Elsevier

Resuscitation

Volume 80, Issue 3, March 2009, Pages 372-378
Resuscitation

Experimental paper
Fluvastatin attenuates severe hemorrhagic shock-induced organ damage in rats

https://doi.org/10.1016/j.resuscitation.2008.12.003Get rights and content

Abstract

Objectives

Multiple organ dysfunction resulting from hemorrhagic shock (HS) and subsequent resuscitation was mediated by several inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10). The present study was designed to investigate the protective effects of fluvastatin on these mediators after HS in rats.

Methods

The experimental rats were randomly divided into three groups. The vehicle group received only vitamin K without HS, the HS-control group received vitamin K and HS, and the HS-experimental group received both vitamin K and fluvastatin (1 mg/kg) before HS. HS was produced by bleeding from a femoral arterial catheter to remove 60% of total blood volume (6 ml/100 g BW) over 30 min. The mean arterial pressure (MAP) and heart rate (HR) were monitored continuously for 12 h after the start of blood withdrawal. The biochemical parameters, including arterial blood gas, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), creatine phosphokinase (CPK), and lactate were obtained at 30 min before induction of HS and at 0, 1, 3, 6, 9 and 12 h after HS. Equal volume of normal saline was given to replace blood volume loss. Cytokine levels including TNF-α and IL-10 in serum were measured at 1 h after HS. Kidney, liver, lung and small intestine were removed for pathology examination at 48 h after HS.

Results

HS significantly increased HR, blood GOT, GPT, BUN, Cre, LDH, CPK, lactate, TNF-α and IL-10 levels, and also induced metabolic acidosis and decreased MAP in rats. Pre-treatment with fluvastatin was found to improve survival rate, preserved MAP, decreased the markers of organ injury, suppressed the release of TNF-α and increased IL-10 after HS in rats.

Conclusion

Pre-treatment with fluvastatin can suppress the release of serum TNF-α and can also increase serum IL-10 level to protect HS-induced multi-organ damage in rats.

Introduction

Hemorrhagic shock (HS) may result in multiple organ dysfunction and eventually death by reducing tissue perfusion and subsequent cellular hypoxia through several inflammatory pathways including leukocytes activation and their sequestration to organs.1, 2, 3 Overwhelming production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) can lead to hemodynamic instability, which if uncontrolled by anti-inflammatory cytokines such as interleukin-10 (IL-10) can lead to multiple organ dysfunction and death after HS.4

HMG-CoA reductase inhibitors (statins) have been shown to exhibit important immunomodulatory effects.5 These pleiotropic effects of statins have been demonstrated to include anti-inflammatory actions, and improvement of endothelial and microvascular function.6 Our previous study found pre-treatment with fluvastatin suppresses the release of tumor necrosis factor-α (TNF-α), increases interleukin-10 (IL-10) production, and decreases the levels of markers of organ injury in endotoxic shock in rats.7 Since HS can produce the same inflammatory effect as endotoxic shock after LPS,8 it is possible that fluvastatin may also play a protective role in HS. In the present study, we examined the effects of pre-treatment with fluvastatin on HS-induced cytokines (TNF-α, and IL-10) and organ damage (liver, kidney, lung, and small intestine) in rats.

Section snippets

Preparation of animals

Twenty-four male Wistar–Kyoto rats weighing 260–300 g were provided by the National Animal Center (Taipei, Taiwan) and housed in the university Animal Center in a controlled environment at a temperature of 22 ± 1 °C with a 12 h light/dark cycle in use. Food and water were given ad libitum. The experimental protocol was approved by the Animal Care and Use Committee of Tzu Chi University. These animals were anesthetized with ether inhalation for about 15 min. After anesthesia, a polyethylene catheter

Survival rate

The survival rate at 48 h after induction of HS was 37.5% in the HS group, 100% in the vehicle group, and 75% in the fluvastatin + HS group (Fig. 1a). The mortality rate in the fluvastatin + HS group was significantly lower than HS groups (p = 0.015).

Mean arterial pressure (MAP) and heart rate (HR)

Mean arterial pressure decreased rapidly after withdrawal of 60% of total blood volume from the femoral arterial catheter in rats. MAP stayed relatively low during the 12 h after induction of HS (Fig. 1b). Compared with the HS group, pre-treatment with

Discussion

This study found that pre-treatment of test rats with fluvastatin improved survival, decreased hypotension after induction of hemorrhage and ameliorated severe HS-induced organ damage (liver, kidney, lung, and small intestine) by decreasing serum TNF-α and increasing serum IL-10 levels in rats.

HS causes rapid and significant loss of intravascular volume. Subsequent fluid resuscitation can induce endothelial cell damage and inflammatory reactions accompanied by accumulation of leukocytes,

Conclusions

In this study, pre-treatment with fluvastatin suppressed the release of TNF-α, increased IL-10 production and decreased the levels of markers of organ injury after induction of HS in rats.

Conflict of interest statement

There are no conflicts of interest by any of the authors related to the manuscript.

Acknowledgements

This work was supported by grants from the Tzu Chi University (TCNRC-C95008) and National Science Council (NSC 96-2314-B-303-004-MY2). The authors are grateful to Mr. Shu Jang Kou of Mike Biological Technologies for his excellent technical advice on the conscious animal experiment.

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    A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2008.12.003.

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