acute kidney injury (AKI). In patients with multiple organ failure, inflammatory cytokines and reactive oxygen species are mobilized into the systemic circulation and marginate to end organs, causing direct local cytotoxic cellular effects.1

N-acetylcysteine (NAC) is a reactive oxygen species (ROS) scavenger2 which elicits beneficial effects on inflammation process, such as suppression of cytokine expression/release, and inhibition of nuclear factor kappa B (NF-κB).3, 4, 5 NAC effects on ALI or AKI has been evaluated in various experimental conditions including endotoxemia,6, 7 fat embolism,8 cardiopulmonary bypass model,5 ischemic renal failure9 and hemorrhagic shock.10

NAC showed beneficial effect in most studies except in HS model.10 In that study, NAC was administrated by oral route for 3 days before the experiment. The plasma half-life of NAC is relatively short and no NAC is detectable 10–12 h after oral administration.11 Besides, recently it was reported that higher dose and continuous infusion of NAC are required to achieve acute antioxidant and anti-inflammatory effects.12, 13 Considering the dose and route of NAC in that study, the effect of NAC could not be maximized in previous study.10

In this context, we hypothesized that continuous administration of high dose NAC would reduce ALI and AKI in HS model.

Section snippets

Methods

This study was approved by the Institutional Animal Care and Use Committee of our hospital in accordance with policies and the animal protection laws.

Basic characteristics

All the animals examined in the study were alive during the experiments. Baseline characteristics including body weights, ABGA, and withdrawn blood amount was comparable between both groups (p > 0.05) (Table 1). MAP did not differ between the control and the NAC group at baseline, during shock state, reperfusion and observation period (p > 0.05) (Fig. 1).

Histological injury

ALI and AKI score were significantly lower in the NAC group (7.0 (5.0–8.25) vs. 8.5 (7.0–11.0), p = 0.04; 1.0 (1.0–2.0) vs. 2.0 (1.8–3.0), p = 0.04,

Discussion

This study demonstrated that continuous infusion of high dose NAC attenuated ALI and AKI in a rat model of HS. Oxidative stress, systemic inflammatory response, and histological injury were significantly lower in rats receiving NAC than in those receiving placebo. To the best of our knowledge, this is the first study evaluating the effect of continuous infusion of NAC on ALI and AKI in HS model.

There are several studies that antioxidants such as allopurinol, tempol, desferrioxamine, or

Conclusion

This study demonstrated that continuous infusion of NAC attenuated inflammatory response and acute lung and kidney injury after hemorrhagic shock in rats. Therefore, NAC could be considered as an adjunctive therapy in ALI and AKI after hemorrhagic shock.

Conflict of interest statement

We have no conflict of interest and any copyright constraints.

Source of support

This study was supported by grant no. 03-2012-022 from the SNUBH Research Fund.

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    A Spanish translated version of the summary of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2012.05.017.

    ☆☆

    This study was presented in 40th Society of Critical Care Medicine Conference and awarded as top 10 abstract.

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