Experimental paperFluvastatin attenuates severe hemorrhagic shock-induced 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.